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Transient Receptor Potential Channels as Targets for Phytochemicals

Louis S. Premkumar^*

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Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois 62702, United States

*E-mail: [email protected]. Phone: 217-545-2179. Fax: 217-545-0145.

Cite this: ACS Chem. Neurosci. 2014, 5, 11, 1117–1130

Publication Date (Web):June 13, 2014

https://doi.org/10.1021/cn500094a

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Abstract

To date, 28 mammalian transient receptor potential (TRP) channels have been cloned and characterized. They are grouped into six subfamilies on the basis of their amino acid sequence homology: TRP Ankyrin (TRPA), TRP Canonical (TRPC), TRP Melastatin (TRPM), TRP Mucolipin (TRPML), TRP Polycystin (TRPP), and TRP Vanilloid (TRPV). Most of the TRP channels are nonselective cation channels expressed on the cell membrane and exhibit variable permeability ratios for Ca²⁺ versus Na⁺. They mediate sensory functions (such as vision, nociception, taste transduction, temperature sensation, and pheromone signaling) and homeostatic functions (such as divalent cation flux, hormone release, and osmoregulation). Significant progress has been made in our understanding of the specific roles of these TRP channels and their activation mechanisms. In this Review, the emphasis will be on the activation of TRP channels by phytochemicals that are claimed to exert health benefits. Recent findings complement the anecdotal evidence that some of these phytochemicals have specific receptors and the activation of which is responsible for the physiological effects. Now, the targets for these phytochemicals are being unveiled; a specific hypothesis can be proposed and tested experimentally to infer a scientific validity of the claims of the health benefits. The broader and pressing issues that have to be addressed are related to the quantities of the active ingredients in a given preparation, their bioavailability, metabolism, adverse effects, excretion, and systemic versus local effects.

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SPECIAL ISSUE

This article is part of the TRPs as Probes and Medications for CNS Disorders special issue.

David Julius and colleagues from the University of California, San Francisco, cloned the receptor for the active ingredient in hot chili pepper, capsaicin, and named it as vanilloid receptor 1 (VR1) because capsaicin has a vanillyl moiety in its structure. (1) It was recognized that the VR1 had a sequence homology to a receptor cloned from a mutant fly (Drosophila melanogaster), in which the electroretinogram exhibited a transient response to continuous light; (2) therefore, it was renamed as transient receptor potential (TRP) Vanilloid 1 (TRPV1). (3, 4) Several TRP channels have been cloned, and some of them are considered as targets for active ingredients in botanicals. For example, TRP Ankyrin 1 (TRPA1), a receptor that carries sensory information from the periphery, is coexpressed with TRPV1, activated by the active ingredient in mustard, allyl isothiocyanate (AITC), (5, 6) and TRP Melastatin 8 (TRPM8), involved in sensing cold temperatures, is activated by menthol extracted from mint leaves. (7, 8) Other TRP channels activated by plant ingredients include TRPC6 by hyperforin, TRPV3 by incensole, and TRPM5 indirectly by glucose (sweet taste receptor-mediated increase in intracellular Ca²⁺). All the subunits of TRP channels that have been cloned so far have six transmembrane domains and a loop between domains five and six, which forms the pore. The channels have a stoichiometry of homo- or heterotetramers. Recently, high resolution structural studies using electron cryomicroscopy have confirmed the tetrameric structure. (9, 10)

Intense research is ongoing to identify the active ingredients in botanicals and their targets to explain the physiological effects they claim to exert. The active ingredient in turmeric is curcumin, which is claimed to be effective in conditions ranging from relieving flatulence to treating Alzheimer’s disease and cancer. However, the bioavailability of curcumin is very low to produce effects systemically either because it is not absorbed or because it is metabolized rapidly by the liver (first-pass metabolism). However, it is important to emphasize that these ingredients can cause significant effects locally in the gastrointestinal (GI) tract. Activation of TRP channels can modulate or promote the release of peptide hormones and neurotransmitters from the sensory and enteric nerve endings and from enteroendocrine cells. It is fascinating to learn that, following a specific type of Bariatric surgery (Roux-en-Y) that involves transposition of the ileum, where the ileum is directly connected to the stomach, unexpectedly, the glucagon-like peptide-1 (GLP-1) levels increased significantly. (11) It is inferred from this effect that when food is directly exposed to the ileum, certain ingredients are able to stimulate specialized cells in the lower GI tract (enteroendocrine cells) to cause release of GLP-1. In an intact GI tract, these ingredients may be degraded because of the high acidic environment (pH 2–3) of the stomach and by the gastric enzymes that are released during digestion. This further emphasizes the local effects of phytochemicals in the GI tract, although some of them are not well absorbed. The purpose of this Review is to provide scientific bases for the effects of plant products by identifying the phytochemicals and their TRP channel targets.

Phytochemicals That Activate Transient Receptor Potential Ankyrin (TRPA)

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TRPA1 is the only identified member of this family, which is a Ca²⁺ permeable nonselective cation channel, predominately expressed in a population of sensory neurons that also express TRPV1. (5, 12) TRPA1 is activated by the phytochemicals such as allyl isothiocyanate (AITC), allicin, diallyldisulfide (DADS), cinnamaldehyde, methylsalicylate, Δ-9-tetrahydrocannabinoid (THC), and synthetic compounds such as icilin, acrolein, N-methylmaleimide (NMM), and (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de)-1,4-benzoxazin-6-yl]-1-apthalenylmethanone (WIN55,212-2). (6, 13-16) TRPA1 can be activated by multiple products of oxidative stress, which include hydrogen peroxide (H₂O₂), hydroxyalkenyl aldehyde (4-hydroxynonenal, 4-HNE), and 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) (17, 18) (Figure 1). TRPA1 can also be activated by bradykinin (BK). (13) Recent studies show that TRPA1 is activated by methylglyoxal (MG). (19) MG is formed from triose phosphate during secondary glucose metabolism in hyperglycemic conditions. It is well-known that MG covalently modifies arginine, lysine, and cysteine residues and forms advanced glycation end products. (20) TRPA1 has been shown to be involved in various sensory processes, such as detection of noxious cold, mechanosensation, and inflammatory hyperalgesia. (5, 13, 16, 21-23)

Figure 1. TRPA1 agonists (phytochemicals, synthetic chemicals, and endogenous molecules). Allicin, 2-propene-1-sulfinothioic acid S-2-propenyl ester; allylisothiocyanate (AITC), 3-isothiocyanato-1-propene, is an organosulfur compound; cinnamaldehyde, (2E)-3-phenylprop-2-enal; Δ⁹-tetrahydrocannabinol, (−)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol; umbellulone, 1-isopropyl-4-methylbicyclo[3.1.0]hex-3-en-2-one; ligustilide, (3Z)-3-butylidene-4,5-dihydro-2-benzofuran-1(3H)-one; methyl salicylate, methyl 2-hydroxybenzoate; icilin, 1-(2-hydroxyphenyl)-4-(3-nitrophenyl)-3,6-dihydropyrimidin-2-one; N-methylmaleimide (oxidizing agent); 4-hydroxynonenal, 4-hydroxy-2-nonenal, an α,β-unsaturated hydroxyalkenal produced by lipid peroxidation, is an endogenous agonist; methylglyoxal, an aldehyde from pyruvic acid, acts both as an aldehyde and ketone, and reacts with free amino acids such as lysine, arginine and thiol groups of cysteine. MG is an endogenous agonist.

TRPA1 can be activated by three different mechanisms, including a mechanism of covalent modification of cysteine residues, which is unique among ion channel activation mechanisms: (1) AITC, allicin, DADS, acrolein, and NMM activate the channel by covalent modification of cysteine residues in the cytoplasmic N-terminals; (2) THC and WIN55,212-2 activate the channel possibly by binding to a site; and (3) BK by activating phospholipase C (PLC). Simultaneous mutations of C619, C639, and C663 significantly reduced NMM- and AITC-induced current. It was further demonstrated that additional mutation of K708 prevented the activation by AITC but THC could still activate the channel. (23) Cysteine residues are involved in covalent modification, yet the membrane current responses induced by TRPA1 agonists such as AITC and NMM are readily reversible. (24)

The active ingredients in cinnamon (Cinnamomum zeylanicum), which belongs to the family Lauraceae, are cinnamaldehye, cinnamyl alcohol, and cinnamyl acetate. Cinnamon is a sweet-smelling spice obtained from the bark of the tree. In early days it was used in perfumes, as an appetite stimulant, and to flavor wines. It is considered to improve digestion and acts as an aphrodisiac and is found to be effective in treating sore throat and common cold.

Cinnamaldehyde ((2E)-3-phenylprop-2-enal) is a TRPA1 agonist (Figure 1, EC₅₀ = 100 μM). (13) The pungency of cinnamon, when it comes in contact with the tongue, is due to its ability to activate TRPA1 expressed at the nerve terminals. Further, the activation of TRPA1 can cause the release of vasoactive peptides, such as calcitonin gene-related peptide (CGRP) and substance P (SP) from the nerve terminals. It is intriguing that fibers that carry pain sensation also innervate the blood vessels, although the blood vessels are considered to be insensate. (25) It is likely that the vasoactive substances released from the nerve terminals have beneficial effects on the cardiovascular functions. Activation of these receptors in the nerve terminals innervating the GI tract sends signals to satiety centers and releases neuropeptides/neurotransmitters locally. It has been shown that cinnamon can decrease blood glucose levels in type 2 diabetes. (26, 27) Diabetic animals treated with cinnamon showed decrease in blood glucose levels, which could be brought about by the release of incretins (glucose-dependent insulinotropic hormone (GIP) and GLP-1) and insulin release caused by activation of TRPA1 receptors. (19)

Garlic (Allium sativum) belongs to the family Alliaceae. There are several claims that consumption of garlic imparts good health. Beneficial effects of garlic in fighting common cold, sore throat, and cough have been reported. (28, 29) Allicin, the active ingredient in garlic, is an organosulfur compound found to have potent antibacterial and antifungal properties (30) (Figure 1). Allicin activates TRPA1 and TRPV1. (15) It is important to note that allicin has a very short half-life (1–5 s), because it rapidly decomposes. When garlic is crushed, the pungent smell is due to formation of allicin from alliin by the enzyme allicinase. When allicin is degraded, it forms 2-propenesulfenic acid, which can bind to free radicals. Other sulfur compounds present in garlic are ajoene, allyl sulfides, and vinyldithiins.

Anticancer effects of ingredients in garlic have been shown in cell lines and in animal experiments. (31) Local application of ingredients in garlic can prevent certain forms of skin cancer. (32) The anticancer effects of ingredients in garlic could be due to a local effect of the phytochemicals in the gastrointestinal tract activating TRPA1 and promoting Ca²⁺ influx, rather than being absorbed and acting systemically. Excessive Ca²⁺ flux leads to cell death.

Mustard belongs to the family Brassicaceae, genus Brassica and species alba (yellow mustard); or genus Snapis and species nigra (black mustard). Mustard seed contains several ingredients, such as glucosinolates (sinigrin), that can be broken down by the enzyme myrosinase to yield isothiocyanates. The active ingredient in pure mustard oil, AITC, activates TRPA1 and is involved in several functions (see cinnamon and garlic) (Figure 1). While eating mustard-laced food, the effect is more of an olfactory sensation (smell) rather than gustatory sensation (taste). Derivatives of AITC have been used as a war gas. Nitrogen mustard (mechlorethamine) is used as an anticancer agent. As discussed earlier, TRPA1 is a highly Ca²⁺-permeable channel, the activation of which can cause neuropeptide/neurotransmitter release and can mediate intracellular Ca²⁺-induced cellular functions.

AITC also is the active phytochemical in horseradish (Armoracia rusticana), which belongs to the family Brassicaceae. It is considered to be pungent; the pungency is due to activation of TRPA1 expressed at the nerve terminals. Wasabi is a common condiment in Japanese cuisine, which has high levels of AITC. When taken orally, it is considered as a remedy for sinusitis, sore throat, and nasal congestion. It is considered to be anthelmintic and bactericidal. Thiopropanal S-oxide is the pungent ingredient in onion (Allium cepa) which belongs to the family Alliaceae. Similar to allicin and AITC, isothiocyanate and thiopropanal S-oxide activate the ion channels TRPA1. (33) AITC activates the channel with an EC₅₀ of 33 μM. (13) When ingested orally, the bioavailability of AITC is high and is considered as a cancer chemopreventive compound. (33)

Curcumin ((E,E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), obtained from turmeric (Curcuma longa), which belongs to the family Zingiberaceae, is an activator of TRPA1. (34) The spice comes from the root of the plant and has a bright-yellow color. There are several claimed effects of curcumin, which include anti-inflammatory, antioxidant, anticancer, antidiabetic, antimicrobial, and so forth. (35) It has been claimed to be effective in a wide variety of conditions, including flatulence, jaundice, menstrual pain, toothache, and colic. The bioavailability of curcumin is very low. In a study, an oral dose of 8 g resulted in blood levels of around 200 ng. (35) However, efforts are being made to improve curcumin bioavailability by various stable preparations, including packaging curcumin in lipid nanoparticles. Longvida is a solid lipid curcumin particle (SLCP) that has a high bioavailability. As discussed earlier, it is possible that turmeric could produce its effects locally by direct contact with the cells in the lumen of the GI tract.

Cystic fibrosis is a condition caused by mutations in the cystic fibrosis transmembrance conductance regulator (CFTR). Curcumin has been shown to be effective in the disease caused by ΔF508 mutation, which results in the production of misfolded CFTR protein. (36-38) Curcumin activates TRPA1, which is expressed in the bronchial mucosa and relieves symptoms of cystic fibrosis.

The phytochemical umbellulone is obtained from Umbellularia californica, which belongs to the family Lauraceae (Figure 1). The tree is called “headache tree” because the vapors from the tree can cause severe headache. Umbellulone is a reactive molecule that binds to cysteine residues in TRPA1, thereby activating the receptor (EC₅₀ = 11.6 μM). The headache may be due to activation of TRPA1 in the trigeminal system. Stimulation of sensory nerve terminals causes neuropeptide release. Since CGRP has been shown to play an important role in migraine type headaches by causing vasodilation of the meningeal vessels, it is likely that umbellulone causes headache by causing CGRP release by activating TRPA1. (39)

Ligustilide, a dihydrophthalide, is a reactive molecule obtained from Angelica acutiloba, which belongs to the family Apiaceae (Figure 1). Ligustilide can bind to thiol groups, and this property could be responsible for activating TRPA1 (EC₅₀ = 44 μM). As this plant ages, it produces dehydroligustilide (EC₅₀ = 539 μM), but this is an antagonist of TRPA1 at lower concentrations (IC₅₀ = 23 μM). The specificity and the reactive nature of these molecules were demonstrated by mutating specific residues required for TRPA1 activation by electrophilic and reactive TRPA1 agonists. Celery contains ligustilide, which could activate TRPA1 and bring about its beneficial gustatory effects. (40)

Paclitaxel obtained from the Pacific yew (Taxus brevifolia), which belongs to the family Taxaceae, is being used to treat certain forms of cancer (Figure 2). One of the side effects of paclitaxel is peripheral neuropathy that can be explained by its ability to activate TRPA1, which mediates tactile and cold allodynia. (41)

Figure 2. Other TRP channel activators. Hyperforin, (1R,5S,6R,7S)-4-hydroxy-5-isobutyryl-6-methyl-1,3,7-tris(3-methyl-2-buten-1-yl)-6-(4-methyl-3-penten-1-yl)bicyclo[3.3.1]non-3-ene-2,9-dione (TRPC6); bisandrographolide, 3-{(E)-2-[6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylenedecahydro-1-naphthalenyl]vinyl}-5-{6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylene-1-[2-(2-oxo-2,5-dihydro-3-furanyl)ethyl]decahydro-1-naphthalenyl}-2(5H)-furanone (TRPV4); paclitaxel, (2α,5β,7β,10β,13α)-4,10-diacetoxy-13-{[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate (TRPA1, TRPV4); dicentrine, (7aS)-10,11-dimethoxy-7-methyl-6,7,7a,8-tetrahydro-5H-[1,3]benzodioxolo[6,5,4-de]benzo[g]quinoline (TRPA1).

Δ(9)-Tetrahydrocannabinol (THC) is a psychoactive compound in Cannabis sativa, which belongs to the family Cannabaceae (Figure 1). As described earlier TRPA1 is activated by covalent modification of cysteine residues. However, when the cysteine residues were mutated, the activation by NMM was abolished, but THC and WIN55,212-2 could still activate the channel possibly by binding to a site. (22) The phytochemicals in cannabis, cannabichromene and cannabigerol, activate TRPA1 with an EC₅₀ of 60 nM and 3.4 μM, respectively. Cannabidiol acid was least potent (EC₅₀ ∼ 12 μM) (42) (Table 1).

Table 1. Phytochemicals That Modulate TRP Channels

plant name	phytochemical	TRP target	EC₅₀ (μM)^a	ref
Cinnamomum zeylanicum	cinnamaldehyde	TRPA1	6.8	6
			61	13
Allium sativum	allicin	TRPA1	7.5	22
	DADS	TRPA1	192	22
Brassica alba	allyl isothiocyanate	TRPA1	64.5	23
Snapis nigra			22	13
			11	6
Curcuma longa	curcumin	TRPA1	ND	34
Umbellularia californica	umbelluline	TRPA1	11.6	39
Angelica acutiloba	ligustilide	TRPA1	44	40
Angelica acutiloba	dehydroligustilide	TRPA1	539	40
Taxus brevifolia	paclitaxel	TRPA1	ND	41
		TRPV4	ND	41
Cannabis sativa	tetrahydrocannabinol	TRPA1	12	6
		TRPM8	0.1 (ant)	42
	cannabidiol	TRPA1	12	42, 119
		TRPV1	3.2	42
		TRPM8	0.1 (ant)	42
		TRPV3	3.7	42
	cannabichromene	TRPA1	0.06	42
	cannabigerol	TRPM8	0.1 (ant)	42
		TRPA1	3.4	144
	cannabidivarin	TRPV4	0.9	144
	tetrahydrocannabivarin	TRPV3	3.7	144
		TRPV4	6.4	144
Lindera megaphylla	dicentrine	TRPA1	ND	43
Nicotiana tabacum	nicotine	TRPA1	∼10	44
Zingiberaceae aframomum melegueta	linalool	TRPA1	117	45
		TRPM8	6700	116
	α-sanshool	TRPA1	69	45
		TRPV1	1.1
	shogaol	TRPA1	11.2	45
		TRPV1	0.2
	paradol	TRPA1	71	45
		TRPV1	1.8
Hypericum perforatum	hyperforin	TRPC6	0.7 (Na+)	48
			1.2 (Ca²⁺)	48
Mentha longifolia	menthol	TRPM8	80	8
		TRPA1	68 (ant)	142
Eucalyptus globulus	eucalyptol	TRPM8	7700	66
Tripterygium wilfordii	triptolide	TRPP	ND	67
Capsicum annuum	capsaicin	TRPV1	0.71	1
			0.3	119
Euphorbia resinifera	Euphorbia resinifera	TRPV1	0.04	1
Ocimum basilicum	eugenol	TRPV1	ND	13, 115
Cinnamonium tamala		TRPV3	ND	123
Artemisia dracunculus		TRPA1	262	13, 116
		TRPM8	ND	13, 116
Piper nigrum	piperine	TRPV1	38	117
Cinnamomum camphora	camphor	TRPV1	4500	120, 142
Rosmarinus officinalis		TRPA1	660 (ant)	120
			68 (ant)	142
Euodia ruticarpa	evodiamine	TRPV1	0.86	121
Zingiber officinale	gingerols	TRPV1	ND	13, 122
		TRPA1	ND	13
Origanum vulgare	thymol	TRPV1	ND	123
	carvacrol	TRPV3	ND	123
		TRPA1	ND	123
Thymus vulgarism	thymol	TRPV3	ND	123
Tasmannia lanceolata	polygodial	TRPV1	ND	124
Vanilla planifolia	vanillin	TRPV1	ND	123, 126
		TRPA1	ND	123
Vernonia tweedieana	α-spinasterol	TRPV1	40 (ant)	127
Boswellia thurifera	incensole	TRPV3	16	143
Andrographis paniculata	bisandrographolide	TRPV4	0.87	159

(Na⁺), sodium flux; (Ca²⁺), calcium flux; (ant), antagonist.

Dicentrine is a naturally occurring aporphine type isoquinoline alkaloid, isolated from the root Lindera megaphylla Hemsl., which belongs to the Lauraceae family (Figure 2). In animal models, dicentrine induced antinociceptive effects. Cinnamaldehyde-induced nocifensive behavior was abolished by dicentrine, but not the capsaicin-induced nocifensive behavior. Based on these studies, it is proposed that the dicentrine effect may involve interaction with TRPA1 channels. (43)

Nicotine is obtained from Nicotiana tabacum of the Solanaceae family. It brings about its stimulatory actions by activating neuronal nicotinic acetylcholine receptors. However, it also produces irritation while smoking, chewing, or snorting. It has been shown that irritation is caused by the activation of TRPA1. Nicotine activates TRPA1 in lower concentrations (EC₅₀ ∼ 10 μM), but inhibits at higher concentrations (>1 mM). (44)

Extracts of Sichuan and melegueta peppers evoke pungent sensations that are mediated by different alkylamides, such as sanshool and shogaol; both activate TRPA1 and TRPV1 channels. Linalool, a terpene in Sichuan peppers, is able to activate TRPA1 but not TRPV1 (45) (Table 1).

Phytochemicals That Activate Transient Receptor Potential Canonical (TRPC)

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TRPC channels have been classified as TRPC1, TRPC2, TRPC3/6/7 and TRPC4/5 on the basis of structural similarities and functions. (46) The channel is formed as a homo- or heterotetramer. The activation mechanism of TRPC channels is not fully clarified. These channels are associated with G-protein coupled receptors and activation of G-protein coupled receptor results in transactivation of TRPC channels and facilitates their openings. (47)

St. John’s wort (Hypericum perforatum) extract is used as an antidepressant, and the mechanism of action is still elusive. One of the active ingredients in the extract has been found to be hyperforin, a bicyclic polyprenylated acylphloroglucinol compound (Figure 2). Hyperforin has been shown to activate TRPC6. (48) In general, antidepressants are selective serotonin and norepinephrine uptake inhibitors, thereby increasing the levels of serotonin and norepinephrine. The neurotransmitter levels can also be increased by promoting their release by causing Ca²⁺ influx at the nerve terminals. Generally, neurotransmitter release occurs in response to an action potential arriving at the nerve terminal and activating voltage-gated Ca²⁺ channels. It is becoming increasingly apparent that Ca²⁺ permeable TRP channels expressed at the presynaptic terminals can cause transmitter release and modulate synaptic transmission, independent of action potentials. TRPV1 and TRPA1 expressed in the presynaptic terminals of the sensory neurons can cause neurotransmitter release. (49-52) The effect of hyperforin could be due to its activation of TRPC6 expressed in central neurons. The effect appears to be specific because TRPC3 is unaffected by hyperforin. TRPC6, like most TRP channels, is a nonspecific cation channel that has a high Ca²⁺ permeability. Hyperforin also exhibits neurotrophic effects leading to axonal sprouting and neurite extension. In confirmation of this effect, neurons from TRPC6 overexpressing animals exhibit enhanced dendritic growth and synapse formation that may play a role in learning and memory formation. (53)

Phytochemicals That Activate Transient Receptor Potential Melastatin (TRPM)

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There are eight members in TRPM family. There are no ankyrin domains in the N-terminus of these channels. These channels are Ca²⁺ and Mg²⁺ permeable, and the permeability to Ca²⁺ ranges from impermeable (TRPM4 and TRPM5) to significantly Ca²⁺ permeable (TRPM6 and TRPM7). (54)

TRPM5

TRPM5 is a channel activated by increases in intracellular Ca²⁺. TRPM5 activation by sweet tastants is by an indirect mechanism of causing an increase in intracellular Ca²⁺ levels by the phytochemicals activating the sweet-taste receptor. Several structurally diverse phytochemicals have been shown to activate the sweet-taste receptor. But the degree of sweetness differs; glucose is less sweet in comparison to sucrose, which is a disaccharide formed by the combination of fructose and glucose. Fructose is the sweetest (73% sweeter than glucose). The plant product stevioside, obtained from Stevia rebaudiana, activates the sweet receptors. Interestingly, although the whole-plant extract can be used as a sweetening agent, it has been shown to cause infertility. However, the pure ingredient from this plant, rebaudioside A, is devoid of this action. (55)

The type 2 taste receptor (T2R) is alpha-gustducin, which is a sweet- and bitter-taste receptor. A knockout of the alpha-gustducin gene causes animals to lose both sweet and bitter taste sensations. T2Rs sense bitter taste. For umami and sweet taste perception, taste receptors type 1 (T1R1), type 2 (T1R2), and type 3 (T1R3) form heterodimers. T1R1 and T1R3 form a complex to sense the umami taste. T1R2 and T1R3 form a complex to taste sweetness. The signal transduction involves the activation of the G-protein-coupled receptor alpha-gustducin, which is coupled to phospholipase Cβ 2 (PLCβ 2). Activation of PLCβ 2 promotes the hydrolysis of PIP2 to form IP3 and DAG. IP3 releases Ca²⁺ from intracellular stores and activates TRPM5, which depolarizes the cell and causes ATP release. ATP acts as a neurotransmitter and mediates signal transduction. (56)

It is becoming evident that the receptors that sense sweet-taste on the tongue are also expressed throughout the GI tract and act as chemosensors. Taste receptors are present in the cells lining the stomach, pancreas, and enteroendocrine cells of the GI tract. Stimulation of brush border cells with tastants releases GLP-1 and peptide YY (PYY). Both alpha-gustducin and TRPM5 receptors are predominately expressed in these cells. It is possible that phytochemicals are able to activate these receptors and promote release of neuropeptides, neurotransmitters and hormones. (57-60)

TRPM8

Mint (Mentha longifolia) belongs to the family Lamiaceae, and peppermint belongs to the species piperita. The decoction of mint leaves is used for stomach aches and for some painful conditions. The active ingredient is menthol (Figure 3); it is used as an ingredient in various balms that are used to relieve pain.

Transient receptor potential melastatin 8 (TRPM8), previously known as menthol and cold receptor 1 (CMR1), is a Ca²⁺ permeant nonspecific cation channel, which is expressed in a subpopulation of primary afferent neurons. TRPM8 is activated by cold (<25 °C), phytochemicals such as menthol and eucalyptol, and the synthetic chemical icilin. Activation of TRPM8 induces a cool/soothing sensation. (7, 8) TRPM8 expressed at the central terminals modulates synaptic transmission. (61, 62) TRPM8 (earlier identified as Trp-p8) is upregulated in prostate cancer and is involved in urinary bladder functions, which broadens the horizon of the involvement of TRPM8 in other physiological and pathophysiological conditions. (63)

Generally, phosphorylation enhances the activity of ion channels. However, it has been demonstrated that a functional downregulation of TRPM8 occurs when PKC is stimulated resulting in an inhibition of TRPM8-mediated channel activity, in contrast to TRPV1, which is robustly potentiated by PKC activation. These effects are due to dephosphorylation of TRPM8 by activation of protein phosphatases. (61)

The activation of TRPM8 sends the cool and soothing sensation to alleviate pain. Therefore, it is expected to be upregulated by phosphorylation in inflammatory conditions. Paradoxically, phosphorylation downregulates TRPM8, thereby compromising the much needed cool and soothing sensation.

It has also been shown that mentholated cigarette smoke exerts a cool and soothing sensation while inhaling; because of this, mentholated cigarettes may encourage the smoking habit. Recently, the United States Food and Drug Administration has issued a warning that mentholated cigarettes are more addictive. (64) Further, menthol can directly interact with the nicotinic acetylcholine receptor and inhibit its function, a mechanism that may explain the reason for smoking a greater number of cigarettes to get the same effect, thereby increasing the addictive potential of nicotine. (65)

Eucalyptol is obtained from the leaves of Eucalyptus globulus in an oil form (Figure 3). It has the structure of a cyclic ether and a monoterpenoid. It has a smell resembling that of camphor. It is added as one of the additives in cigarettes. Eucalyptol is a TRPM8 agonist (EC₅₀ = 7.7 mM). (66)

Phytochemicals That Activate Transient Receptor Potential Polycystin (TRPP)

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The TRPP family is made up of three channel members, namely, TRPP1, TRPP2, and TRPP3. TRPP1 is an ion channel, which is considered to be involved in polycystic kidney disease. The disease is characterized by the formation of multiple cysts, hence the name polycystic kidney disease, eventually leading to kidney failure. In this disease, cysts are also found in liver, pancreas, and other inner surfaces covered by tubular epithelial cells. In tubular epithelial cells, ciliary action transduces a mechanical stimulus and opens a Ca²⁺ permeable ion channel, such as polycystin-2 (PC2 or TRPP1), and increases the intracellular Ca²⁺ levels and causes cell cycle arrest. Mutations in TRPP and/or the associated protein, polycystin 1 (PC1), result in autosomal dominant polycystic kidney disease (ADPKD).

Triptolide, a diterpene (Figure 2) obtained from Tripterygium wilfordii, induces Ca²⁺ influx in tubular epithelial cells and controls their proliferation, resulting in reduced cyst formation and alleviation of symptoms associated with kidney damage in a murine model of ADPKD. (67)

Phytochemicals That Activate Transient Receptor Potential Vanilloid (TRPV)

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There are six members in the TRPV family, the name is derived by the activation of TRP Vanilloid 1 (TRPV1) by molecules consisting of a vanillyl moiety. The other members of this family are TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6. (68-70) While comparing the Ca²⁺ permeability, it has become clear that TRPV5 and TRPV6 channels are purely Ca²⁺ permeable. They form homo- or heterotetrameric structures. (71) The high resolution structure of TRPV1 has been recently published, aided by electron cryomicroscopy. (9, 10)

TRVP1

TRPV1, formerly known as vanilloid receptor 1 (VR1), is a nonselective cation channel with high Ca²⁺ permeability, which is expressed predominantly in a population of small-diameter sensory neurons. It functions as a polymodal receptor in the peripheral sensory nerve terminals and modulates synaptic transmission at the first sensory synapse. (1, 49, 51, 72-74) A recent study has shown its expression in the dorsal horn inhibitory interneurons. (75) Capsaicin has been shown to modulate synaptic transmission in other brain regions. (76-80) Activation of TRPV1 results in two functional components: (1) sending the impulses to the brain by generating an action potential at the nerve endings (afferent function) and (2) releasing vaso/neuroactive substances by virtue of its Ca²⁺ permeability, such as histamine, bradykinin, CGRP, and SP, from the peripheral nerve terminals (efferent action).

TRPV1 is activated by heat (>42 °C) and phytochemicals such as capsaicin, resiniferatoxin (RTX), tinyatoxin (TNX), camphor, carvacrol, and thymol. It is activated by endogenous ligands such as protons, anandamide, arachidonic acid metabolites, and N-arachidonyl dopamine (NADA). (1, 27, 49, 54, 68, 81-86)

Although TRPV1 is considered mainly to be involved in thermal sensory perception, its distribution in regions that are not exposed to its activation temperature ranges raises the possibility of its involvement in other functions. TRPV1 can be detected using RT-PCR and radioligand binding throughout the neuroaxis, and the identification of specific ligands such as NADA in certain brain regions further suggests its roles in the CNS. (51, 75, 87-90) TRPV1 is present in the smooth muscles of the blood vessels and bronchi, where activation of the receptor leads to vasodilation by releasing CGRP, acetylcholine, or nitric oxide from nerve terminals and bronchoconstriction by promoting Ca²⁺ influx, respectively. (91-93) TRPV1 is found in the nerve terminals, supplying the urinary bladder and the urothelium, indicating a role in urinary bladder function, such as micturition. (94, 95) Interestingly, TRPV1 is also involved in the regulation of body temperature. Subcutaneous injection of capsaicin decreases the body temperature by 2–3 °C. TRPV1 antagonists increase the body temperature to the same extent. (96, 97)

TRPV1 has emerged as a potential target for developing analgesics. Potent TRPV1 antagonists have been developed and shown to be effective in alleviating pain in several animal models. Unfortunately, development of hyperthermia following their administration has halted the clinical trials. (94) However, findings suggest that certain compounds may be devoid of the effect of elevating core body temperature. (98)

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) (Figure 4), an active ingredient in hot chili pepper (Capsicum annuum or frutescens), which belongs to the family Solanaceae. The nonpungent bell peppers belong to the species annuum, and hot peppers belong to the species frutescens.

Figure 4. TRPV1 agonists. Vanillin, has the vanillyl moiety, that is essential for activating TRPV1 channels; Capsaicin, (E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methyl-6-nonenamide, has a vanilloid and an aceyl moiety; dihydrocapsaicin, the structure of which is a 6,7-dihydro derivative of capsaicin; resiniferatoxin, has a complex structure, but shares a homovanillyl group, which is necessary for the activity of all vanilloids; eugenol, 2-methoxy-4-(2-propenyl)phenol and is a member of the allylbenzene class of chemical compounds; Cannabidiol, 2-[(1R,6R)-6-isopropenyl-3-methyl-3-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol; anandamide or arachidonylethanolamide or arachidonic acid N-(hydroxyethyl)amide consists of the acyl moiety and is an edogenous ligand of TRPV1 and cannabinoid receptor 1 (CB1).

The hotness of chili peppers is due to the chemical content of capsaicin. Purified capsaciin activated TRPV1 with a EC₅₀ of 711.9 nM. (1) Other capsinoids such as capsiate, dihydrocapsiate, and nordihydrocapsiate have been isolated and purified. The degree of hotness can be quantified by using the Scoville scale. A Scoville unit is the “number” of times the alcoholic extract has to be diluted to lose the pungency. A sweet bell pepper has a score of 0 Scoville units and the Habanero, Savina, and Naga Jolokia (ghost peppers) are calibrated to have scores of 400 000, 600 000, and 1 000 000 Scoville units, respectively. For example, ghost pepper extract has to be diluted one million times to lose its pungency. Capsaicin and dihydrocapsaicin have the Scoville scores of 16 000 000 and 15 000 000, respectively. Shogaol from ginger has the score of 160 000 units, piperine from pepper has the score of 100 000 units, and gingerol from ginger has a score of 60 000 units. Commercially available pepper spray has the score of 2 500 000 units, and police-grade pepper spray has the score of 5 500 000 Scoville units.

When capsaicin binds to its receptor, the ion channel opens, but when constantly activated, the receptor enters a desensitization state. On the other hand, sensitization is a phenomenon, where the receptor activity is enhanced by phosphorylation. Overexpression and overactivation of TRPV1 is observed in various painful conditions. Topical capsaicin application has been useful to treat conditions such as arthritis, diabetic peripheral neuropathy, shingles, and psoriasis by exerting a local effect. (85, 86, 99, 100) The mechanism of pain relief has been proposed to be due to desensitization of the receptor or degeneration/ablation of the nerve terminals. (101)

Altered expression of TRPV1 is found in cancers involving prostate, bladder, pancreas, tongue, skin, liver, and colon. Capsaicin can induce its effects by causing Ca²⁺ influx through TRPV1 overexpressed in cancerous cells, which can lead to cell death by apoptosis or necrosis. (85)

In diabetes, consuming a hot chili pepper containing meal showed a decrease in the amount of insulin required to combat the postprandial increase in glucose. TRPV1 may play a role in this effect. (102, 103) Capsaicin has been reported to increase oxygen consumption and thermogenesis, which might lead to weight loss. There are studies to support a potential neurogenic mechanism by which TRPV1-sensitive sensory neurons may regulate energy and fat metabolism. Capsaicin prevents adipogenesis by apoptotic mechanism. Capsaicin or N-oleoylethanolamide, an endogenous ligand of TRPV1, reduced food intake by conveying information through the vagus nerve and affecting satiety centers. TRPV1 knockout animals, when fed a high-fat diet, although the food intake was the same, they gained less weight as compared to their wild-type counterparts. (104, 105)

Although there is no direct evidence that hot chili pepper containing spicy food increases acid secretion in the stomach, in certain conditions, such as gastroesophageal reflux disease (GERD), increased expression of TRPV1 in the esophagus can induce a burning sensation. (106) Capsaicin has been shown to worsen the condition in patients with irritable bowel syndrome (IBS) and Crohn’s disease. Activation of TRPV1 has been shown to cause the release of gastric acid in the stomach, but other studies have reported otherwise. (107)

Urinary bladder hyperreflexia is a condition that has been shown to be related to overexpression of TRPV1 in the nerve terminals innervating the bladder. Excretion of capsaicin through the kidneys can accumulate in the bladder and exert an effect on the urinary bladder. (85)

Resiniferatoxin (RTX) and tinyatoxin (TNX) are the most potent among all the known natural, synthetic, and endogenous agonists of TRPV1. These pure chemicals obtained from a cactus-like spurge Euphorbia resinifera/poissonii. Purified RTX activates TRPV1 with an EC₅₀ of 39.1 nM. (1) In fact, RTX can maximally activate single channel TRPV1 currents in picomolar ranges. (108) RTX/TNX have the Scoville scores of 16 000 000 000 and 5 300 000 000, respectively. RTX, a phorbol related diterpene (resiniferonol 9,13,14-orthophenylacetate 20-homovanillate), has a complex structure with a phorbol and a vanillyl moiety (Figure 4). Its ultrapotency was thought to be due to the phorbol moiety, which could activate protein kinase C (PKC) and promote phosphorylation of TRPV1. This notion was abandoned because of the higher concentrations of RTX required to activate PKC. The tritiated form ([³H]RTX) has been used as a tool in ligand-binding assays. (68, 109) Binding of capsaicin and RTX to TRPV1 involves amino acid residues, which have been shown to reside within N- and C-cytosolic and transmembrane domains of the channel. (110-112) RTX could induce nerve terminal ablation by sustained Ca²⁺ influx and prevent nociceptive transmission. Intrathecal administation of RTX provides a long-lasting pain relief. (51, 113, 114) A clinical trial is ongoing to determine the effectiveness of intrathecal administation of RTX in debilitating terminal cancer pain conditions (NCT00804154). Intravesicular irrigation of RTX containing solution has yielded a significant improvement in urinary bladder hyperreflexia by its ability to ablate TRPV1 expressing nerve terminals in the urinary bladder. (95) Resiniferatoxin and tinyatoxin are used as pesticides.

Basil (Ocimum basilicum) belongs to the family Lamiaceae. Basil and oregano have the ingredient β-caryophyllene, a natural bicyclic sesquiterpene, which is an agonist of cannabinoid receptor 2 (CB2) and has been shown to be involved in anti-inflammatory actions. Eugenol, a phenylpropene and an allyl chain-substituted guaiacol is one of the active ingredients in basil and clove (Figure 4). Other ingredients include citral that provides the citrus smell to basil, camphene in the African blue basil, and anethole in licorice and basil. Eugenol has anti-inflammatory properties by blocking the cyclooxygenase enzyme. Eugenol activates TRPV1 and TRPV3 (115) (Table 1).

Bay leaves (Cinnamonium tamala) belong to the family Lauraceae. The active ingredients include β-caryophyllene, eugenol, and linalool, a naturally occurring terpene alcohol found in many flowers and spice plants. As discussed above, eugenol can activate TRPV1 and TRPV3 ion channels and linalool can activate TRPA1. (116)

Black pepper (Piper nigrum) belongs to the family Piperaceae. The active ingredients have been isolated. The main ingredient is piperine. Other alkaloids present in black pepper include chavicine and piperidine (Figure 3). Piperine activates TRPV1. (117) The pungency of pepper is due to the alkaloid piperine and is quantified to have a score of 100 000 Scoville units as compared to the ghost pepper, which has a score of 1 000 000 Scoville units. It is also used to treat conditions such as sore throat and bronchitis. It improves digestion and acts as a carminative. Piperine is known to inhibit the liver metabolizing enzyme CYP3A4, thereby increasing the bioavailability of other drugs. Piperine has been shown to significantly increase the bioavailability of curcumin by interfering with its metabolism. (118)

As discussed earlier, several ingredients in Cannabis sativa can activate TRP channels. (119) Cannabidiol (CBD) does not exhibit any psychotropic effects. Recently, CBD has gained attention because of its effectiveness in treating refractory epilepsies in children. CBD and other active ingredients in cannabis are considered as activators of TRPV1 (Figure 4). CBD activates TRPV1 with EC₅₀ of 3.2 μM as compared to activation by capsaicin (EC₅₀ of 0.3–0.7 μM). (1, 119)

Camphor, a terpenoid, is a transparent solid obtained from an evergreen tree Cinnamomum camphora. Another source of camphor is from dried rosemary (Rosmarinus officinalis). Camphor is an activator of TRPV1. (120)

Clove (Eugenia caryophyllis or Syzgium aromaticum) belongs to the family Myrtaceae. Clove oil is commonly used to treat toothaches and used as a local anesthetic in dental procedures. The principal active ingredients in clove are eugenol and salicylic acid. The effects of both of these active ingredients are useful in painful conditions. Eugenol activates TRPV1 and TRPV3 channels. (115)

Evodiamine, an active ingredient from the Rutadeae family of plants (Euodia ruticarpa), is a TRPV1 agonist. It is being used as a dietary supplement; it has been shown to induce thermogenesis. (121)

Ginger (Zingiber officinale) belongs to the family Zingiberaceae. The active ingredients in ginger are gingerols, shogaols, and zingiberene. They exist in different forms (6, 8, 10) depending on the alkyl carbon chain. The pungency is quantified to be 60 000 Scoville units. Structurally, it is related to capsaicin and piperine. Heat converts gingerol to zingerone. When gingerol is dehydrated, it is converted to a more potent compound, shogaol (EC₅₀ = 0.2 μM; 160 000 Scoville units). All these ingredients can activate TRPV1 and TRPA1. (122) The alcoholic extract has been shown to possess antioxidant properties.

Oregano (Origanum vulgare) belongs to the family Lamiaceae. It contains several phytochemicals, such as thymol, carvacrol, and rosmarinic acid. The antioxidant properties are stronger than those of synthetic antioxidants, such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). Thymol and carvacrol can activate TRPV1 and TRPV3 ion channels (123) (Table 1).

Polygodial, a drimane-type sesquiterpene dialdehyde, is an active ingredient obtained from the Dorrigo pepper (Tasmannia lanceolata). Polygodial activates TRPV1 and TRPA1. (124, 125)

Tarragon (Artemisia dracunculus) is a perennial herb that belongs to the family Asteraceae. The active ingredient that is responsible for the characteristic taste is considered to be cis-pellitorin. The ingredients in tarragon oil include methyl eugenol (36%) and methyl chavicol (16%). Eugenol is a TRPV1 and TRPV3 channel agonist. (115)

Thyme (Thymus vulgarism) belongs to the family Lamiaceae. The major ingredient in thyme oil is thymol; other ingredients are borneol, linalool, myrcene, and p-cymene. It is incorporated as an antiseptic in mouthwash and in toothpaste. Thymol and linalool have been shown to activate TRPV3 and TRPA1, respectively. (45, 116, 123)

Vanilla (Vanilla planifolia) belongs to the family Orchidaceae (Figure 4). The smell is due to the active ingredient vanillin, which is structurally related to eugenol or guaiacol. It is used for flavoring ice creams, confectionaries, tobacco, beverages, and so forth. The natural flavor is due to vanillic aldehyde, but the artificial flavor ethylvanillin is as potent as the natural vanilla. It has mild CNS effects, is regarded as an aphrodisiac, and is useful to treat impotence. Vanillin can activate TRPV1 and TRPV3 ion channels. (126)

Most phytochemicals have been shown to activate TRP channels. The active phytochemical in the dichloromethane fraction from the leaves of the medicinal plant Vernonia tweedieana that belongs to the family Asteraceae was identified to be α-spinasterol, which acts as a potent antagonist of TRPV1. The antagonistic effects were demonstrated by the displacement of tritiated RTX ([³H]RTX) and inhibition of capsaicin-induced Ca²⁺ influx. α-Spinasterol exhibited an antinociceptive effect to noxious heat, but the mechanical threshold was unaffected. The specific action involving TRPV1 was confirmed by the lack of antinociceptive effect in mice systemically treated with RTX, which is known to ablate TRPV1 expressing neurons. Its effectiveness was demonstrated by its ability to reduce inflammatory hypersensitivity induced by complete Freund’s adjuvant (CFA). Interestingly, the body temperature was unaffected by its antagonistic action. (127)

TRPV3

TRPV3 is a thermosensitive channel that has a high sequence homology with TRPV1. TRPV3 was initially found to be exclusively expressed in the keratinocytes; however, further studies have shown its expression in sensory and central neurons, nasal mucosa, tongue, kidney, and testis. TRPV3 expression has been shown to be enhanced in painful conditions and is being pursued as a target for developing analgesics. (129-135)

Nerve terminals of the sensory neurons in the periphery are surrounded by keratinocytes; therefore substances such as ATP, prostaglandins, and nerve growth factor released from keratinocytes can make the nerve terminals more excitable. (136, 137) TRPV3 knockout animals lacked ATP release from peripheral terminals. (138) Activation of PLC has been shown to modulate the function of TRPV3 by PIP2-mediated mechanism and by IP3-mediated increase in intracellular Ca²⁺ levels. (138, 139) Overexpression of TRPV3 in animals results in a “hairless” phenotype, indicating the involvement in functions other than nociception. (140, 141)

Several of the TRPV1 activating phytochemicals also activate TRPV3. This may be due to the possibility of coassembly of channels withTRPV1 and TRPV3 subunits. These compounds include thymol, carvacrol, camphor, and eugenol. The channel is also activated by menthol and moderate heat (between 30 and 35 °C). (70, 115, 123, 142) Frankincense is a resin obtained from the frankincense tree (Boswellia thurifera), which belongs to the family Buseraceae. The active ingredient is boswellia acid. Myrrh is another resin from the species commiphora. It has been shown that the active ingredient in these resins, incensole, has psychoactive properties. Incensole smoke is used in religious ceremonies to attain higher levels of meditation. Incensole is an activator of TRPV3. (143)

Compounds in Cannabis sativa, CBD and tetrahydrocannabivarin, caused TRPV3-mediated Ca²⁺ influx with a EC₅₀ of ∼3.7 μM. Cannabigerovarin and cannabigerolic acid interacted with the channel by causing reduced carvacrol induced Ca²⁺ influx. (144)

TRPV4

TRPV4 is expressed in hypothalamus, sensory neurons, trachea, kidney, cochlear hair cells, vascular smooth muscle cells, endothelial cells, and keratinocytes. (145-148) TRPV4 is activated by cell-swelling induced by hypotonicity, shear stress, heat (>27 °C), diacyl glycerol (DAG), phorbol esters, 5′,6′-epoxyeicosatrienoic acid (5′,6′-EET), and 4-α-phorbol 12,13-didecanoate (4-α-PDD). (146-151) TRPV4 mediates mechanical sensitivity by direct activation of the channel as well as by second messengers produced by mechanical stimuli. (152-154) The role of TRPV4 in nociception is confirmed by the administration of antisense oligodeoxynucleotide. (155-158)

As discussed under activators of TRPA1, paclitaxel is obtained from the Pacific yew and is used to treat certain forms of cancer (Figure 2). The tactile and cold allodynia induced by paclitaxel have been attributed to its ability to activate both TRPV4 and TRPA1. When antagonists of these TRP channels were administered individually, tactile allodynia induced by paclitaxel was alleviated partially. However, a combination of both completely alleviated tactile allodynia. Paclitaxel-induced CGRP release from mouse esophagus was abolished by TRPA1 and TRPV4 antagonists, suggesting that TRPA1 and TRPV4 contribute to paclitaxel-induced neuropathy. (41) Bisandrographolide and andrographolide are diterpenoids purified from Andrographis paniculata, which belongs to the family Acanthaceae (Figure 2). Bisandrographolide is able to selectively activate TRPV4 without having any effects on TRPV1, TRPV2, and TRPV3. The abundant phytochemical in the extract, andrographolide, failed to activate TRPV4. (159)

Cannabidivarin and tetrahydrocannabivarin from cannabis induced TRPV4-mediated Ca²⁺ influx with an EC₅₀ of 0.9–6.4 μm. whereas cannabigerolic acid, cannabigerovarin, cannabinol, and cannabigerol interacted with TRPV4 causing reduced 4-α-PDD induced responses. (144)

Concluding Remarks

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The TRP family of ion channels has emerged as targets for phytochemicals in botanicals. From the scientific studies, it is becoming apparent that specific and potent active ingredients are being isolated and identified from botanicals. More interestingly, specific receptors for the active ingredients are also being identified, cloned, and characterized. Further, there are endogenous ligands for some of these receptors. The classic examples are endorphin and enkephalin for opioid receptors and anandamide for cannabinoid and TRPV1 receptors. The presence of endogenous ligands strengthens the argument that phytochemicals can fulfill the deficiency of the endogenous ligands or can overactivate the receptor to exert unphysiological responses. TRP channels are expressed in neuronal and nonneuronal cells. Activation of these receptors at the nerve terminals can initiate an afferent sensory signal by depolarizing the nerve terminal and generating an action potential. On the other hand, activation of TRP channels at the nerve terminals can cause an efferent function of releasing peptide hormones that can act locally on other cells in a paracrine fashion (local release) and stimulate the cells to release hormones in an endocrine fashion (release into the blood). Expression of TRP channels in nonneuronal cells, such as pancreatic beta cells and enteroendocrine cells, can release insulin and GLP-1, respectively, which can play a role in glucose homeostasis. It is important to consider the specificity of action, potency, and the bioavailability of these phytochemicals. It is certain that more phytochemicals and their TRP channel targets will be identified in the future to attribute scientific bases for the physiological effects and the health benefits produced by botanicals.

Author Information

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Corresponding Author
- Louis S. Premkumar - Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois 62702, United States; Email: [email protected]
Funding
This work is supported by a grant from NIDA (DA028017).
Notes
The authors declare no competing financial interest.

Acknowledgment

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I thank Somaja Louis for critically reading the manuscript.

References

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This article references 159 other publications.

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Capsaicin, the main pungent ingredient in 'hot' chili peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. The authors have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons. This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels. The cloned capsaicin receptor is also activated by increases in temp. in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.

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ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures

Story, Gina M.; Peier, Andrea M.; Reeve, Alison J.; Eid, Samer R.; Mosbacher, Johannes; Hricik, Todd R.; Earley, Taryn J.; Hergarden, Anne C.; Andersson, David A.; Hwang, Sun Wook; McIntyre, Peter; Jegla, Tim; Bevan, Stuart; Patapoutian, Ardem

Cell (Cambridge, MA, United States) (2003), 112 (6), 819-829CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

Mammals detect temp. with specialized neurons in the peripheral nervous system. Four TRPV-class channels have been implicated in sensing heat, and one TRPM-class channel in sensing cold. The combined range of temps. that activate these channels covers a majority of the relevant physiol. spectrum sensed by most mammals, with a significant gap in the noxious cold range. Here, we describe the characterization of ANKTM1, a cold-activated channel with a lower activation temp. compared to the cold and menthol receptor, TRPM8. ANKTM1 is a distant family member of TRP channels with very little amino acid similarity to TRPM8. It is found in a subset of nociceptive sensory neurons where it is coexpressed with TRPV1/VR1 (the capsaicin/heat receptor) but not TRPM8. Consistent with the expression of ANKTM1, we identify noxious cold-sensitive sensory neurons that also respond to capsaicin but not to menthol.

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Jordt, S. E., Bautista, D. M., Chuang, H. H., McKemy, D. D., Zygmunt, P. M., Hogestatt, E. D., Meng, I. D., and Julius, D. (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1 Nature 427, 260– 265

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Mustard oils and cannabinoids excite sensory nerve fibers through the TRP channel ANKTM1

Jordt, Sven-Eric; Bautista, Diana M.; Chuang, Huai-hu; McKemy, David D.; Zygmunt, Peter M.; Hoegestaett, Edward D.; Meng, Ian D.; Julius, David

Nature (London, United Kingdom) (2004), 427 (6971), 260-265CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

Wasabi, horseradish and mustard owe their pungency to isothiocyanate compds. Topical application of mustard oil (allyl isothiocyanate) to the skin activates underlying sensory nerve endings, thereby producing pain, inflammation and robust hypersensitivity to thermal and mech. stimuli. Despite their widespread use in both the kitchen and the lab., the mol. mechanism through which isothiocyanates mediate their effects remains unknown. Here we show that mustard oil depolarizes a subpopulation of primary sensory neurons that are also activated by capsaicin, the pungent ingredient in chilli peppers, and by Δ9-tetrahydrocannabinol (THC), the psychoactive component of marijuana. Both allyl isothiocyanate and THC mediate their excitatory effects by activating ANKTM1, a member of the TRP ion channel family recently implicated in the detection of noxious cold. These findings identify a cellular and mol. target for the pungent action of mustard oils and support an emerging role for TRP channels as ionotropic cannabinoid receptors.

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Peier, A. M., Moqrich, A., Hergarden, A. C., Reeve, A. J., Andersson, D. A., Story, G. M., Earley, T. J., Dragoni, I., McIntyre, P., Bevan, S., and Patapoutian, A. (2002) A TRP channel that senses cold stimuli and menthol Cell 108, 705– 715

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A TRP channel that senses cold stimuli and menthol

Peier, Andrea M.; Moqrich, Aziz; Hergarden, Anne C.; Reeve, Alison J.; Andersson, David A.; Story, Gina M.; Earley, Taryn J.; Dragoni, Ilaria; McIntyre, Peter; Bevan, Stuart; Patapoutian, Ardem

Cell (Cambridge, MA, United States) (2002), 108 (5), 705-715CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

A distinct subset of sensory neurons are thought to directly sense changes in thermal energy through their termini in the skin. Very little is known about the mols. that mediate thermoreception by these neurons. Vanilloid receptor 1 (VR1), a member of the TRP family of channels, is activated by noxious heat. Here the authors describe the cloning and characterization of TRPM8, a distant relative of VR1. TRPM8 is specifically expressed in a subset of pain- and temp.-sensing neurons. Cells overexpressing the TRPM8 channel can be activated by cold temps. and by a cooling agent, menthol. The identification of a cold-sensing TRP channel in a distinct subpopulation of sensory neurons implicates an expanded role for this family of ion channels in somatic sensory detection.

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McKemy, D. D., Neuhausser, W. M., and Julius, D. (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation Nature 416, 52– 58

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Identification of a cold receptor reveals a general role for TRP channels in thermosensation

McKemy, David D.; Neuhausser, Werner M.; Julius, David

Nature (London, United Kingdom) (2002), 416 (6876), 52-58CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

The cellular and mol. mechanisms that enable us to sense cold are not well understood. Insights into this process have come from the use of pharmacol. agents, such as menthol, that elicit a cooling sensation. Here we have characterized and cloned a menthol receptor from trigeminal sensory neurons that is also activated by thermal stimuli in the cool to cold range. This cold- and menthol-sensitive receptor, CMR1, is a member of the TRP family of excitatory ion channels, and we propose that it functions as a transducer of cold stimuli in the somatosensory system. These findings, together with our previous identification of the heat-sensitive channels VR1 and VRL-1, demonstrate that TRP channels detect temps. over a wide range and are the principal sensors of thermal stimuli in the mammalian peripheral nervous system.

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Cao, E., Liao, M., Cheng, Y., and Julius, D. (2013) TRPV1 structures in distinct conformations reveal activation mechanisms Nature 504, 113– 118

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TRPV1 structures in distinct conformations reveal activation mechanisms

Cao, Erhu; Liao, Maofu; Cheng, Yifan; Julius, David

Nature (London, United Kingdom) (2013), 504 (7478), 113-118CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

Transient receptor potential (TRP) channels are polymodal signal detectors that respond to a wide range of phys. and chem. stimuli. Elucidating how these channels integrate and convert physiol. signals into channel opening is essential to understanding how they regulate cell excitability under normal and pathophysiol. conditions. Here we exploit pharmacol. probes (a peptide toxin and small vanilloid agonists) to det. structures of two activated states of the capsaicin receptor, TRPV1. A domain (consisting of transmembrane segments 1-4) that moves during activation of voltage-gated channels remains stationary in TRPV1, highlighting differences in gating mechanisms for these structurally related channel superfamilies. TRPV1 opening is assocd. with major structural rearrangements in the outer pore, including the pore helix and selectivity filter, as well as pronounced dilation of a hydrophobic constriction at the lower gate, suggesting a dual gating mechanism. Allosteric coupling between upper and lower gates may account for rich physiol. modulation exhibited by TRPV1 and other TRP channels.

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Liao, M., Cao, E., Julius, D., and Cheng, Y. (2013) Structure of the TRPV1 ion channel determined by electron cryo-microscopy Nature 504, 107– 112

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Structure of the TRPV1 ion channel determined by electron cryo-microscopy

Liao, Maofu; Cao, Erhu; Julius, David; Cheng, Yifan

Nature (London, United Kingdom) (2013), 504 (7478), 107-112CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

Transient receptor potential (TRP) channels are sensors for a wide range of cellular and environmental signals, but elucidating how these channels respond to phys. and chem. stimuli has been hampered by a lack of detailed structural information. Here, the authors exploited advances in electron cryo-microscopy to det. the structure of a mammalian TRP channel, TRPV1, at 3.4 Å resoln., breaking the side-chain resoln. barrier for membrane proteins without crystn. Like voltage-gated channels, TRPV1 exhibited 4-fold symmetry around a central ion pathway formed by transmembrane segments 5-6 (S5-S6) and the intervening pore loop, which was flanked by S1-S4 voltage-sensor-like domains. TRPV1 had a wide extracellular 'mouth' with a short selectivity filter. The conserved 'TRP domain' interacted with the S4-S5 linker, consistent with its contribution to allosteric modulation. Subunit organization was facilitated by interactions among cytoplasmic domains, including N-terminal ankyrin repeats. These observations provide a structural blueprint for understanding unique aspects of TRP channel function.

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Bikman, B. T., Zheng, D., Pories, W. J., Chapman, W., Pender, J. R., Bowden, R. C., Reed, M. A., Cortright, R. N., Tapscott, E. B., Houmard, J. A., Tanner, C. J., Lee, J., and Dohm, G. L. (2008) Mechanism for improved insulin sensitivity after gastric bypass surgery J. Clin. Endocrinol. Metab. 93, 4656– 4663

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Mechanism for improved insulin sensitivity after gastric bypass surgery

Bikman, Benjamin T.; Zheng, Donghai; Pories, Walter J.; Chapman, William; Pender, John R.; Bowden, Rita C.; Reed, Melissa A.; Cortright, Ronald N.; Tapscott, Edward B.; Houmard, Joseph A.; Tanner, Charles J.; Lee, Jihyun; Dohm, G. Lynis

Journal of Clinical Endocrinology and Metabolism (2008), 93 (12), 4656-4663CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)

Surgical treatments of obesity were shown to induce rapid and prolonged improvements in insulin sensitivity. The aim of the study was to investigate the effects of gastric bypass surgery and the mechanisms that explain the improvement in insulin sensitivity. The authors performed a cross-sectional, nonrandomized, controlled study. This study was conducted jointly between the Departments of Exercise Science and Physiol. at East Carolina University in Greenville, North Carolina. Subjects were recruited into 4 groups: 1) lean [body mass index (BMI < 25 kg/m2; n = 93]; 2) wt.-matched (BMI = 25 to 35 kg/m2; n = 310); 3) morbidly obese (BMI > 35 kg/m2; n = 43); and 4) postsurgery patients (BMI ≈ 30 kg/m2; n = 40)]. Postsurgery patients were wt. stable 1 yr after surgery. Whole-body insulin sensitivity, muscle glucose transport, and muscle insulin signaling were assessed. Postsurgery subjects had insulin sensitivity index values that were similar to the lean and higher than morbidly obese and wt.-matched control subjects. Glucose transport was higher in the postsurgery vs. morbidly obese and wt.-matched groups. IRS1-pSer312 in the postsurgery group was lower than morbidly obese and wt.-matched groups. Inhibitor κBα was higher in the postsurgery vs. the morbidly obese and wt.-matched controls, indicating reduced inhibitor of κB kinase β activity. Insulin sensitivity and glucose transport are greater in the postsurgery patients than predicted from the wt.-matched group, suggesting that improved insulin sensitivity after bypass is due to something other than, or in addn. to, wt. loss. Improved insulin sensitivity is related to reduced inhibitor of κB kinase β activity and enhanced insulin signaling in muscle.

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Corey, D. P., Garcia-Anoveros, J., Holt, J. R., Kwan, K. Y., Lin, S. Y., Vollrath, M. A., Amalfitano, A., Cheung, E. L., Derfler, B. H., Duggan, A., Geleoc, G. S., Gray, P. A., Hoffman, M. P., Rehm, H. L., Tamasauskas, D., and Zhang, D. S. (2004) TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells Nature 432, 723– 730

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13
Bandell, M., Story, G. M., Hwang, S. W., Viswanath, V., Eid, S. R., Petrus, M. J., Earley, T. J., Patapoutian, A., Bautista, D. M., Movahed, P., Hinman, A., Axelsson, H. E., Sterner, O., Hogestatt, E. D., Julius, D., Jordt, S. E., and Zygmunt, P. M. (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin Neuron 41, 849– 857

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Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin

Bandell, Michael; Story, Gina M.; Hwang, Sun Wook; Viswanath, Veena; Eid, Samer R.; Petrus, Matt J.; Earley, Taryn J.; Patapoutian, Ardem

Neuron (2004), 41 (6), 849-857CODEN: NERNET; ISSN:0896-6273. (Cell Press)

Six members of the mammalian transient receptor potential (TRP) ion channels respond to varied temp. thresholds. The natural compds. capsaicin and menthol activate noxious heat-sensitive TRPV1 and cold-sensitive TRPM8, resp. The burning and cooling perception of capsaicin and menthol demonstrate that these ion channels mediate thermosensation. The authors show that, in addn. to noxious cold, pungent natural compds. present in cinnamon oil, wintergreen oil, clove oil, mustard oil, and ginger all activate TRPA1 (ANKTM1). Bradykinin, an inflammatory peptide acting through its G protein-coupled receptor, also activates TRPA1. The authors further show that phospholipase C is an important signaling component for TRPA1 activation. Cinnamaldehyde, the most specific TRPA1 activator, excites a subset of sensory neurons highly enriched in cold-sensitive neurons and elicits nociceptive behavior in mice. Collectively, these data demonstrate that TRPA1 activation elicits a painful sensation and provide a potential mol. model for why noxious cold can paradoxically be perceived as burning pain.

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Bautista, D. M., Movahed, P., Hinman, A., Axelsson, H. E., Sterner, O., Hogestatt, E. D., Julius, D., Jordt, S. E., and Zygmunt, P. M. (2005) Pungent products from garlic activate the sensory ion channel TRPA1 Proc. Natl. Acad. Sci. U.S.A. 102, 12248– 12252

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Pungent products from garlic activate the sensory ion channel TRPA1

Bautista, Diana M.; Movahed, Pouya; Hinman, Andrew; Axelsson, Helena E.; Sterner, Olov; Hogestatt, Edward D.; Julius, David; Jordt, Sven-Eric; Zygmunt, Peter M.

Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (34), 12248-12252CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

Garlic belongs to the Allium family of plants that produce organosulfur compds., such as allicin and diallyl disulfide (DADS), which account for their pungency and spicy aroma. Many health benefits have been ascribed to Allium exts., including hypotensive and vasorelaxant activities. However, the mol. mechanisms underlying these effects remain unknown. Intriguingly, allicin and DADS share structural similarities with allyl isothiocyanate, the pungent ingredient in wasabi and other mustard plants that induces pain and inflammation by activating TRPA1, an excitatory ion channel on primary sensory neurons of the pain pathway. Here we show that allicin and DADS excite an allyl isothiocyanate-sensitive subpopulation of sensory neurons and induce vasodilation by activating capsaicin-sensitive perivascular sensory nerve endings. Moreover, allicin and DADS activate the cloned TRPA1 channel when expressed in heterologous systems. These and other results suggest that garlic excites sensory neurons primarily through activation of TRPA1. Thus different plant genera, including Allium and Brassica, have developed evolutionary convergent strategies that target TRPA1 channels on sensory nerve endings to achieve chem. deterrence.

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Macpherson, L. J., Geierstanger, B. H., Viswanath, V., Bandell, M., Eid, S. R., Hwang, S., and Patapoutian, A. (2005) The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin Curr. Biol. 15, 929– 934

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The Pungency of Garlic: Activation of TRPA1 and TRPV1 in Response to Allicin

Macpherson, Lindsey J.; Geierstanger, Bernhard H.; Viswanath, Veena; Bandell, Michael; Eid, Samer R.; Hwang, SunWook; Patapoutian, Ardem

Current Biology (2005), 15 (10), 929-934CODEN: CUBLE2; ISSN:0960-9822. (Cell Press)

A review. Summary: Garlic's pungent flavor has made it a popular ingredient in cuisines around the world and throughout history. Garlic's health benefits have been elevated from folklore to clin. study [1-5]. Although there is some controversy as to the efficacy of garlic, garlic products are one of the most popular herbal supplements in the U.S. [6]. Chem. complex, garlic contains different assortments of sulfur compds. depending on whether the cloves are intact, crushed, cooked, or raw [7]. Raw garlic, when cut and placed on the tongue or lips, elicits painful burning and prickling sensations through unknown mechanisms. Here, we show that raw but not baked garlic activates TRPA1 and TRPV1, two temp.-activated ion channels that belong to the transient receptor potential (TRP) family [8-12]. These thermoTRPs are present in the pain-sensing neurons that innervate the mouth. We further show that allicin, an unstable component of fresh garlic, is the chem. responsible for TRPA1 and TRPV1 activation and is therefore likely to cause garlic's pungency.

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Kwan, K. Y., Allchorne, A. J., Vollrath, M. A., Christensen, A. P., Zhang, D. S., Woolf, C. J., and Corey, D. P. (2006) TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction Neuron 50, 277– 289

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17
Andersson, D. A., Gentry, C., Moss, S., and Bevan, S. (2008) Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress J. Neurosci. 28, 2485– 2494

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17
Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress

Andersson, David A.; Gentry, Clive; Moss, Sian; Bevan, Stuart

Journal of Neuroscience (2008), 28 (10), 2485-2494CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)

Transient receptor potential A1 (TRPA1) is expressed in a subset of nociceptive sensory neurons where it acts as a sensor for environmental irritants, including acrolein, and some pungent plant ingredients such as allyl isothiocyanate and cinnamaldehyde. These exogenous compds. activate TRPA1 by covalent modification of cysteine residues. We have used electrophysiol. methods and measurements of intracellular calcium concn. ([Ca2+]i) to show that TRPA1 is activated by several classes of endogenous thiolreactive mols. TRPA1 was activated by hydrogen peroxide (H2O2; EC50, 230 μM), by endogenously occurring alkenyl aldehydes (EC50: 4-hydroxynonenal 19.9 μM, 4-oxo-nonenal 1.9 μM, 4-hydroxyhexenal 38.9 μM) and by the cyclopentenone prostaglandin, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, EC50: 5.6 μM). The effect of H2O2 was reversed by treatment with dithiothreitol indicating that H2O2 acts by promoting the formation of disulfide bonds whereas the actions of the alkenyl aldehydes and 15d-PGJ2 were not reversed, suggesting that these agents form Michael adducts. H2O2 and the naturally occurring alkenyl aldehydes and 15d-PGJ2 acted on a subset of isolated rat and mouse sensory neurons [∼25% of rat dorsal root ganglion (DRG) and ∼50% of nodose ganglion neurons] to evoke a depolarizing inward current and an increase in [Ca2+]i in TRPA1 expressing neurons. The abilities of H2O2, alkenyl aldehydes and 15d-PGJ2 to raise [Ca2+]i in mouse DRG neurons were greatly reduced in neurons from trpa1-/- mice. Furthermore, intraplantar injection of either H2O2 or 15d-PGJ2 evoked a nocifensive/pain response in wild-type mice, but not in trpa1-/- mice. These data demonstrate that multiple agents produced during episodes of oxidative stress can activate TRPA1 expressed in sensory neurons.

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Bessac, B. F., Sivula, M., von Hehn, C. A., Escalera, J., Cohn, L., and Jordt, S. E. (2008) TRPA1 is a major oxidant sensor in murine airway sensory neurons J. Clin. Invest. 118, 1899– 1910

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TRPA1 is a major oxidant sensor in murine airway sensory neurons

Bessac, Bret F.; Sivula, Michael; von Hehn, Christian A.; Escalera, Jasmine; Cohn, Lauren; Jordt, Sven-Eric

Journal of Clinical Investigation (2008), 118 (5), 1899-1910CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)

Sensory neurons in the airways are finely tuned to respond to reactive chems. threatening airway function and integrity. Nasal trigeminal nerve endings are particularly sensitive to oxidants formed in polluted air and during oxidative stress as well as to chlorine, which is frequently released in industrial and domestic accidents. Oxidant activation of airway neurons induces respiratory depression, nasal obstruction, sneezing, cough, and pain. While normally protective, chemosensory airway reflexes can provoke severe complications in patients affected by inflammatory airway conditions like rhinitis and asthma. Here, we showed that both hypochlorite, the oxidizing mediator of chlorine, and hydrogen peroxide, a reactive oxygen species, activated Ca2+ influx and membrane currents in an oxidant-sensitive subpopulation of chemosensory neurons. These responses were absent in neurons from mice lacking TRPA1, an ion channel of the transient receptor potential (TRP) gene family. TRPA1 channels were strongly activated by hypochlorite and hydrogen peroxide in primary sensory neurons and heterologous cells. In tests of respiratory function, Trpa1-/- mice displayed profound deficiencies in hypochlorite- and hydrogen peroxide-induced respiratory depression as well as decreased oxidant-induced pain behavior. Our results indicate that TRPA1 is an oxidant sensor in sensory neurons, initiating neuronal excitation and subsequent physiol. responses in vitro and in vivo.

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Cao, D. S., Zhong, L., Hsieh, T. H., Abooj, M., Bishnoi, M., Hughes, L., and Premkumar, L. S. (2012) Expression of transient receptor potential ankyrin 1 (TRPA1) and its role in insulin release from rat pancreatic beta cells PloS One 7, e38005

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20
Brownlee, M. (2001) Biochemistry and molecular cell biology of diabetic complications Nature 414, 813– 820

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Biochemistry and molecular cell biology of diabetic complications

Brownlee, Michael

Nature (London, United Kingdom) (2001), 414 (6865), 813-820CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

A review. Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main mol. mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycemia-induced process of overprodn. of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

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Nagata, K., Duggan, A., Kumar, G., and Garcia-Anoveros, J. (2005) Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing J. Neurosci. 25, 4052– 4061

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Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing

Nagata, Keiichi; Duggan, Anne; Kumar, Gagan; Garcia-Anoveros, Jaime

Journal of Neuroscience (2005), 25 (16), 4052-4061CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)

Mechanosensory channels of sensory cells mediate the sensations of hearing, touch, and some forms of pain. The TRPA1 (a member of the TRP family of ion channel proteins) channel is activated by pain-producing chems., and its inhibition impairs hair cell mechanotransduction. As shown here and previously, TRPA1 is expressed by hair cells as well as by most nociceptors (small neurons of dorsal root, trigeminal, and nodose ganglia) and localizes to their sensory terminals (mechanosensory stereocilia and peripheral free nerves, resp.). Thus, TRPA1 channels are proposed to mediate transduction in both hair cells and nociceptors. Accordingly, we find that heterologously expressed TRPA1 display channel behaviors expected for both auditory and nociceptive transducers. First, TRPA1 and the hair cell transducer share a unique set of pore properties not described for any other channel (block by gadolinium, amiloride, gentamicin, and ruthenium red, a ranging conductance of ∼100 pS that is reduced to 54% by calcium, permeating calcium-induced potentiation followed by closure, and reopening by depolarization), supporting a direct role of TRPA1 as a pore-forming subunit of the hair cell transducer. Second, TRPA1 channels inactivate in hyperpolarized cells but remain open in depolarized cells. This property provides a mechanism for the lack of desensitization, coincidence detection, and allodynia that characterize pain by allowing a sensory neuron to respond constantly to sustained stimulation that is suprathreshold (i.e., noxious) and yet permitting the same cell to ignore sustained stimulation that is subthreshold (i.e., innocuous). Our results support a TRPA1 role in both nociceptor and hair cell transduction.

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Obata, K., Katsura, H., Mizushima, T., Yamanaka, H., Kobayashi, K., Dai, Y., Fukuoka, T., Tokunaga, A., Tominaga, M., and Noguchi, K. (2005) TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury J. Clin. Invest. 115, 2393– 2401

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23
Hinman, A., Chuang, H. H., Bautista, D. M., and Julius, D. (2006) TRP channel activation by reversible covalent modification Proc. Natl. Acad. Sci. U.S.A. 103, 19564– 19568

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TRP channel activation by reversible covalent modification

Hinman, Andrew; Chuang, Huai-hu; Bautista, Diana M.; Julius, David

Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (51), 19564-19568CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

Allyl isothiocyanate, the pungent principle of wasabi and other mustard oils, produces pain by activating TRPA1, an excitatory ion channel on sensory nerve endings. Isothiocyanates are membrane--permeable electrophiles that form adducts with thiols and primary amines, suggesting that covalent modification, rather than classical lock-and-key binding, accounts for their agonist properties. Indeed, we show that the thio1 reactive compds. of diverse structure activate TRPA1 in a manner that relies on covalent modification of cysteine residues within the cytoplasmic N terminus of the channel. These findings suggest an unusual paradigm whereby natural products activate a receptor through direct, reversible, and covalent protein modification.

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Raisinghani, M., Zhong, L., Jeffry, J. A., Bishnoi, M., Pabbidi, R. M., Pimentel, F., Cao, D. S., Evans, M. S., and Premkumar, L. S. (2011) Activation characteristics of transient receptor potential ankyrin 1 and its role in nociception Am. J. Physiol.: Cell Physiol. 301, C587– 600

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25
Premkumar, L. S. and Raisinghani, M. (2006) Nociceptors in cardiovascular functions: complex interplay as a result of cyclooxygenase inhibition Mol. Pain 2, 26

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Nociceptors in cardiovascular functions: complex interplay as a result of cyclooxygenase inhibition

Premkumar Louis S; Raisinghani Manish

Molecular pain (2006), 2 (), 26 ISSN:.

Prostaglandins (PGs) are requisite components of inflammatory pain as indicated by the efficacy of cyclooxygenase 1/2 (COX1/2) inhibitors. PGs do not activate nociceptive ion channels directly, but sensitize them by downstream mechanisms linked to G-protein coupled receptors. Antiinflammatory effects are purported to arise from inhibition of synthesis and/or release of proinflammatory agents. Release of these agents from peripheral and central terminals of sensory neurons modulates nociceptive input from the periphery and synaptic transmission at the first sensory synapse, respectively. Heart and blood vessels are densely innervated by sensory nerve endings that express chemo-, mechano-, and thermo-sensitive receptors. Activation of these receptors mediates synthesis and/or release of vasoactive agents by virtue of their Ca2+permeability. In this article, we discuss that inhibition of COX2 reduces PG synthesis and renders beneficial effects by preventing sensitization of nociceptors, but at the same time, it might contribute to deleterious cardiovascular effects by compromising the synthesis and/or release of vasoactive agents.

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Khan, A., Safdar, M., Ali Khan, M. M., Khattak, K. N., and Anderson, R. A. (2003) Cinnamon improves glucose and lipids of people with type 2 diabetes Diabetes Care 26, 3215– 3218

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26
Cinnamon improves glucose and lipids of people with type 2 diabetes

Khan Alam; Safdar Mahpara; Ali Khan Mohammad Muzaffar; Khattak Khan Nawaz; Anderson Richard A

Diabetes care (2003), 26 (12), 3215-8 ISSN:0149-5992.

OBJECTIVE: The objective of this study was to determine whether cinnamon improves blood glucose, triglyceride, total cholesterol, HDL cholesterol, and LDL cholesterol levels in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 60 people with type 2 diabetes, 30 men and 30 women aged 52.2 +/- 6.32 years, were divided randomly into six groups. Groups 1, 2, and 3 consumed 1, 3, or 6 g of cinnamon daily, respectively, and groups 4, 5, and 6 were given placebo capsules corresponding to the number of capsules consumed for the three levels of cinnamon. The cinnamon was consumed for 40 days followed by a 20-day washout period. RESULTS: After 40 days, all three levels of cinnamon reduced the mean fasting serum glucose (18-29%), triglyceride (23-30%), LDL cholesterol (7-27%), and total cholesterol (12-26%) levels; no significant changes were noted in the placebo groups. Changes in HDL cholesterol were not significant. CONCLUSIONS: The results of this study demonstrate that intake of 1, 3, or 6 g of cinnamon per day reduces serum glucose, triglyceride, LDL cholesterol, and total cholesterol in people with type 2 diabetes and suggest that the inclusion of cinnamon in the diet of people with type 2 diabetes will reduce risk factors associated with diabetes and cardiovascular diseases.

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Hlebowicz, J., Darwiche, G., Bjorgell, O., and Almer, L. O. (2007) Effect of cinnamon on postprandial blood glucose, gastric emptying, and satiety in healthy subjects Am. J. Clin. Nutr. 85, 1552– 1556

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Effect of cinnamon on postprandial blood glucose, gastric emptying, and satiety in healthy subjects

Hlebowicz, Joanna; Darwiche, Gassan; Bjoergell, Ola; Almer, Lars-Olof

American Journal of Clinical Nutrition (2007), 85 (6), 1552-1556CODEN: AJCNAC; ISSN:0002-9165. (American Society for Nutrition)

Background: Previous studies of patients with type 2 diabetes showed that cinnamon lowers fasting serum glucose, triacylglycerol, and LDL- and total cholesterol concns. Objective: We aimed to study the effect of cinnamon on the rate of gastric emptying, the postprandial blood glucose response, and satiety in healthy subjects. Design: The gastric emptying rate (GER) was measured by using standardized real-time ultrasonog. Fourteen healthy subjects were assessed by using a crossover trial. The subjects were examd. after an 8-h fast if they had normal fasting blood glucose concns. GER was calcd. as the percentage change in the antral cross-sectional area 15-90 min after ingestion of 300 g rice pudding (GER1) or 300 g rice pudding and 6 g cinnamon (GER2). Results: The median value of GER1 was 37%, and that of GER2 was 34.5%. The addn. of cinnamon to the rice pudding significantly delayed gastric emptying and lowered the postprandial glucose response (P < 0.05 for both). The redn. in the postprandial blood glucose concn. was much more noticeable and pronounced than was the lowering of the GER. The effect of cinnamon on satiety was not significant. Conclusions: The intake of 6 g cinnamon with rice pudding reduces postprandial blood glucose and delays gastric emptying without affecting satiety. Inclusion of cinnamon in the diet lowers the postprandial glucose response, a change that is at least partially explained by a delayed GER.

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Lissiman, E., Bhasale, A. L., and Cohen, M. (2009) Garlic for the common cold Cochrane Database Syst. Rev. 3, CD006206
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Lissiman, E., Bhasale, A. L., and Cohen, M. (2012) Garlic for the common cold Cochrane Database Syst. Rev. 14, CD006206
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Cutler, R. R., Odent, M., Hajj-Ahmad, H., Maharjan, S., Bennett, N. J., Josling, P. D., Ball, V., Hatton, P., and Dall’Antonia, M. (2009) In vitro activity of an aqueous allicin extract and a novel allicin topical gel formulation against Lancefield group B streptococci J. Antimicrob. Chemother. 63, 151– 154

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In vitro activity of an aqueous allicin extract and a novel allicin topical gel formulation against Lancefield group B streptococci

Cutler, Ronald R.; Odent, Michel; Hajj-Ahmad, Hussein; Maharjan, Sunil; Bennett, Norman J.; Josling, Peter D.; Ball, Vanessa; Hatton, Paulette; Dall'Antonia, Martino

Journal of Antimicrobial Chemotherapy (2009), 63 (1), 151-154CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)

Background Studies have shown the efficacy of intra-partum antibiotics in preventing early-onset group B streptococcal sepsis. This approach results in a high intra-partum antibiotic use. The same antibiotics used in prophylaxis are also first-line treatment for neonatal sepsis, and antibiotic exposure in the peri-natal period has been shown to be a risk factor for late-onset serious bacterial infections and allergic disease. Antibiotic exposure in the peri-natal period is becoming a major public health issue; alternative strategies are needed. Garlic has been traditionally used to treat vaginal infections. Allicin is the main antibacterial agent isolated from garlic. The aim of the study was to investigate the in vitro activity of a novel allicin ext. in aq. and gel formulation against 76 clin. isolates of Lancefield group B streptococci (GBS). MICs and MBCs of allicin were detd. for 76 GBS isolates by agar diln. and microtiter plate methods. Killing kinetics were detd. for a selected 16 of the 76 strains. Agar diffusion tests were compared for allicin liq. and gel (500 mg/L). Results and conclusions MICs and MBCs of allicin liq. were 35 to 95 mg/L and 75 to 315 mg/L, resp. Time/dose kill curves produced a 2-3 log redn. in cfu/mL within 3 h and no detectable growth at 8 and 24 h. A novel 500 mg/L allicin gel produced an av. zone size of 23 ± 6 mm compared with 21 ± 6 mm for allicin in water. Aq. allicin is bactericidal against GBS isolates and maintains activity in a novel gel formulation.

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Khanum, F., Anilakumar, K. R., and Viswanathan, K. R. (2004) Anticarcinogenic properties of garlic: a review Crit. Rev. Food. Sci. Nutr. 44, 479– 488

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Shenoy, N. R. and Choughuley, A. S. (1992) Inhibitory effect of diet related sulphydryl compounds on the formation of carcinogenic nitrosamines Cancer Lett. 65, 227– 232

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Inhibitory effect of diet related sulfhydryl compounds on the formation of carcinogenic nitrosamines

Shenoy, Narmada R.; Choughuley, Ahmed S. U.

Cancer Letters (Shannon, Ireland) (1992), 65 (3), 227-32CODEN: CALEDQ; ISSN:0304-3835.

The authors studied the modifying effect of sulfhydryl compd. viz., cysteine (CE), cystine (CI), glutathione (GU), cysteamine (CEA), cystamine (CEI), cysteic acid (CIA) and thioglycolic acid (TGA) on the nitrosation of model amines viz., pyrrolidine (PYR), piperidine (NPIP) and morpholine (NMOR). The present work also describes the inhibitory effect of onion and garlic juices on the nitrosation reactions. Most of these compds. behave as antinitrosating agents and their inhibitory activity towards formation of carcinogenic nitrosamines, under different conditions is described.

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Koizumi, K., Iwasaki, Y., Narukawa, M., Iitsuka, Y., Fukao, T., Seki, T., Ariga, T., and Watanabe, T. (2009) Diallyl sulfides in garlic activate both TRPA1 and TRPV1 Biochem. Biophys. Res. Commun. 382, 545– 548

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Leamy, A. W., Shukla, P., McAlexander, M. A., Carr, M. J., and Ghatta, S. (2011) Curcumin ((E,E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) activates and desensitizes the nociceptor ion channel TRPA1 Neurosci. Lett. 503, 157– 162

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Gupta, S. C., Patchva, S., and Aggarwal, B. B. (2013) Therapeutic roles of curcumin: lessons learned from clinical trials AAPS J. 15, 195– 218

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Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials

Gupta, Subash C.; Patchva, Sridevi; Aggarwal, Bharat B.

AAPS Journal (2013), 15 (1), 195-218CODEN: AJAOB6; ISSN:1550-7416. (Springer)

A review. Extensive research over the past half century has shown that curcumin (diferuloylmethane), a component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling pathways. Extensive clin. trials over the past quarter century have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects have been obsd. in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn's disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis. Curcumin has also shown protection against hepatic conditions, chronic arsenic exposure, and alc. intoxication. Dose-escalating studies have indicated the safety of curcumin at doses as high as 12 g/day over 3 mo. Curcumin's pleiotropic activities emanate from its ability to modulate numerous signaling mols. such as pro-inflammatory cytokines, apoptotic proteins, NF-κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E2, prostate-specific antigen, adhesion mols., phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1, creatinine, HO-1, AST, and ALT in human participants. In clin. trials, curcumin has been used either alone or in combination with other agents. Various formulations of curcumin, including nanoparticles, liposomal encapsulation, emulsions, capsules, tablets, and powder, have been examd. In this review, we discuss in detail the various human diseases in which the effect of curcumin has been investigated.

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Song, Y., Sonawane, N. D., Salinas, D., Qian, L., Pedemonte, N., Galietta, L. J., and Verkman, A. S. (2004) Evidence against the rescue of defective DeltaF508-CFTR cellular processing by curcumin in cell culture and mouse models J. Biol. Chem. 279, 40629– 40633

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Gao, J., Zhou, H., Lei, T., Zhou, L., Li, W., Li, X., and Yang, B. (2011) Curcumin inhibits renal cyst formation and enlargement in vitro by regulating intracellular signaling pathways Eur. J. Pharmacol. 654, 92– 99

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Curcumin inhibits renal cyst formation and enlargement in vitro by regulating intracellular signaling pathways

Gao, Jinsheng; Zhou, Hong; Lei, Tianluo; Zhou, Li; Li, Weidong; Li, Xuejun; Yang, Baoxue

European Journal of Pharmacology (2011), 654 (1), 92-99CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)

Autosomal dominant polycystic kidney disease, a common inherited disease affecting about 1/1000 and 1/400 live births, is characterized by massive enlargement of fluid-filled cysts and eventually causes renal failure. The purpose of this study is to identify the inhibitory effect of curcumin on renal cyst development and to investigate the inhibitory mechanism. Madin-Darby canine kidney (MDCK) cyst model and murine embryonic kidney cyst model were used to evaluate inhibitory activity. Cell viability, proliferation, apoptosis, CFTR function and expression, and signaling pathways in MDCK cells were detd. to explore the mechanism of cyst inhibition. Curcumin was found to significantly inhibit MDCK cyst development. At max. dose curcumin caused 62% inhibition of the cyst formation (IC50 was 0.12 μM). Curcumin slowed cyst enlargement in both MDCK cyst model and embryonic kidney cyst model with dose-response relationship. Curcumin neither induced cytotoxicity nor apoptosis in MDCK cells at < 100 μM. Curcumin failed to affect the chloride transporter CFTR expression and function. Interestingly, curcumin inhibited forskolin-promoted cell proliferation and promoted the tubule formation in MDCK cells, which indicates curcumin promotes MDCK cell differentiation. Furthermore, curcumin reduced the intracellular signaling proteins Ras, B-raf, p-MEK, p-ERK, c-fos, Egr-1, but increased Raf-1 and NAB2 in MDCK cells exposed to forskolin. These results define that curcumin inhibits renal cyst formation and enlargement and suggest that curcumin might be developed as a candidate drug for polycystic kidney disease.

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Sohma, Y., Yu, Y. C., and Hwang, T. C. (2013) Curcumin and genistein: the combined effects on disease-associated CFTR mutants and their clinical implications Curr. Pharm. Des. 19, 3521– 3528

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Curcumin and genistein: the combined effects on disease-associated CFTR mutants and their clinical implications

Sohma, Yoshiro; Yu, Ying-Chun; Hwang, Tzyh-Chang

Current Pharmaceutical Design (2013), 19 (19), 3521-3528CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)

A review. Genistein and curcumin are major components of Asian foods, soybean and curry turmeric resp. These compds. have been intensively investigated for their chem. and biol. features conferring their anti-cancer activity. Genistein and curcumin have also been investigated for their potentiation effects on disease-assocd. CFTR mutants such as ΔF508 and G551D. Recently, we investigated the combined effect of genistein and curcumin on G551D-CFTR, which exhibits gating defects without abnormalities in protein synthesis or trafficking using the patch-clamp technique. We found that genistein and curcumin showed additive effects on their potentiation of G551D-CFTR in high concn. range and also, more importantly, showed a significant synergistic effect in their min. concn. ranges. These results are consistent with the idea that multiple mechanisms are involved in the action of these CFTR potentiators. In this review, we revisit the pharmacol. of genistein and curcumin on CFTR and also propose new pharmaceutical implications of combined use of these compds. in the development of drugs for CF pharmacotherapy.

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Nassini, R., Materazzi, S., Vriens, J., Prenen, J., Benemei, S., De Siena, G., la Marca, G., Andre, E., Preti, D., Avonto, C., Sadofsky, L., Di Marzo, V., De Petrocellis, L., Dussor, G., Porreca, F., Taglialatela-Scafati, O., Appendino, G., Nilius, B., and Geppetti, P. (2012) The ‘headache tree’ via umbellulone and TRPA1 activates the trigeminovascular system Brain 135, 376– 390

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Zhong, J., Pollastro, F., Prenen, J., Zhu, Z., Appendino, G., and Nilius, B. (2011) Ligustilide: a novel TRPA1 modulator Pfluegers Arch. 462, 841– 849

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Ligustilide: a novel TRPA1 modulator

Zhong, Jian; Pollastro, Federica; Prenen, Jean; Zhu, Zhiming; Appendino, Giovanni; Nilius, Bernd

Pfluegers Archiv (2011), 462 (6), 841-849CODEN: PFLABK; ISSN:0031-6768. (Springer GmbH)

TRPA1 is activated by electrophilic compds. such as mustard oil (MO). Here, we demonstrate a bimodal sensitivity of TRPA1 to ligustilide (Lig), an electrophilic volatile dihydrophthalide of dietary and medicinal relevance. Lig is a potent TRPA1 activator and is also capable to induce a modest block of MO activated currents. Aromatization to dehydroligustilide (DH-Lig), as occurs during aging of its botanical sources, reversed this profile, enhancing TRPA1 inhibition and reducing activation. Mutation of the reactive cysteines in mouseTRPA1 (C622S, C642S, C666S) dramatically reduced activation by MO and significantly reduced that by Lig, but had an almost negligible effect on the action of DH-Lig, whose activation mechanism of TRPA1 is therefore largely independent from the alkylation of cysteine residues. Taken together, these observations show that the phthalide structural motif is a versatile platform to investigate the modulation of TRPA1 by small mols., being tunable in terms of activation/inhibition profile and mechanism of interaction. Finally, the action of Lig on TRPA1 may contribute to the gustatory effects of celery, its major dietary source, and to the pharmacol. action of important plants from the Chinese and native American traditional medicines.

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Materazzi, S., Fusi, C., Benemei, S., Pedretti, P., Patacchini, R., Nilius, B., Prenen, J., Creminon, C., Geppetti, P., and Nassini, R. (2012) TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism Pfluegers Arch. 463, 561– 569

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TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism

Materazzi, Serena; Fusi, Camilla; Benemei, Silvia; Pedretti, Pamela; Patacchini, Riccardo; Nilius, Bernd; Prenen, Jean; Creminon, Christophe; Geppetti, Pierangelo; Nassini, Romina

Pfluegers Archiv (2012), 463 (4), 561-569CODEN: PFLABK; ISSN:0031-6768. (Springer GmbH)

Paclitaxel produces a sensory neuropathy, characterized by mech. and cold hypersensitivity, which are abated by antioxidants. The transient receptor potential vanilloid 4 (TRPV4) channel was reported to contribute to paclitaxel-evoked allodynia in rodents. We recently showed that TRP ankyrin 1 (TRPA1) channel mediates oxaliplatin-evoked cold and mech. allodynia, and the drug targets TRPA1 via generation of oxidative stress. Here, we have explored whether TRPA1 activation contributes to paclitaxel-induced mech. and cold hypersensitivity and whether this activation is mediated by oxidative stress generation. Paclitaxel-evoked mech. allodynia was reduced partially by the TRPA1 antagonist, HC-030031, and the TRPV4 antagonist, HC-067047, and was completely abated by the combination of the 2 antagonists. The reduced paclitaxel-evoked mech. allodynia, obsd. in TRPA1-deficient mice, was completely abolished when mice were treated with HC-067047. Cold allodynia was abated completely by HC-030031 and in TRPA1-deficient mice. Exposure to paclitaxel of slices of mouse esophagus released the sensory neuropeptide, calcitonin gene-related peptide (CGRP). This effect was abolished by capsaicin desensitization and in calcium-free medium (indicating neurosecretion from sensory nerve terminals), partially reduced by either HC-030031 or HC-067047, and completely abated in the presence of glutathione (GSH). Finally, the reduced CGRP release, obsd. in esophageal slices of TRPA1-deficient mice, was further inhibited by GSH. Paclitaxel via oxygen radical formation targets TRPA1 and TRPV4, and both channels are key for the delayed development of mech. allodynia. Cold allodynia is, however, entirely dependent on TRPA1.

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De Petrocellis, L., Vellani, V., Schiano-Moriello, A., Marini, P., Magherini, P. C., Orlando, P., and Di Marzo, V. (2008) Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8 J. Pharmacol. Exp. Ther. 325, 1007– 1015

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Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8

De Petrocellis, Luciano; Vellani, Vittorio; Schiano-Moriello, Aniello; Marini, Pietro; Magherini, Pier Cosimo; Orlando, Pierangelo; Di Marzo, Vincenzo

Journal of Pharmacology and Experimental Therapeutics (2008), 325 (3), 1007-1015CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)

The plant cannabinoids (phytocannabinoids), cannabidiol (CBD), and Δ9-tetrahydrocannabinol (THC) were previously shown to activate transient receptor potential channels of both vanilloid type 1 (TRPV1) and ankyrin type 1 (TRPA1), resp. Furthermore, the endocannabinoid anandamide is known to activate TRPV1 and was recently found to antagonize the menthol- and icilin-sensitive transient receptor potential channels of melastatin type 8 (TRPM8). In this study, we investigated the effects of six phytocannabinoids [i.e., CBD, THC, CBD acid, THC acid, cannabichromene (CBC), and cannabigerol (CBG)] on TRPA1- and TRPM8-mediated increase in intracellular Ca2+ in either HEK-293 cells overexpressing the two channels or rat dorsal root ganglia (DRG) sensory neurons. All of the compds. tested induced TRPA1-mediated Ca2+ elevation in HEK-293 cells with efficacy comparable with that of mustard oil isothiocyanates (MO), the most potent being CBC (EC50 = 60 nM) and the least potent being CBG and CBD acid (EC50 = 3.4-12.0 μM). CBC also activated MO-sensitive DRG neurons, although with lower potency (EC50 = 34.3 μM). Furthermore, although none of the compds. tested activated TRPM8-mediated Ca2+ elevation in HEK-293 cells, they all, with the exception of CBC, antagonized this response when it was induced by either menthol or icilin. CBD, CBG, THC, and THC acid were equipotent (IC50 = 70-160 nM), whereas CBD acid was the least potent compd. (IC50 = 0.9-1.6 μM). CBG inhibited Ca2+ elevation also in icilin-sensitive DRG neurons with potency (IC50 = 4.5 μM) similar to that of anandamide (IC50 = 10 μM). Our findings suggest that phytocannabinoids and cannabis exts. exert some of their pharmacol. actions also by interacting with TRPA1 and TRPM8 channels, with potential implications for the treatment of pain and cancer.

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Montrucchio, D. P., Cordova, M. M., and Santos, A. R. (2013) Plant derived aporphinic alkaloid S-(+)-dicentrine induces antinociceptive effect in both acute and chronic inflammatory pain models: evidence for a role of TRPA1 channels PloS One 8, e67730

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Talavera, K., Gees, M., Karashima, Y., Meseguer, V. M., Vanoirbeek, J. A., Damann, N., Everaerts, W., Benoit, M., Janssens, A., Vennekens, R., Viana, F., Nemery, B., Nilius, B., and Voets, T. (2009) Nicotine activates the chemosensory cation channel TRPA1 Nat. Neurosci. 12, 1293– 1299

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Nicotine activates the chemosensory cation channel TRPA1

Talavera, Karel; Gees, Maarten; Karashima, Yuji; Meseguer, Victor M.; Vanoirbeek, Jeroen A. J.; Damann, Nils; Everaerts, Wouter; Benoit, Melissa; Janssens, Annelies; Vennekens, Rudi; Viana, Felix; Nemery, Benoit; Nilius, Bernd; Voets, Thomas

Nature Neuroscience (2009), 12 (10), 1293-1299CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)

Topical application of nicotine, as used in nicotine replacement therapies, causes irritation of the mucosa and skin. This reaction has been attributed to activation of nicotinic acetylcholine receptors (nAChRs) in chemosensory neurons. In contrast with this view, the chemosensory cation channel transient receptor potential A1 (TRPA1) is crucially involved in nicotine-induced irritation. Micromolar concns. of nicotine activated heterologously expressed mouse and human TRPA1. Nicotine acted in a membrane-delimited manner, stabilizing the open state(s) and destabilizing the closed state(s) of the channel. In the presence of the general nAChR blocker hexamethonium, nociceptive neurons showed nicotine-induced responses that were strongly reduced in TRPA1-deficient mice. Finally, TRPA1 mediated the mouse airway constriction reflex to nasal instillation of nicotine. The identification of TRPA1 as a nicotine target suggests that existing models of nicotine-induced irritation should be revised and may facilitate the development of smoking cessation therapies with less adverse effects.

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Riera, C. E., Menozzi-Smarrito, C., Affolter, M., Michlig, S., Munari, C., Robert, F., Vogel, H., Simon, S. A., and Le Coutre, J. (2009) Compounds from Sichuan and Melegueta peppers activate, covalently and non-covalently, TRPA1 and TRPV1 channels Br. J. Pharmacol. 157, 1398– 1409

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Compounds from Sichuan and Melegueta peppers activate, covalently and non-covalently, TRPA1 and TRPV1 channels

Riera, C. E.; Menozzi-Smarrito, C.; Affolter, M.; Michlig, S.; Munari, C.; Robert, F.; Vogel, H.; Simon, S. A.; Le Coutre, J.

British Journal of Pharmacology (2009), 157 (8), 1398-1409CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)

Background and purpose: Oily exts. of Sichuan and Melegueta peppers evoke pungent sensations mediated by different alkylamides [mainly hydroxy-α-sanshool (α-SOH)] and hydroxyarylalkanones (6-shogaol and 6-paradol). We assessed how transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (TRPV1), two chemosensory ion channels, participate in these pungent sensations. Exptl. approach: The structure-activity relationships of these mols. on TRPA1 and TRPV1 was measured by testing natural and synthetic analogs using calcium and voltage imaging on dissocd. dorsal root ganglia neurons and human embryonic kidney 293 cells expressing the wild-type channels or specific cysteine mutants using glutathione trapping as a model to probe TRPA1 activation. In addn., using Trpv1 knockout mice, the compds.' aversive responses were measured in a taste brief-access test. Key results: For TRPA1 activation, the cis C6 double bond in the polyenic chain of α-SOH was crit., whereas no structural specificity was required for activation of TRPV1. Both 6-shogaol and 6-paradol were found to activate TRPV1 and TRPA1 channels, whereas linalool, an abundant terpene in Sichuan pepper, activated TRPA1 but not TRPV1 channels. Alkylamides and 6-shogaol act on TRPA1 by covalent bonding whereas none of these compds. activated TRPV1 through such interactions. Finally, TRPV1 mutant mice retained sensitivity to 6-shogaol but were not responsive to α-SOH. Conclusions and implications: The pungent nature of components of Sichuan and Melegueta peppers was mediated via interactions with TRPA1 and TRPV1 channels and may explain the aversive properties of these compds.

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Vazquez, G., Wedel, B. J., Aziz, O., Trebak, M., and Putney, J. W., Jr. (2004) The mammalian TRPC cation channels Biochim. Biophys. Acta 1742, 21– 36

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The mammalian TRPC cation channels

Vazquez, Guillermo; Wedel, Barbara J.; Aziz, Omar; Trebak, Mohamed; Putney, James W.

Biochimica et Biophysica Acta, Molecular Cell Research (2004), 1742 (1-3), 21-36CODEN: BBAMCO; ISSN:0167-4889. (Elsevier B.V.)

A review. Transient Receptor Potential-Canonical (TRPC) channels are mammalian homologs of Transient Receptor Potential (TRP), a Ca2+-permeable channel involved in the phospholipase C-regulated photoreceptor activation mechanism in Drosophila. The seven mammalian TRPCs constitute a family of channels which have been proposed to function as store-operated as well as second messenger-operated channels in a variety of cell types. TRPC channels, together with other more distantly related channel families, make up the larger TRP channel superfamily. This review summarizes recent findings on the structure, regulation and function of the apparently ubiquitous TRPC cation channels.

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Birnbaumer, L. (2009) The TRPC class of ion channels: a critical review of their roles in slow, sustained increases in intracellular Ca(2+) concentrations Annu. Rev. Pharmacol. Toxicol. 49, 395– 426

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Leuner, K., Kazanski, V., Muller, M., Essin, K., Henke, B., Gollasch, M., Harteneck, C., and Muller, W. E. (2007) Hyperforin--a key constituent of St. John’s wort specifically activates TRPC6 channels FASEB J. 21, 4101– 4111

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Sikand, P. and Premkumar, L. S. (2007) Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse J. Physiol. 581, 631– 647

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Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse

Sikand, Parul; Premkumar, Louis S.

Journal of Physiology (Oxford, United Kingdom) (2007), 581 (2), 631-647CODEN: JPHYA7; ISSN:0022-3751. (Blackwell Publishing Ltd.)

Sensory input from the periphery to the CNS is critically dependent on the strength of synaptic transmission at the first sensory synapse formed between primary afferent dorsal root ganglion (DRG) and superficial dorsal horn (DH) neurons of the spinal cord. Transient receptor potential vanilloid 1 (TRPV1) expressed on a subset of sensory neurons plays an important role in chronic inflammatory thermal nociception. Activation of protein kinase C (PKC) sensitizes TRPV1, which may contribute to the pathophysiol. of chronic pain conditions. In this study, the authors have examd. the modulation of TRPV1-mediated enhancement of excitatory synaptic transmission in response to PKC activation. Miniature excitatory postsynaptic currents (mEPSCs) from embryonic rat DRG-DH neuronal cocultures were recorded by patch clamping DH neurons. Capsaicin potently increased the frequency but not the amplitude of mEPSCs in a calcium-dependent manner, suggesting TRPV1-mediated glutamate release from presynaptic terminals of sensory neurons. Continued or repeated applications of capsaicin reduced the frequency of mEPSCs over time. The PKC activator phorbol 12,13-dibutyrate (PDBu) alone increased mEPSC events to a certain extent in a reversible manner but capsaicin further synergistically enhanced the frequency of mEPSCs. The PKC inhibitor bisindolylmaleimide (BIM) abolished PDBu-mediated potentiation of TRPV1-dependent increases in mEPSC frequency, suggesting modulation of TRPV1 by PKC-induced phosphorylation. In addn., at normal body temps. (∼37°) PKC-mediated enhancement of mEPSC frequency is significantly decreased by a specific TRPV1 antagonist, suggesting a physiol. role of TRPV1 at the central terminals. Furthermore, bradykinin (BK) significantly potentiated TRPV1-modulated synaptic responses by activating the PLC-PKC pathway. The authors' results indicate that TRPV1 activation can modulate excitatory synaptic transmission at the first sensory synapse and its effects can further be augmented by activation of PKC. Increased gain of sensory input by TRPV1-induced enhancement of glutamate release and its potentiation by various inflammatory mediators may contribute to persistent pain conditions. Selective targeting of TRPV1 expressed on the central terminals of sensory neurons may serve as a strategy to alleviate chronic intractable pain conditions.

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Cao, D. S., Yu, S. Q., and Premkumar, L. S. (2009) Modulation of transient receptor potential Vanilloid 4-mediated membrane currents and synaptic transmission by protein kinase C Mol. Pain 5, 5

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Modulation of transient receptor potential Vanilloid 4-mediated membrane currents and synaptic transmission by protein kinase C

Cao De-Shou; Yu Shuang-Quan; Premkumar Louis S

Molecular pain (2009), 5 (), 5 ISSN:.

BACKGROUND: Transient receptor potential Vanilloid (TRPV) receptors are involved in nociception and are expressed predominantly in sensory neurons. TRPV1, a non-selective cation channel has been extensively studied and is responsible for inflammatory thermal hypersensitivity. In this study, the expression and function of TRPV4 have been characterized and compared with those of TRPV1. RESULTS: Immunohistochemical studies revealed that both TRPV1 and TRPV4 were co-expressed in dorsal root ganglion (DRG) neuronal cell bodies and in the central terminals of laminae I and II of the spinal dorsal horn (DH). In Ca2+ fluorescence imaging and whole-cell patch-clamp experiments, TRPV1- and TRPV4-mediated responses were observed in a population of the same DRG neurons. Sensitization of TRPV1 has been shown to be involved in inflammatory pain conditions. Incubation with phorbol 12, 13-dibutyrate (PDBu), a PKC activator, resulted in a significant potentiation of TRPV4 currents in DRG neurons. In TRPV4 expressing HEK 293T cells, PDBu increased 4alpha-phorbol 12, 13-didecanoate (4alpha-PDD)-induced single-channel activity in cell-attached patches, which was abrogated by bisindolylmaleimide (BIM), a selective PKC inhibitor. TRPV4 is also expressed at the central terminals of sensory neurons. Activation of TRPV4 by 4alpha-PDD increased the frequency of miniature excitatory post synaptic currents (mEPSCs) in DRG-DH neuronal co-cultures. 4alpha-PDD-induced increase in the frequency of mEPSCs was further enhanced by PDBu. The expression of TRP channels has been shown in other areas of the CNS; application of 4alpha-PDD significantly increased the mEPSC frequency in cultured hippocampal neurons, which was further potentiated by PDBu, whereas, TRPV1 agonist capsaicin did not modulate synaptic transmission. CONCLUSION: These results indicate that TRPV4 and TRPV1 are co-expressed in certain DRG neurons and TRPV4 can be sensitized by PKC not only in DRG neuronal cell bodies, but also in the central sensory and non-sensory nerve terminals. Co-expression of TRPV1 and TRPV4 ion channels, their modulation of synaptic transmission and their sensitization by PKC may synergistically play a role in nociception.

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Jeffry, J. A., Yu, S. Q., Sikand, P., Parihar, A., Evans, M. S., and Premkumar, L. S. (2009) Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia PloS One 4, e7021

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Evans, M. S., Cheng, X., Jeffry, J. A., Disney, K. E., and Premkumar, L. S. (2012) Sumatriptan inhibits TRPV1 channels in trigeminal neurons Headache 52, 773– 784

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Zhou, J., Du, W., Zhou, K., Tai, Y., Yao, H., Jia, Y., and Ding, Y. (2008) Critical role of TRPC6 channels in the formation of excitatory synapses Nat. Neurosci. 11, 741– 743

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Critical role of TRPC6 channels in the formation of excitatory synapses

Zhou, Jian; Du, Wanlu; Zhou, Kechun; Tai, Yilin; Yao, Hailan; Jia, Yichang; Ding, Yuqiang; Wang, Yizheng

Nature Neuroscience (2008), 11 (7), 741-743CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)

TRPC6 promotes the formation of synapses in a CaMKIV-CREB-dependent manner. TRPC6-expressing transgenic animals showed increased nos. of spines and demonstrated enhanced learning on behavioral tasks. TRPC6 promotes the formation of synapses in a CaMKIV-CREB-dependent manner. TRPC6-expressing transgenic animals showed increased nos. of spines and demonstrated enhanced learning on behavioral tasks. The transient receptor potential canonical (TRPC) channels are Ca2+-permeable, nonselective cation channels with different biol. functions, but their roles in brain are largely unknown. Here we report that TRPC6 was localized to excitatory synapses and promoted their formation via a CaMKIV-CREB-dependent pathway. TRPC6 transgenic mice showed enhancement in spine formation, and spatial learning and memory in Morris water maze. These results reveal a previously unknown role of TRPC6 in synaptic and behavioral plasticity.

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Nilius, B. and Owsianik, G. (2011) The transient receptor potential family of ion channels Genome Biol. 12, 218

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The transient receptor potential family of ion channels

Nilius, Bernd; Owsianik, Grzegorz

Genome Biology (2011), 12 (), 218CODEN: GNBLFW; ISSN:1474-760X. (BioMed Central Ltd.)

A review. The transient receptor potential (TRP) multigene superfamily encodes integral membrane proteins that function as ion channels. Members of this family are conserved in yeast, invertebrates and vertebrates. The TRP family is subdivided into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin) and TRPN (NOMPC-like); the latter is found only in invertebrates and fish. TRP ion channels are widely expressed in many different tissues and cell types, where they are involved in diverse physiol. processes, such as sensation of different stimuli or ion homeostasis. Most TRPs are non-selective cation channels, only few are highly Ca2+ selective, some are even permeable for highly hydrated Mg2+ ions. This channel family shows a variety of gating mechanisms, with modes of activation ranging from ligand binding, voltage and changes in temp. to covalent modifications of nucleophilic residues. Activated TRP channels cause depolarization of the cellular membrane, which in turn activates voltage-dependent ion channels, resulting in a change of intracellular Ca2+ concn.; they serve as gatekeeper for transcellular transport of several cations (such as Ca2+ and Mg2+), and are required for the function of intracellular organelles (such as endosomes and lysosomes). Because of their function as intracellular Ca2+ release channels, they have an important regulatory role in cellular organelles. Mutations in several TRP genes have been implicated in diverse pathol. states, including neurodegenerative disorders, skeletal dysplasia, kidney disorders and pain, and ongoing research may help find new therapies for treatments of related diseases.

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Carakostas, M. C., Curry, L. L., Boileau, A. C., and Brusick, D. J. (2008) Overview: the history, technical function and safety of rebaudioside A, a naturally occurring steviol glycoside, for use in food and beverages Food Chem. Toxicol. 46 (Suppl 7) S1– S10

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Medler, K. F. (2011) Multiple roles for TRPs in the taste system: not your typical TRPs Adv. Exp. Med. Biol. 704, 831– 846

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Sprous, D. and Palmer, K. R. (2010) The T1R2/T1R3 sweet receptor and TRPM5 ion channel taste targets with therapeutic potential Prog. Mol. Biol. Transl. Sci. 91, 151– 208

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The T1R2/T1R3 sweet receptor and TRPM5 ion channel: taste targets with therapeutic potential

Sprous, Dennis; Palmer, Kyle R.

Progress in Molecular Biology and Translational Science (2010), 91 (Membrane Proteins as Drug Targets), 151-208CODEN: PNARC5 ISSN:. (Elsevier Inc.)

A review. A review on the hypothesis of gastrointestinal taste signaling and the potential for T1R2/T1R3 and TRPM5 as targets of therapeutic intervention in obesity and diabetes. Topics covered include ingestive behaviors as therapeutic endpoints, taste signaling proteins as targets for the drug discovery approach, obesity and diabetes, T1R2/T1R3 sweet receptor, TRPM5 ion channel, morphol. and functional characteristics of type II taste cells, morphol. and functional characteristics of gut chemosensory cells, taste signaling in the gut, type II taste cells are not secretory cells, discovery of useful ligands for sweet receptors and TRPM5, creating focused libraries through chemoinformatics, computational and chemoinformatics methods, and directions for drug discovery.

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Palmer, R. K. (2007) The pharmacology and signaling of bitter, sweet, and umami taste sensing Mol. Interv. 7, 87– 98

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Depoortere, I. (2014) Taste receptors of the gut: emerging roles in health and disease Gut 63, 179– 190

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Kaji, I., Karaki, S. I., and Kuwahara, A. (2014) Taste Sensing in the Colon Curr. Pharm. Des. 20, 2766– 2774

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Taste Sensing in the Colon

Kaji, Izumi; Karaki, Shin-ichiro; Kuwahara, Atsukazu

Current Pharmaceutical Design (2014), 20 (16), 2766-2774CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)

The colonic lumen is continually exposed to many compds., including beneficial and harmful compds. that are produced by colonic microflora. The intestinal epithelia form a barrier between the internal and luminal (external) environments. Chem. receptors that sense the luminal environment are thought to play important roles as sensors and as modulators of epithelial cell functions. The recent mol. identification of various membrane receptor proteins has revealed the sensory role of intestinal epithelial cells. Nutrient sensing by these receptors in the small intestine is implicated in nutrient absorption and metab. However, little is known about the physiol. roles of chemosensors in the large intestine. Since 1980s, researchers have examd. the effects of short-chain fatty acids (SCFA), the primary products of commensal bacteria, on gut motility, secretion, and incretin release, for example. In this decade, the SCFA receptor genes and their expression were identified in the mammalian colon. Furthermore, many other chem. receptors, including taste and olfactory receptors have been found in colonic epithelial cells. These findings indicate that the large intestinal epithelia express chemosensors that detect the luminal contents, particularly bacterial metabolites, and induce the host defense systems and the modulation of systemic metab. via incretin release. In this review, we describe the local effects of chem. stimuli on the lumen assocd. with the expression pattern of sensory receptors. We propose that sensory receptors expressed in the colonic mucosa play important roles in luminal chemosensing to maintain homeostasis.

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Premkumar, L. S., Raisinghani, M., Pingle, S. C., Long, C., and Pimentel, F. (2005) Downregulation of transient receptor potential melastatin 8 by protein kinase C-mediated dephosphorylation J. Neurosci. 25, 11322– 11329

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Downregulation of transient receptor potential melastatin 8 by protein kinase C-mediated dephosphorylation

Premkumar Louis S; Raisinghani Manish; Pingle Sandeep C; Long Cheng; Pimentel Fatima

The Journal of neuroscience : the official journal of the Society for Neuroscience (2005), 25 (49), 11322-9 ISSN:.

Transient receptor potential melastatin 8 (TRPM8) and transient receptor potential vanilloid 1 (TRPV1) are ion channels that detect cold and hot sensations, respectively. Their activation depolarizes the peripheral nerve terminals resulting in action potentials that propagate to brain via the spinal cord. These receptors also play a significant role in synaptic transmission between dorsal root ganglion (DRG) and dorsal horn (DH) neurons. Here, we show that TRPM8 is functionally downregulated by activation of protein kinase C (PKC) resulting in inhibition of membrane currents and increases in intracellular Ca2+ compared with upregulation of TRPV1 in cloned and native receptors. Bradykinin significantly downregulates TRPM8 via activation of PKC in DRG neurons. Activation of TRPM8 or TRPV1 at first sensory synapse between DRG and DH neurons leads to a robust increase in frequency of spontaneous/miniature EPSCs. PKC activation blunts TRPM8- and facilitates TRPV1-mediated synaptic transmission. Significantly, downregulation is attributable to PKC-mediated dephosphorylation of TRPM8 that could be reversed by phosphatase inhibitors. These findings suggest that inflammatory thermal hyperalgesia mediated by TRPV1 may be further aggravated by downregulation of TRPM8, because the latter could mediate the much needed cool/soothing sensation.

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Tsuzuki, K., Xing, H., Ling, J., and Gu, J. G. (2004) Menthol-induced Ca2+ release from presynaptic Ca2+ stores potentiates sensory synaptic transmission J. Neurosci. 24, 762– 771

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Menthol-induced Ca2+ release from presynaptic Ca2+ stores potentiates sensory synaptic transmission

Tsuzuki, Kenzo; Xing, Hong; Ling, Jennifer; Gu, Jianguo G.

Journal of Neuroscience (2004), 24 (3), 762-771CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)

Menthol and many of its derivs. produce profound sensory and mental effects. The receptor for menthol has been cloned and named cold- and menthol-sensitive receptor-1 (CMR1) or transient receptor potential channel M8 (TRPM8) receptor. Using a dorsal root ganglion (DRG) and dorsal horn (DH) coculture system as a model for the first sensory synapse in the CNS, we studied menthol effects on sensory synaptic transmission and the underlying mechanisms. We found that menthol increased the frequency of miniature EPSCs (mEPSCs). The effects persisted under an extracellular Ca2+-free condition but were abolished by intracellular BAPTA and pretreatment with thapsigargin. Menthol-induced increases of mEPSC frequency were blocked by 2-aminoethoxydiphenylborane (2-APB) but not affected by the phospholipase C inhibitor U73122 or by the cADP receptor inhibitor 8-bromo-cADPR (8Br-cADPR). Double-patch recordings from DRG-DH pairs showed that menthol could potentiate evoked EPSCs (eEPSCs) and change the paired-pulse ratio of eEPSCs. A Ca2+ imaging study on DRG neurons demonstrated that menthol could directly release Ca2+ from intracellular Ca2+ stores. Menthol-induced Ca2+ release was abolished by 2-APB but not affected by U73122 or 8Br-cADPR. Taken together, our results indicate that menthol can act directly on presynaptic Ca2+ stores of sensory neurons to release Ca2+, resulting in a facilitation of glutamate release and a modulation of neuronal transmission at sensory synapses. Expression of TRPM8 receptor on presynaptic Ca2+ stores, a novel localization for this ligand-gated ion channel, is also strongly suggested.

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Tsavaler, L., Shapero, M. H., Morkowski, S., and Laus, R. (2001) Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins Cancer Res. 61, 3760– 3769
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Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins

Tsavaler, Larisa; Shapero, Michael H.; Morkowski, Stan; Laus, Reiner

Cancer Research (2001), 61 (9), 3760-3769CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)

The authors have identified and cloned a novel gene, trp-p8, by screening a prostate-specific subtracted cDNA library. The 5694-bp cDNA has a 3312-bp open reading frame, which codes for a 1104 amino acid putative protein with seven transmembrane domains. The predicted protein revealed significant homol. with the transient receptor potential (trp) family of Ca2+ channel proteins. Northern blot anal. indicated that trp-p8 expression within normal human tissues is mostly restricted to prostate epithelial cells. In situ hybridization anal. showed that trp-p8 mRNA expression was at moderate levels in normal prostate tissue and appears to be elevated in prostate cancer. Notably, trp-p8 mRNA was also expressed in a no. of nonprostatic primary tumors of breast, colon, lung, and skin origin, whereas transcripts encoding trp-p8 were hardly detected or not detected in the corresponding normal human tissues.

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Uhl, G. R., Walther, D., Behm, F. M., and Rose, J. E. (2011) Menthol preference among smokers: association with TRPA1 variants Nicotine Tob. Res. 13, 1311– 1315

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Menthol Preference Among Smokers: Association With TRPA1 Variants

Uhl, George R.; Walther, Donna; Behm, Frederique M.; Rose, Jed E.

Nicotine & Tobacco Research (2011), 13 (12), 1311-1315CODEN: NTREF6; ISSN:1462-2203. (Oxford University Press)

Introduction: Preference for smoking menthol cigarettes differs from individual to individual and population to population in ways that may provide higher levels of nicotine intake and contribute to smoking's morbidity and mortality. Menthol acts at sites that include the transient receptor potential (TRP) A1 channel that is expressed by nociceptors in the lung and airways, suggesting that individual and population differences in TRPA1 sequences might contribute to obsd. differences in menthol preference among smokers. Methods: We have thus sought assocn. between menthol preference and common variants in the TRPA1 gene in heavier and lighter European-American smokers. Smokers were recruited for studies of smoking cessation in North Carolina and of substance abuse genetics in Maryland. Results: A common TRPA1 haplotype is defined by 1 missense and 10 intronic single nucleotide polymorphisms that display significant (.006 < p < .05; χ2) assocn. with preference for mentholated cigarettes in heavy smokers (odds ratio ca. 1.3). There are smaller trends in the same direction in lighter smokers. Conclusions: This TRPA1 haplotype provides a novel biol. basis for individual differences in menthol preference and possibly for actions of other agents that act at TRPA1.

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Hans, M., Wilhelm, M., and Swandulla, D. (2012) Menthol suppresses nicotinic acetylcholine receptor functioning in sensory neurons via allosteric modulation Chem. Senses 37, 463– 469

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Menthol Suppresses Nicotinic Acetylcholine Receptor Functioning in Sensory Neurons via Allosteric Modulation

Hans, M.; Wilhelm, M.; Swandulla, D.

Chemical Senses (2012), 37 (5), 463-469CODEN: CHSED8; ISSN:0379-864X. (Oxford University Press)

In this study, we have investigated how the function of native and recombinant nicotinic acetylcholine receptors (nAChRs) is modulated by the monoterpenoid alc. from peppermint (-) menthol. In trigeminal neurons (TG), we found that nicotine (75 μM)-activated whole-cell currents through nAChRs were reversibly reduced by menthol in a concn.-dependent manner with an IC50 of 111 μM. To analyze the mechanism underlying menthol's action in more detail, we used single channel and whole-cell recordings from recombinant human α4β2 nAChR expressed in HEK tsA201 cells. Here, we found a shortening of channel open time and a prolongation of channel closed time, and an increase in single channel amplitude leading in summary to a redn. in single channel current. Furthermore, menthol did not affect nicotine's EC50 value for currents through recombinant human α4β2 nAChRs but caused a significant redn. in nicotine's efficacy. Taken together, these findings indicate that menthol is a neg. allosteric modulator of nAChRs.

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Willis, D. N., Liu, B., Ha, M. A., Jordt, S. E., and Morris, J. B. (2011) Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants FASEB J. 25, 4434– 4444

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Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants

Willis, Daniel N.; Liu, Boyi; Ha, Michael A.; Jordt, Sven-Eric; Morris, John B.

FASEB Journal (2011), 25 (12), 4434-4444, 10.1096/fj.11-188383CODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)

Menthol, the cooling agent in peppermint, is added to almost all com. available cigarettes. Menthol stimulates olfactory sensations, and interacts with transient receptor potential melastatin 8 (TRPM8) ion channels in cold-sensitive sensory neurons, and transient receptor potential ankyrin 1 (TRPA1), an irritant-sensing channel. It is highly controversial whether menthol in cigarette smoke exerts pharmacol. actions affecting smoking behavior. Using plethysmog., we investigated the effects of menthol on the respiratory sensory irritation response in mice elicited by smoke irritants (acrolein, acetic acid, and cyclohexanone). Menthol, at a concn. (16 ppm) lower than in smoke of mentholated cigarettes, immediately abolished the irritation response to acrolein, an agonist of TRPA1, as did eucalyptol (460 ppm), another TRPM8 agonist. Menthol's effects were reversed by a TRPM8 antagonist, AMTB. Menthol's effects were not specific to acrolein, as menthol also attenuated irritation responses to acetic acid, and cyclohexanone, an agonist of the capsaicin receptor, TRPV1. Menthol was efficiently absorbed in the respiratory tract, reaching local concns. sufficient for activation of sensory TRP channels. These expts. demonstrate that menthol and eucalyptol, through activation of TRPM8, act as potent counterirritants against a broad spectrum of smoke constituents. Through suppression of respiratory irritation, menthol may facilitate smoke inhalation and promote nicotine addiction and smoking-related morbidities.

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Leuenroth, S. J., Okuhara, D., Shotwell, J. D., Markowitz, G. S., Yu, Z., Somlo, S., and Crews, C. M. (2007) Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease Proc. Natl. Acad. Sci. U.S.A. 104, 4389– 4394

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Szallasi, A. and Blumberg, P. M. (1999) Vanilloid (Capsaicin) receptors and mechanisms Pharmacol. Rev. 51, 159– 212
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Vanilloid (capsaicin) receptors and mechanisms

Szallasi, Arpad; Blumberg, Peter M.

Pharmacological Reviews (1999), 51 (2), 159-211CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)

A review with 560 refs. Topics discussed include the targets and actions of capsaicin; direct evidence for a vanilloid (capsaicin) receptor (VR); anatomical localization and tissue specificity of VRs; evidence for multiple VRs; biochem. pharmacol. of VRs; requirements for ligand recognition by VRs; vanilloid mechanisms; diverse biol. actions of vanilloids; species-related differences in vanilloid actions; question on the existence of endogenous vanilloids; vanilloids in clin. practice; and the question on whether vanilloids are carcinogens, anticarcinogens or neither.

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Vennekens, R., Owsianik, G., and Nilius, B. (2008) Vanilloid transient receptor potential cation channels: an overview Curr. Pharm. Des. 14, 18– 31

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Vanilloid transient receptor potential cation channels: an overview

Vennekens, Rudi; Owsianik, Grzegorz; Nilius, Bernd

Current Pharmaceutical Design (2008), 14 (1), 18-31CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)

A review. The mammalian branch of the transient receptor potential (TRP) superfamily of cation channels consists of 28 members. They can be subdivided in six main subfamilies: the TRPC ('canonical'), TRPV ('vanilloid'), TRPM ('melastatin'), TRPP ('polycystin'), TRPML ('mucolipin'), and TRPA ('ankyrin') groups. The TRPV subfamily comprises channels that are critically involved in nociception and thermo-sensing (TRPV1, TRPV2, TRPV3, TRPV4) as well as highly Ca2+ selective channels involved in Ca2+ absorption/resorption in mammals (TRPV5, TRPV6). In this review we summarize fundamental physiol. properties of all TRPV members in the light of various cellular functions of these channels and their significance in the systemic context of the mammalian organism.

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Vriens, J., Nilius, B., and Vennekens, R. (2008) Herbal compounds and toxins modulating TRP channels Curr. Neuropharmacol. 6, 79– 96

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Herbal compounds and toxins modulating TRP channels

Vriens, Joris; Nilius, Bernd; Vennekens, Rudi

Current Neuropharmacology (2008), 6 (1), 79-96CODEN: CNUEAN; ISSN:1875-6190. (Bentham Science Publishers Ltd.)

A review. Although the benefits are sometimes obvious, traditional or herbal medicine is regarded with skepticism, because the mechanism through which plant compds. exert their powers are largely elusive. Recent studies have shown however that many of these plant compds. interact with specific ion channels and thereby modulate the sensing mechanism of the human body. Esp. members of the Transient Receptor Potential (TRP) channels have drawn large attention lately as the receptors for plant-derived compds. such as capsaicin and menthol. TRP channels constitute a large and diverse family of channel proteins that can serve as versatile sensors that allow individual cells and entire organisms to detect changes in their environment. For this family, a striking no. of empirical views have turned into mechanism-based actions of natural compds. In this review we will give an overview of herbal compds. and toxins, which modulate TRP channels.

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Hellwig, N., Albrecht, N., Harteneck, C., Schultz, G., and Schaefer, M. (2005) Homo- and heteromeric assembly of TRPV channel subunits J. Cell Sci. 118, 917– 928

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Homo- and heteromeric assembly of TRPV channel subunits

Hellwig, Nicole; Albrecht, Nadine; Harteneck, Christian; Schultz, Guenter; Schaefer, Michael

Journal of Cell Science (2005), 118 (5), 917-928CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)

The vanilloid receptor-related TRP channels (TRPV1-6) mediate thermosensation, pain perception and epithelial Ca2+ entry. As the specificity of TRPV channel heteromerization and determinants governing the assembly of TRPV subunits were largely elusive, we investigated the TRPV homo- and heteromultimerization. To analyze the assembly of TRPV subunits in living cells, we generated fluorescent fusion proteins or FLAG-tagged TRPV channel subunits. The interaction between TRPV subunits was assessed by anal. of the subcellular colocalization, fluorescence resonance energy transfer and coimmunopptn. Our results demonstrate that TRPV channel subunits do not combine arbitrarily. With the exception of TRPV5 and TRPV6, TRPV channel subunits preferentially assemble into homomeric complexes. Truncation of TRPV1, expression of cytosolic termini of TRPV1 or TRPV4 and construction of chimeric TRPV channel subunits revealed that the specificity and the affinity of the subunit interaction is synergistically provided by interaction modules located in the transmembrane domains and in the cytosolic termini. The relative contribution of intramolecularly linked interaction modules presumably controls the overall affinity and the specificity of TRPV channel assembly.

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Tominaga, M., Caterina, M. J., Malmberg, A. B., Rosen, T. A., Gilbert, H., Skinner, K., Raumann, B. E., Basbaum, A. I., and Julius, D. (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli Neuron 21, 531– 543

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The cloned capsaicin receptor integrates multiple pain-producing stimuli

Tominaga, Makoto; Caterina, Michael J.; Malmberg, Annika B.; Rosen, Tobias A.; Gilbert, Heather; Skinner, Kate; Raumann, Brigitte; Basbaum, Allan I.; Julius, David

Neuron (1998), 21 (3), 531-543CODEN: NERNET; ISSN:0896-6273. (Cell Press)

Capsaicin, the main pungent ingredient in "hot" chili peppers, elicits burning pain by activating specific (vanilloid) receptors on sensory nerve endings. The cloned vanilloid receptor (VR1) is a cation channel that is also activated by noxious heat. Here, anal. of heat-evoked single channel currents in excised membrane patches suggests that heat gates VR1 directly. We also show that protons decrease the temp. threshold for VR1 activation such that even moderately acidic conditions (pH≤5.9) activate VR1 at room temp. VR1 can therefore be viewed as a mol. integrator of chem. and phys. stimuli that elicit pain. Immunocytochem. anal. indicates that the receptor is located in a neurochem. heterogeneous population of small diam. primary afferent fibers. A role for VR1 in injury-induced hypersensitivity at the level of the sensory neuron is presented.

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Nakatsuka, T., Furue, H., Yoshimura, M., and Gu, J. G. (2002) Activation of central terminal vanilloid receptor-1 receptors and alpha beta-methylene-ATP-sensitive P2X receptors reveals a converged synaptic activity onto the deep dorsal horn neurons of the spinal cord J. Neurosci. 22, 1228– 1237

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Activation of central terminal vanilloid receptor-1 receptors and αβ-methylene-ATP-sensitive P2X receptors reveals a converged synaptic activity onto the deep dorsal horn neurons of the spinal cord

Nakatsuka, Terumasa; Furue, Hidemasa; Yoshimura, Megumu; Gu, Jianguo G.

Journal of Neuroscience (2002), 22 (4), 1228-1237CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)

The excitatory and inhibitory circuits connecting to lamina V neurons after the activation of afferent central terminal vanilloid receptor-1 (VR1) receptors and P2X receptors were examd. using a spinal cord slice prepn. and patch-clamp recordings from spinal cord dorsal horn neurons. The single neurons in lamina V often received excitatory inputs from two chem. defined afferent pathways, one of which was polysynaptic from capsaicin-sensitive afferent terminals. In this pathway, the capsaicin-sensitive afferent input first activated interneurons in superficial laminas, and then the excitatory activity was transmitted onto lamina V neurons. The second excitatory input was monosynaptic from αβm-ATP-sensitive/capsaicin-insensitive afferent terminals. Both capsaicin-sensitive and αβm-ATP-sensitive/capsaicin-insensitive pathways also recruited polysynaptic inhibitory inputs to lamina V neurons. The simultaneous activation of both capsaicin-sensitive afferent pathways and αβm-ATP-sensitive/capsaicin-insensitive pathways could generate a temporal summation of excitatory inputs onto single lamina V neurons. These convergent pathways may provide a mechanism of sensory integration for two chem. defined sensory inputs and may have implications in different sensory states.

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Baccei, M. L., Bardoni, R., and Fitzgerald, M. (2003) Development of nociceptive synaptic inputs to the neonatal rat dorsal horn: glutamate release by capsaicin and menthol J. Physiol. 549, 231– 242

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Development of nociceptive synaptic inputs to the neonatal rat dorsal horn: Glutamate release by capsaicin and menthol

Baccei, Mark L.; Bardoni, Rita; Fitzgerald, Maria

Journal of Physiology (Cambridge, United Kingdom) (2003), 549 (1), 231-242CODEN: JPHYA7; ISSN:0022-3751. (Cambridge University Press)

To study the postnatal development of nociceptive synaptic inputs in the superficial dorsal horn of the neonatal rat spinal cord, we examd. the effect of capsaicin and menthol on glutamatergic mEPSCs in postnatal day (P) 0-1, P5-6 and P9-11 slices of spinal cord. Capsaicin (100 nM to 2 μM) increased the mEPSC frequency in a concn.-dependent manner at all ages tested, with a significant enhancement of the effect between P5 and P10. This effect was sensitive to vanilloid receptor (VR) antagonists. The elevation in mEPSC frequency occurred at concns. of capsaicin (100 nM) that did not alter the distribution of mEPSC amplitudes and was abolished by a dorsal rhizotomy, demonstrating that capsaicin acts via presynaptic VR1 receptors localized on primary afferents. Menthol significantly increased the mEPSC frequency with a similar developmental pattern to capsaicin without consistently affecting mEPSC amplitude. The increase in mEPSC frequency following capsaicin did not depend on transmembrane calcium influx since it persisted in zero [Ca2+]o. The facilitation of spontaneous glutamate release by capsaicin was sufficient to evoke action potentials in neonatal dorsal horn neurons but was accompanied by a block of EPSCs evoked by elec. stimulation of the dorsal root. These results indicate that VR1-expressing nociceptive primary afferents form functional synaptic connections in the superficial dorsal horn from birth and that activation of the VR1 receptor increases spontaneous glutamate release via an undetd. mechanism. In addn., the data suggest that immature primary afferents express functional menthol receptors that are capable of modulating transmitter release. These results have important functional implications for infant pain processing.

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Kim, Y. H., Back, S. K., Davies, A. J., Jeong, H., Jo, H. J., Chung, G., Na, H. S., Bae, Y. C., Kim, S. J., Kim, J. S., Jung, S. J., and Oh, S. B. (2012) TRPV1 in GABAergic interneurons mediates neuropathic mechanical allodynia and disinhibition of the nociceptive circuitry in the spinal cord Neuron 74, 640– 647

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Doyle, M. W., Bailey, T. W., Jin, Y. H., and Andresen, M. C. (2002) Vanilloid receptors presynaptically modulate cranial visceral afferent synaptic transmission in nucleus tractus solitarius J. Neurosci. 22, 8222– 8229

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Vanilloid receptors presynaptically modulate cranial visceral afferent synaptic transmission in nucleus tractus solitarius

Doyle, Mark W.; Bailey, Timothy W.; Jin, Young-Ho; Andresen, Michael C.

Journal of Neuroscience (2002), 22 (18), 8222-8229CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)

Though the central terminals of cranial visceral afferents express vanilloid receptor 1 (VR1), little is known about their functional properties at this first synapse within the nucleus tractus solitarius (NTS). Here, we examd. whether VR1 modulates afferent synaptic transmission. In horizontal brainstem slices, solitary tract (ST) activation evoked EPSCs. Monosynaptic EPSCs had low synaptic jitter (SD of latency to successive shocks) averaging 84.03+3.74 μsec (n = 72) and were completely blocked by the non-NMDA antagonist 2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline (NBQX). Sustained exposure to the VR1 agonist capsaicin (CAP; 100 nM) blocked ST EPSCs (CAP-sensitive) in some neurons but not others (CAP-resistant). CAP-sensitive EPSCs had longer latencies than CAP-resistant EPSCs (4.65±0.27 ms, n = 48 vs. 3.53±0.28 ms, n = 24, resp.; p = 0.011), but they had similar jitter. CAP evoked two transient responses in CAP-sensitive neurons: a rapidly developing inward current (Icap) (108.1±22.9 pA; n = 21) and an increase in spontaneous synaptic activity. After 3-5 min in CAP, Icap subsided and ST EPSCs disappeared. NBQX completely blocked Icap. The VR1 antagonist capsazepine (10-20 μM) attenuated CAP responses. Anatomically, second-order NTS neurons were identified by 4-(4-dihexadecylamino)styryl-N-methylpyridinium iodide transported from the cervical aortic depressor nerve (ADN) to stain central terminals. Neurons with fluorescent ADN contacts had CAP-sensitive EPSCs (n = 5) with latencies and jitter similar to those of unlabeled monosynaptic neurons. Thus, consistent with presynaptic VR1 localization, CAP selectively activates a subset of ST axons to release glutamate that acts on non-NMDA receptors. Because the CAP sensitivity of cranial afferents is exclusively assocd. with unmyelinated axons, VR1 identifies C-fiber afferent pathways within the brainstem.

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Marinelli, S., Di Marzo, V., Berretta, N., Matias, I., Maccarrone, M., Bernardi, G., and Mercuri, N. B. (2003) Presynaptic facilitation of glutamatergic synapses to dopaminergic neurons of the rat substantia nigra by endogenous stimulation of vanilloid receptors J. Neurosci. 23, 3136– 3144

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Presynaptic facilitation of glutamatergic synapses to dopaminergic neurons of the rat substantia nigra by endogenous stimulation of vanilloid receptors

Marinelli, Silvia; Di Marzo, Vincenzo; Berretta, Nicola; Matias, Isabel; Maccarrone, Mauro; Bernardi, Giorgio; Mercuri, Nicola B.

Journal of Neuroscience (2003), 23 (8), 3136-3144CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)

Growing evidence regarding the function of vanilloid receptor-1 (VR1) in the brain suggests potential central roles of this receptor, previously described to occur primarily in peripheral sensory neurons. In the present study, the authors used electrophysiol. and biochem. techniques to investigate the function and the endogenous stimulation of VR1 in dopaminergic neurons of the substantia nigra pars compacta (SNc). The VR1 agonist capsaicin increased the frequency of both TTX-sensitive and -insensitive spontaneous EPSCs (sEPSCs) without affecting their amplitude, suggesting a presynaptic site of action. In contrast, no effect was detected with regard to GABAergic transmission. No increase in sEPSC frequency was obsd. in the presence of cadmium chloride, while the voltage-dependent calcium channel antagonist ω-conotoxin MVIIC did not prevent capsaicin action. The VR1 antagonists capsazepine and iodoresiniferatoxin (IRTX) blocked the effects of capsaicin. Importantly, IRTX per se reduced sEPSC frequency, suggesting a tonic activity of VR1. The endogenous VR1 agonist anandamide (AEA) produced an IRTX-sensitive increase in the frequency of sEPSCs on dopaminergic neurons that was more pronounced when protein kinase A had been activated. Furthermore, mass spectrometric analyses and binding expts. revealed high levels of endogenous AEA and specific binding of AEA to VR1 receptors in the SNc. These data suggest a tonic facilitation of glutamate release exerted by VR1 in the SNc through a stimulation of VR1 by endovanilloids, including anandamide. The increase in sEPSC frequency by VR1 onto midbrain dopaminergic neurons suggests the involvement of these receptors in motor and cognitive functions involving the dopaminergic system.

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Marinelli, S., Vaughan, C. W., Christie, M. J., and Connor, M. (2002) Capsaicin activation of glutamatergic synaptic transmission in the rat locus coeruleus in vitro J. Physiol. 543, 531– 540

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Capsaicin activation of glutamatergic synaptic transmission in the rat locus coeruleus in vitro

Marinelli, Silvia; Vaughan, Christopher W.; Christie, MacDonald J.; Connor, Mark

Journal of Physiology (Cambridge, United Kingdom) (2002), 543 (2), 531-540CODEN: JPHYA7; ISSN:0022-3751. (Cambridge University Press)

The vanilloid receptor protein (VR1) is a well-characterized integrator of noxious stimuli in peripheral sensory neurons. There is evidence for the presence of VR1 in the central nervous system, but little information as to its role there. In this study we have examd. the actions of agonists for VR1 receptors in the rat locus coeruleus (LC), using whole-cell patch-clamp recordings from acutely isolated neurons and neurons in slices. Superfusion with capsaicin resulted in a concn.-dependent increase in the frequency of isolated miniature excitatory postsynaptic currents (mEPSCs) in LC neurons. The mean amplitude of the mEPSCs was not affected by capsaicin. The effects of capsaicin (1 μM) were abolished by the VR1 receptor antagonists capsazepine (10 μM) and iodoresiniferatoxin (300 nM). Removal of extracellular Ca2+ abolished the capsaicin-induced increase in frequency of mEPSCs. Capsaicin superfusion had no consistent effects on evoked excitatory postsynaptic currents. Capsaicin superfusion also resulted in the release of an adrenoceptor agonist in the LC but did not affect the membrane currents of acutely isolated LC neurons. These data demonstrate that the VR1 receptor appears to be located presynaptically on afferents to the LC, and that activation of VR1 may serve to potentiate the release of glutamate and adrenaline/noradrenaline in this brain region.

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Gibson, H. E., Edwards, J. G., Page, R. S., Van Hook, M. J., and Kauer, J. A. (2008) TRPV1 channels mediate long-term depression at synapses on hippocampal interneurons Neuron 57, 746– 759

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Grueter, B. A., Brasnjo, G., and Malenka, R. C. (2010) Postsynaptic TRPV1 triggers cell type-specific long-term depression in the nucleus accumbens Nat. Neurosci. 13, 1519– 1525

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Postsynaptic TRPV1 triggers cell type-specific long-term depression in the nucleus accumbens

Grueter, Brad A.; Brasnjo, Gabor; Malenka, Robert C.

Nature Neuroscience (2010), 13 (12), 1519-1525CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)

Synaptic modifications in the nucleus accumbens (NAc) are important for adaptive and pathol. reward-dependent learning. Medium spiny neurons (MSNs), the major cell type in the NAc, participate in two parallel circuits that subserve distinct behavioral functions, yet little is known about differences in their electrophysiol. and synaptic properties. Using bacterial artificial chromosome transgenic mice, we found that synaptic activation of group I metabotropic glutamate receptors in NAc MSNs in the indirect, but not direct, pathway led to the prodn. of endocannabinoids, which activated presynaptic CB1 receptors to trigger endocannabinoid-mediated long-term depression (eCB-LTD) as well as postsynaptic transient receptor potential vanilloid 1 (TRPV1) channels to trigger a form of LTD resulting from endocytosis of AMPA receptors. These results reveal a previously unknown action of TRPV1 channels and indicate that the postsynaptic generation of endocannabinoids can modulate synaptic strength in a cell type-specific fashion by activating distinct pre- and postsynaptic targets.

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Premkumar, L. S. and Ahern, G. P. (2000) Induction of vanilloid receptor channel activity by protein kinase C Nature 408, 985– 990

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Caterina, M. J. and Julius, D. (2001) The vanilloid receptor: a molecular gateway to the pain pathway Annu. Rev. Neurosci. 24, 487– 517

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The vanilloid receptor: a molecular gateway to the pain pathway

Caterina, Michael J.; Julius, David

Annual Review of Neuroscience (2001), 24 (), 487-517CODEN: ARNSD5; ISSN:0147-006X. (Annual Reviews Inc.)

A review with 163 refs. The detection of painful stimuli occurs primarily at the peripheral terminals of specialized sensory neurons called nociceptors. These small-diam. neurons transduce signals of a chem., mech., or thermal nature into action potentials and transmit this information to the central nervous system, ultimately eliciting a perception of pain or discomfort. Little is known about the proteins that detect noxious stimuli, esp. those of a phys. nature. Here, the authors review recent advances in the mol. characterization of the capsaicin (vanilloid) receptor, an excitatory ion channel expressed by nociceptors, which contributes to the detection and integration of pain-producing chem. and thermal stimuli. The anal. of vanilloid receptor gene knockout mice confirms the involvement of this channel in pain sensation, as well as in hypersensitivity to noxious stimuli following tissue injury. At the same time, these studies demonstrate the existence of redundant mechanisms for the sensation of heat-evoked pain.

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Minke, B. and Cook, B. (2002) TRP channel proteins and signal transduction Physiol. Rev. 82, 429– 472

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Clapham, D. E. (2003) TRP channels as cellular sensors Nature 426, 517– 524

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TRP channels as cellular sensors

Clapham, David E.

Nature (London, United Kingdom) (2003), 426 (6966), 517-524CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

A review. TRP channels are the vanguard of our sensory systems, responding to temp., touch, pain, osmolarity, pheromones, taste and other stimuli. But their role is much broader than classical sensory transduction. They are an ancient sensory app. for the cell, not just the multicellular organism, and they have been adapted to respond to all manner of stimuli, from both within and outside the cell.

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Premkumar, L. S. and Bishnoi, M. (2011) Disease-related changes in TRPV1 expression and its implications for drug development Curr. Top. Med. Chem. 11, 2192– 2209

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Disease-related changes in TRPV1 expression and its implications for drug development

Premkumar, Louis S.; Bishnoi, Mahendra

Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2011), 11 (17), 2192-2209CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)

A review. The transient receptor potential vanilloid 1(TRPV1) channel has been a topic of great interest, since its discovery in 1997. It is a homotetrameric non-selective cation channel predominantly expressed in a population of sensory neurons and its involvement in different modalities of pain has been extensively studied. However, TRPV1 has also been shown to be expressed in non-sensory neurons and non-neuronal cells. TRPV1 is considered as a potential target for drug development, based on its tissue distribution and its role in physiol. functions. Here, we summarize the evidence for disease-related alterations in TRPV1 expression and function and review the current perspectives for the therapeutic potential of TRPV1 agonists and antagonists in the treatment of a wide range of diseases.

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Julius, D. (2013) TRP channels and pain Annu. Rev. Cell Dev. Biol. 29, 355– 384

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Mezey, E., Toth, Z. E., Cortright, D. N., Arzubi, M. K., Krause, J. E., Elde, R., Guo, A., Blumberg, P. M., and Szallasi, A. (2000) Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human Proc. Natl. Acad. Sci. U.S.A. 97, 3655– 3660

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Huang, S. M., Bisogno, T., Trevisani, M., Al-Hayani, A., De Petrocellis, L., Fezza, F., Tognetto, M., Petros, T. J., Krey, J. F., Chu, C. J., Miller, J. D., Davies, S. N., Geppetti, P., Walker, J. M., and Di Marzo, V. (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors Proc. Natl. Acad. Sci. U.S.A. 99, 8400– 8405

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Mishra, S. K., Tisel, S. M., Orestes, P., Bhangoo, S. K., and Hoon, M. A. (2011) TRPV1-lineage neurons are required for thermal sensation EMBO J. 30, 582– 593

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Cavanaugh, D. J., Chesler, A. T., Braz, J. M., Shah, N. M., Julius, D., and Basbaum, A. I. (2011) Restriction of transient receptor potential vanilloid-1 to the peptidergic subset of primary afferent neurons follows its developmental downregulation in nonpeptidergic neurons J. Neurosci. 31, 10119– 10127

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Restriction of transient receptor potential vanilloid-1 to the peptidergic subset of primary afferent neurons follows its developmental downregulation in nonpeptidergic neurons

Cavanaugh, Daniel J.; Chesler, Alexander T.; Braz, Joao M.; Shah, Nirao M.; Julius, David; Basbaum, Allan I.

Journal of Neuroscience (2011), 31 (28), 10119-10127CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)

Primary afferent "pain" fibers (nociceptors) are divided into subclasses based on distinct mol. and anatomical features, and these classes mediate noxious modality-specific contributions to behaviors evoked by painful stimuli. Whether the heat and capsaicin receptor transient receptor potential vanilloid-1 (TRPV1) is expressed heterogeneously across several sensory populations, or is selectively expressed by a unique nociceptor subclass, however, is unclear. Here we used two lines of Trpv1 reporter mice to investigate the primary afferent expression of TRPV1, both during development and in the adult. We demonstrate, using Cre-induced lineage tracing, that during development TRPV1 is transiently expressed in a wide range of dorsal root ganglion neurons, and that its expression is gradually refined, such that TRPV1 transcripts become restricted to a specific subset of peptidergic sensory neurons. Finally, the remarkable sensitivity that is characteristic of these reporter mice revealed an innervation of central and peripheral targets by TRPV1+ primary afferents in the adult that is considerably more extensive than has previously been appreciated.

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Lundberg, J. M., Martling, C. R., and Saria, A. (1983) Substance P and capsaicin-induced contraction of human bronchi Acta Physiol. Scand. 119, 49– 53

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Mitchell, J. A., Williams, F. M., Williams, T. J., and Larkin, S. W. (1997) Role of nitric oxide in the dilator actions of capsaicin-sensitive nerves in the rabbit coronary circulation Neuropeptides 31, 333– 338

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Zygmunt, P. M., Petersson, J., Andersson, D. A., Chuang, H., Sorgard, M., Di Marzo, V., Julius, D., Hogestatt, E. D., and Wang, Y. (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide Nature 400, 452– 457

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Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide

Zygmunt, Peter M.; Petersson, Jesper; Andersson, David A.; Chuang, Huai-Hu; Sorgard, Morten; Di Marzo, Vincenzo; Julius, David; Hogestatt, Edward D.

Nature (London) (1999), 400 (6743), 452-457CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)

The endogenous cannabinoid receptor agonist anandamide is a powerful vasodilator of isolated vascular prepns., but its mechanism of action is unclear. Here we show that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP). The selective CGRP-receptor antagonist 8-37 CGRP, but not the cannabinoid CB1 receptor blocker SR141716A, inhibited the vasodilator effect of anandamide. Other endogenous (2-arachidonylglycerol, palmitylethanolamide) and synthetic (HU 210, WIN 55,212-2, CP 55,940) CB1 and CB2 receptor agonists could not mimic the action of anandamide. The selective vanilloid receptor antagonist capsazepine inhibited anandamide-induced vasodilation and release of CGRP. In patch-clamp expts. on cells expressing the cloned vanilloid receptor (VR1), anandamide induced a capsazepine-sensitive current in whole cells and isolated membrane patches. Our results indicate that anandamide induces vasodilation by activating vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another mol. target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.

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Birder, L. A., Nakamura, Y., Kiss, S., Nealen, M. L., Barrick, S., Kanai, A. J., Wang, E., Ruiz, G., De Groat, W. C., Apodaca, G., Watkins, S., and Caterina, M. J. (2002) Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1 Nat. Neurosci. 5, 856– 860

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Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1

Birder, L. A.; Nakamura, Y.; Kiss, S.; Nealen, M. L.; Barrick, S.; Kanai, A. J.; Wang, E.; Ruiz, G.; de Groat, W. C.; Apodaca, G.; Watkins, S.; Caterina, M. J.

Nature Neuroscience (2002), 5 (9), 856-860CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)

In the urinary bladder, the capsaicin-gated ion channel TRPV1 is expressed both within afferent nerve terminals and within the epithelial cells that line the bladder lumen. To det. the significance of this expression pattern, we analyzed bladder function in mice lacking TRPV1. Compared with wild-type littermates, trpv1-/- mice had a higher frequency of low-amplitude, non-voiding bladder contractions. This alteration was accompanied by redns. in both spinal cord signaling and reflex voiding during bladder filling (under anesthesia). In vitro, stretch-evoked ATP release and membrane capacitance changes were diminished in bladders excised from trpv1-/- mice, as was hypoosmolality-evoked ATP release from cultured trpv1-/- urothelial cells. These findings indicate that TRPV1 participates in normal bladder function and is essential for normal mech. evoked purinergic signaling by the urothelium.

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Cruz, F. and Dinis, P. (2007) Resiniferatoxin and botulinum toxin type A for treatment of lower urinary tract symptoms Neurourol. Urodyn. 26, 920– 927

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Resiniferation and botulinum toxin type A for treatment of lower urinary tract symptoms

Cruz, Francisco; Dinis, Paulo

Neurourology and Urodynamics (2007), 26 (6, Suppl.), 920-927CODEN: NEUREM; ISSN:0733-2467. (Wiley-Liss, Inc.)

A review. Resiniferatoxin (RTX) and botulinum toxin subtype A (BTX-A) are increasingly viewed as potential treatments for lower urinary tract symptoms (LUTS) refractory to conventional therapy. RTX, a capsaicin analog devoid of severe pungent properties, acts by desensitizing the transient receptor potential vanilloid type 1 (TRPV1) receptor and inactivating C-fibers. BTX-A cleaves sol. N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in afferent and efferent nerve endings, therefore impeding the fusion of synaptic vesicles with the neuronal membrane necessary for the release of neurotransmitters. In patients with neurogenic and idiopathic detrusor overactivity, RTX and BTX-A have been shown to increase the vol. to first detrusor contraction, increase bladder capacity, and improve urinary incontinence and quality of life. Recent data also suggest a role for these neurotoxins in treating urgency, the primary symptom in overactive bladder (OAB) syndrome. Furthermore, exptl. data strongly support the use of both neurotoxins in the treatment of pain and frequency in patients with interstitial cystitis/painful bladder syndrome (IC/PBS), although the results from available clin. trials for this use are still inconclusive. In spite of promising results overall, it should be made clear that the administration of these neurotoxins is still considered an exptl. procedure and that more clin. studies are necessary before a license for their use will be issued by health authorities.

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Varga, A., Nemeth, J., Szabo, A., McDougall, J. J., Zhang, C., Elekes, K., Pinter, E., Szolcsanyi, J., and Helyes, Z. (2005) Effects of the novel TRPV1 receptor antagonist SB366791 in vitro and in vivo in the rat Neurosci. Lett. 385, 137– 142

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97
Gavva, N. R. (2008) Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV1 Trends Pharmacol. Sci. 29, 550– 557

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Lehto, S. G., Tamir, R., Deng, H., Klionsky, L., Kuang, R., Le, A., Lee, D., Louis, J. C., Magal, E., Manning, B. H., Rubino, J., Surapaneni, S., Tamayo, N., Wang, T., Wang, J., Wang, J., Wang, W., Youngblood, B., Zhang, M., Zhu, D., Norman, M. H., and Gavva, N. R. (2008) Antihyperalgesic effects of (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluorom ethyl)phenyl)-acrylamide (AMG8562), a novel transient receptor potential vanilloid type 1 modulator that does not cause hyperthermia in rats J. Pharmacol. Exp. Ther. 326, 218– 229

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Antihyperalgesic effects of (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)acrylamide (AMG8562), a novel transient receptor potential vanilloid type 1 modulator that does not cause hyperthermia in rats

Lehto, Sonya G.; Tamir, Rami; Deng, Hong; Klionsky, Lana; Kuang, Rongzhen; Le, April; Lee, Doo; Louis, Jean-Claude; Magal, Ella; Manning, Barton H.; Rubino, John; Surapaneni, Sekhar; Tamayo, Nuria; Wang, Tingrong; Wang, Judy; Wang, Jue; Wang, Weiya; Youngblood, Brad; Zhang, Maosheng; Zhu, Dawn; Norman, Mark H.; Gavva, Narender R.

Journal of Pharmacology and Experimental Therapeutics (2008), 326 (1), 218-229CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)

Antagonists of the vanilloid receptor TRPV1 (transient receptor potential vanilloid type 1) have been reported to produce antihyperalgesic effects in animal models of pain. These antagonists, however, also caused concomitant hyperthermia in rodents, dogs, monkeys, and humans. Antagonist-induced hyperthermia was not obsd. in TRPV1 knockout mice, suggesting that the hyperthermic effect is exclusively mediated through TRPV1. Since antagonist-induced hyperthermia is considered a hurdle for developing TRPV1 antagonists as therapeutics, we investigated the possibility of eliminating hyperthermia while maintaining antihyperalgesia. Here, we report four potent and selective TRPV1 modulators with unique in vitro pharmacol. profiles (profiles A through D) and their resp. effects on body temp. We found that profile C modulator, (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)acrylamide (AMG8562), blocks capsaicin activation of TRPV1, does not affect heat activation of TRPV1, potentiates pH 5 activation of TRPV1 in vitro, and does not cause hyperthermia in vivo in rats. We further profiled AMG8562 in an on-target (agonist) challenge model, rodent pain models, and tested for its side effects. We show that AMG8562 significantly blocks capsaicin-induced flinching behavior, produces statistically significant efficacy in complete Freund's adjuvant- and skin incision-induced thermal hyperalgesia, and acetic acid-induced writhing models, with no profound effects on locomotor activity. Based on the data shown here, we conclude that it is feasible to modulate TRPV1 in a manner that does not cause hyperthermia while maintaining efficacy in rodent pain models.

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Pabbidi, R. M., Yu, S. Q., Peng, S., Khardori, R., Pauza, M. E., and Premkumar, L. S. (2008) Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity Mol. Pain 4, 9

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Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity

Pabbidi Reddy M; Yu Shuang-Quan; Peng Siying; Khardori Romesh; Pauza Mary E; Premkumar Louis S

Molecular pain (2008), 4 (), 9 ISSN:.

A common complication associated with diabetes is painful or painless diabetic peripheral neuropathy (DPN). The mechanisms and determinants responsible for these peripheral neuropathies are poorly understood. Using both streptozotocin (STZ)-induced and transgene-mediated murine models of type 1 diabetes (T1D), we demonstrate that Transient Receptor Potential Vanilloid 1 (TRPV1) expression varies with the neuropathic phenotype. We have found that both STZ- and transgene-mediated T1D are associated with two distinct phases of thermal pain sensitivity that parallel changes in TRPV1 as determined by paw withdrawal latency (PWL). An early phase of hyperalgesia and a late phase of hypoalgesia are evident. TRPV1-mediated whole cell currents are larger and smaller in dorsal root ganglion (DRG) neurons collected from hyperalgesic and hypoalgesic mice. Resiniferatoxin (RTX) binding, a measure of TRPV1 expression is increased and decreased in DRG and paw skin of hyperalgesic and hypoalgesic mice, respectively. Immunohistochemical labeling of spinal cord lamina I and II, dorsal root ganglion (DRG), and paw skin from hyperalgesic and hypoalgesic mice reveal increased and decreased TRPV1 expression, respectively. A role for TRPV1 in thermal DPN is further suggested by the failure of STZ treatment to influence thermal nociception in TRPV1 deficient mice. These findings demonstrate that altered TRPV1 expression and function contribute to diabetes-induced changes in thermal perception.

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Van Buren, J. J., Bhat, S., Rotello, R., Pauza, M. E., and Premkumar, L. S. (2005) Sensitization and translocation of TRPV1 by insulin and IGF-I Mol. Pain 1, 17

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Sensitization and translocation of TRPV1 by insulin and IGF-I

Van Buren Jeremy J; Bhat Satyanarayan; Rotello Rebecca; Pauza Mary E; Premkumar Louis S

Molecular pain (2005), 1 (), 17 ISSN:.

Insulin and insulin-like growth factors (IGFs) maintain vital neuronal functions. Absolute or functional deficiencies of insulin or IGF-I may contribute to neuronal and vascular complications associated with diabetes. Vanilloid receptor 1 (also called TRPV1) is an ion channel that mediates inflammatory thermal nociception and is present on sensory neurons. Here we demonstrate that both insulin and IGF-I enhance TRPV1-mediated membrane currents in heterologous expression systems and cultured dorsal root ganglion neurons. Enhancement of membrane current results from both increased sensitivity of the receptor and translocation of TRPV1 from cytosol to plasma membrane. Receptor tyrosine kinases trigger a signaling cascade leading to activation of phosphatidylinositol 3-kinase (PI(3)K) and protein kinase C (PKC)-mediated phosphorylation of TRPV1, which is found to be essential for the potentiation. These findings establish a link between the insulin family of trophic factors and vanilloid receptors.

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Bishnoi, M., Bosgraaf, C. A., Abooj, M., Zhong, L., and Premkumar, L. S. (2011) Streptozotocin-induced early thermal hyperalgesia is independent of glycemic state of rats: role of transient receptor potential vanilloid 1(TRPV1) and inflammatory mediators Mol. Pain 7, 52

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Streptozotocin-induced early thermal hyperalgesia is independent of glycemic state of rats: role of transient receptor potential vanilloid 1(TRPV1) and inflammatory mediators

Bishnoi Mahendra; Bosgraaf Christine A; Abooj Mruvil; Zhong Linlin; Premkumar Louis S

Molecular pain (2011), 7 (), 52 ISSN:.

BACKGROUND: Streptozotocin (STZ) is used as a common tool to induce diabetes and to study diabetes-induced complications including diabetic peripheral neuropathy (DPN). Previously, we have reported that STZ induces a direct effect on neurons through expression and function of the Transient receptor potential vanilloid 1 (TRPV1) channel in sensory neurons resulting in thermal hyperalgesia, even in non-diabetic STZ-treated mice. In the present study, we investigated the role of expression and function of TRPV1 in the central sensory nerve terminals in the spinal cord in STZ-induced hyperalgesia in rats. RESULTS: We found that a proportion of STZ-treated rats were normoglycemic but still exhibited thermal hyperalgesia and mechanical allodynia. Immunohistochemical data show that STZ treatment, irrespective of glycemic state of the animal, caused microglial activation and increased expression of TRPV1 in spinal dorsal horn. Further, there was a significant increase in the levels of pro-inflammatory mediators (IL-1β, IL-6 and TNF-α) in spinal cord tissue, irrespective of the glycemic state. Capsaicin-stimulated release of calcitonin gene related peptide (CGRP) was significantly higher in the spinal cord of STZ-treated animals. Intrathecal administration of resiniferatoxin (RTX), a potent TRPV1 agonist, significantly attenuated STZ-induced thermal hyperalgesia, but not mechanical allodynia. RTX treatment also prevented the increase in TRPV1-mediated neuropeptide release in the spinal cord tissue. CONCLUSIONS: From these results, it is concluded that TRPV1 is an integral component of initiating and maintaining inflammatory thermal hyperalgesia, which can be alleviated by intrathecal administration of RTX. Further, the results suggest that enhanced expression and inflammation-induced sensitization of TRPV1 at the spinal cord may play a role in central sensitization in STZ-induced neuropathy.

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Akiba, Y., Kato, S., Katsube, K., Nakamura, M., Takeuchi, K., Ishii, H., and Hibi, T. (2004) Transient receptor potential vanilloid subfamily 1 expressed in pancreatic islet beta cells modulates insulin secretion in rats Biochem. Biophys. Res. Commun. 321, 219– 225

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103
Razavi, R., Chan, Y., Afifiyan, F. N., Liu, X. J., Wan, X., Yantha, J., Tsui, H., Tang, L., Tsai, S., Santamaria, P., Driver, J. P., Serreze, D., Salter, M. W., and Dosch, H. M. (2006) TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes Cell 127, 1123– 1135

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104
Wang, X., Miyares, R. L., and Ahern, G. P. (2005) Oleoylethanolamide excites vagal sensory neurones, induces visceral pain and reduces short-term food intake in mice via capsaicin receptor TRPV1 J. Physiol. 564, 541– 547

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Oleoylethanolamide excites vagal sensory neurones, induces visceral pain and reduces short-term food intake in mice via capsaicin receptor TRPV1

Wang, Xiangbin; Miyares, Rosa Linda; Ahern, Gerard P.

Journal of Physiology (Oxford, United Kingdom) (2005), 564 (2), 541-547CODEN: JPHYA7; ISSN:0022-3751. (Blackwell Publishing Ltd.)

Oleoylethanolamide (OEA) is an endogenous lipid that regulates feeding and body wt. Although the effects of OEA are believed to depend on activation of vagal sensory afferent neurons, the mechanisms involved in exciting these neurons are unclear. Here we show that OEA directly excited nodose ganglion neurons, the cell bodies of vagal afferents. OEA depolarized these neurons and evoked inward currents that were restricted to capsaicin-sensitive cells. These currents were fully blocked by the TRPV1 inhibitor, capsazepine, and no responses to OEA were obsd. in neurons cultured from TRPV1-null mice. Similarly, OEA induced a rise in Ca+ concn. in wild-type but not TRPV1-deficient neurons, and responses to OEA were greater at 37°C compared to room temp. Significantly, OEA administration in mice induced visceral pain-related behaviors that were inhibited by capsazepine and absent in TRPV1-null animals. Further, OEA reduced 30-min food intake in wild-type but not in TRPV1-null mice. Thus, the acute behavioral effects of OEA may result from visceral malaise via the activation of TRPV1.

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Ahern, G. P. (2013) Transient receptor potential channels and energy homeostasis Trends Endocrinol. Metab. 24, 554– 560

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Transient receptor potential channels and energy homeostasis

Ahern, Gerard P.

Trends in Endocrinology and Metabolism (2013), 24 (11), 554-560CODEN: TENME4; ISSN:1043-2760. (Elsevier Ltd.)

A review. Transient receptor potential (TRP) channels are members of an ancient class of ion channels that are present in most mammalian tissues. Consistent with their wide tissue distribution, TRPs are capable of influencing diverse physiol. processes including adipocyte function, energy intake and energy expenditure. TRPs function as transduction channels downstream of G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases, and some can also be direct sensors of chem. irritants that influence food intake or regulate body temp. and thermogenesis. TRP agonists were shown to reduce body wt. and adiposity, suggesting that they might be exploited as therapeutic targets. In this review I discuss the current knowledge of how TRP channels influence energy balance.

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Kindt, S., Vos, R., Blondeau, K., and Tack, J. (2009) Influence of intra-oesophageal capsaicin instillation on heartburn induction and oesophageal sensitivity in man Neurogastroenterol. Motil. 21, 1032– e1082

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Influence of intra-esophageal capsaicin instillation on heartburn induction and esophageal sensitivity in man

Kindt, S.; Vos, R.; Blondeau, K.; Tack, J.

Neurogastroenterology & Motility (2009), 21 (10), 1032-1038CODEN: NMOTEK; ISSN:1350-1925. (Wiley-Blackwell)

Heartburn is the most typical gastro-esophageal reflux disease (GERD) symptom. The transient receptor potential vanilloid receptor-1 (TRPV1) is a candidate mediator of heartburn. Exposure of TRPV1 to capsaicin is characterized by activation, followed by desensitization. Our aim was to investigate the effect of intra-esophageal capsaicin instillation on esophageal symptom perception (activation) and on sensitivity to esophageal acid perfusion and esophageal balloon distention (desensitization). In a first protocol (n = 10), saline or capsaicin soln. were instilled in the mid-esophagus and symptoms were rated at 5-min intervals for 60 min. In a second study (n = 10), esophageal 0.1 N hydrochloric acid perfusion was performed 60 min after pretreatment with saline, low or high dose capsaicin. In a third study (n = 10), sensitivity to esophageal balloon distention was detd. before and at 30-min intervals up to 90 min after pretreatment with saline, low or high dose capsaicin. Areas under the curve (AUC) for symptom intensities under different conditions were calcd. and compared with Kruskal-Wallis test. Esophageal capsaicin instillation induced transient symptoms of retrosternal and epigastric burning in a dose-dependent fashion. After esophageal capsaicin or saline instillation, there was no difference in symptom pattern and intensities induced by esophageal acid perfusion. After esophageal capsaicin or saline instillation, sensitivity to esophageal balloon distention and esophageal compliance were not significantly altered. Esophageal instillation of the TRPV1 receptor agonist capsaicin induces symptoms of retrosternal and epigastric burning in a dose-dependent fashion. Pretreatment with capsaicin does not desensitize the esophagus to acid perfusion or to balloon distention.

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Okumi, H., Tashima, K., Matsumoto, K., Namiki, T., Terasawa, K., and Horie, S. (2012) Dietary agonists of TRPV1 inhibit gastric acid secretion in mice Planta Med. 78, 1801– 1806

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Raisinghani, M., Pabbidi, R. M., and Premkumar, L. S. (2005) Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin J. Physiol. 567, 771– 786

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Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin

Raisinghani, Manish; Pabbidi, Reddy M.; Premkumar, Louis S.

Journal of Physiology (Oxford, United Kingdom) (2005), 567 (3), 771-786CODEN: JPHYA7; ISSN:0022-3751. (Blackwell Publishing Ltd.)

Transient receptor potential vanilloid 1 (TRPV1) is a Ca2+ permeable non-selective cation channel activated by phys. and chem. stimuli. Resiniferatoxin (RTX), an ultrapotent agonist of TRPV1, is under investigation for treatment of urinary bladder hyper-reflexia and chronic pain conditions. Here, we have detd. the characteristics of RTX-induced responses in cells expressing native and cloned rat TRPV1. Whole-cell currents increase with repeated application of submaximal concns. of RTX until a maximal response is attained and do not deactivate even after prolonged washout. Interestingly, the rate of activation and block by capsazepine of RTX-induced currents are significantly slower than for capsaicin-induced currents. RTX-induced whole-cell currents are outwardly rectifying, but to a lesser extent than capsaicin-induced currents. RTX-induced single channel currents exhibit multiple conductance states and outward rectification. The open probability (Po) of RTX-induced currents is higher at all potentials as compared to capsaicin-induced currents, which showed a strong voltage-dependent decrease at neg. potentials. Single-channel kinetic analyses reveal that open-time distribution of RTX-induced currents can be fitted with three exponential components at neg. and pos. potentials. The areas of distribution of the longer open time consts. are significantly larger than capsaicin-induced currents. The closed-time distribution of RTX-induced currents can be fitted with three exponential components as compared to capsaicin-induced currents, which require four exponential components. Current-clamp expts. reveal that low concns. of RTX caused a slow and sustained depolarization beyond threshold while generating few action potentials. Concns. of capsaicin required for the same extent of depolarization generated a significantly greater no. of action potentials. These properties of RTX may play a role in its clin. usefulness.

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Roberts, J. C., Davis, J. B., and Benham, C. D. (2004) [3H]Resiniferatoxin autoradiography in the CNS of wild-type and TRPV1 null mice defines TRPV1 (VR-1) protein distribution Brain Res. 995, 176– 183

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[3H]Resiniferatoxin autoradiography in the CNS of wild-type and TRPV1 null mice defines TRPV1 (VR-1) protein distribution

Roberts, Jennifer C.; Davis, John B.; Benham, Christopher D.

Brain Research (2004), 995 (2), 176-183CODEN: BRREAP; ISSN:0006-8993. (Elsevier Science B.V.)

Knowledge of the distribution and function of the vanilloid receptor (VR-1 or TRPV1) in the CNS lacks the detailed appreciation of its role in the peripheral nervous system. The radiolabeled vanilloid agonist [3H]resiniferatoxin (RTX) has been used to indicate the presence of TRPV1 receptor protein in the brain but low specific binding has complicated interpretation of this data. Recently, support for a more widespread CNS distribution of TRPV1 mRNA and protein has been provided by RT-PCR and antibody data. The authors have exploited the availability of TRPV1 null mice and used [3H]RTX autoradiog. in the CNS of TRPV1 wild-type and TRPV1 null mice to identify the component of [3H]RTX binding to TRPV1 receptor protein. In the brains of TRPV1+/+ mice, specific [3H]RTX binding was broadly localized with the greatest binding in the olfactory nuclei, the cerebral cortex, dentate gyrus, thalamus, hypothalamus, periaqueductal gray, superior colliculus, locus coeruleus and cerebellar cortex. Specific binding was also seen in the spinal cord and sensory (dorsal root and trigeminal) ganglia. This binding was much lower but not abolished in most regions in the TRPV1-/- mice. Nonspecific binding was low in all cases. The present study unequivocally demonstrates a widespread and discrete distribution pattern of the TRPV1 receptor protein in the rat central nervous system. The presence of TRPV1 receptors in several brain regions suggests that it may function as a cannabinoid-gated channel in the CNS.

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Chou, M. Z., Mtui, T., Gao, Y. D., Kohler, M., and Middleton, R. E. (2004) Resiniferatoxin binds to the capsaicin receptor (TRPV1) near the extracellular side of the S4 transmembrane domain Biochemistry 43, 2501– 2511

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Jung, J., Lee, S. Y., Hwang, S. W., Cho, H., Shin, J., Kang, Y. S., Kim, S., and Oh, U. (2002) Agonist recognition sites in the cytosolic tails of vanilloid receptor 1 J. Biol. Chem. 277, 44448– 44454

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Gavva, N. R., Klionsky, L., Qu, Y., Shi, L., Tamir, R., Edenson, S., Zhang, T. J., Viswanadhan, V. N., Toth, A., Pearce, L. V., Vanderah, T. W., Porreca, F., Blumberg, P. M., Lile, J., Sun, Y., Wild, K., Louis, J. C., and Treanor, J. J. (2004) Molecular determinants of vanilloid sensitivity in TRPV1 J. Biol. Chem. 279, 20283– 20295

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Molecular determinants of vanilloid sensitivity in TRPV1

Gavva, Narender R.; Klionsky, Lana; Qu, Yusheng; Shi, Licheng; Tamir, Rami; Edenson, Steve; Zhang, T. J.; Viswanadhan, Vellarkad N.; Toth, Attila; Pearce, Larry V.; Vanderah, Todd W.; Porreca, Frank; Blumberg, Peter M.; Lile, Jack; Sun, Yax; Wild, Ken; Louis, Jean-Claude; Treanor, James J. S.

Journal of Biological Chemistry (2004), 279 (19), 20283-20295CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

Vanilloid receptor 1 (TRPV1), a membrane-assocd. cation channel, is activated by the pungent vanilloid from chili peppers, capsaicin, and the ultra potent vanilloid from Euphorbia resinifera, resiniferatoxin (RTX), as well as by phys. stimuli (heat and protons) and proposed endogenous ligands (anandamide, N-arachidonyldopamine, N-oleoyldopamine, and products of lipoxygenase). Only limited information is available in TRPV1 on the residues that contribute to vanilloid activation. Interestingly, rabbits have been suggested to be insensitive to capsaicin and have been shown to lack detectable [3H]RTX binding in membranes prepd. from their dorsal root ganglia. The authors have cloned rabbit TRPV1 (oTRPV1) and report that it exhibits high homol. to rat and human TRPV1. Like its mammalian orthologs, oTRPV1 is selectively expressed in sensory neurons and is sensitive to protons and heat activation but is 100-fold less sensitive to vanilloid activation than either rat or human. Here the authors identify key residues (Met547 and Thr550) in transmembrane regions 3 and 4 (TM3/4) of rat and human TRPV1 that confer vanilloid sensitivity, [3H]RTX binding and competitive antagonist binding to rabbit TRPV1. The authors also show that these residues differentially affect ligand recognition as well as the assays of functional response vs. ligand binding. Furthermore, these residues account for the reported pharmacol. differences of RTX, PPAHV (phorbol 12-phenyl-acetate 13-acetate 20-homovanillate) and capsazepine between human and rat TRPV1. Based on the authors' data the authors propose a model of the TM3/4 region of TRPV1 bound to capsaicin or RTX that may aid in the development of potent TRPV1 antagonists with utility in the treatment of sensory disorders.

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Brown, D. C., Iadarola, M. J., Perkowski, S. Z., Erin, H., Shofer, F., Laszlo, K. J., Olah, Z., and Mannes, A. J. (2005) Physiologic and antinociceptive effects of intrathecal resiniferatoxin in a canine bone cancer model Anesthesiology 103, 1052– 1059

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Iadarola, M. J. and Mannes, A. J. (2011) The vanilloid agonist resiniferatoxin for interventional-based pain control Curr. Top. Med. Chem. 11, 2171– 2179

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The vanilloid agonist resiniferatoxin for interventional-based pain control

Iadarola, Michael J.; Mannes, Andrew J.

Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2011), 11 (17), 2171-2179CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)

A review. The idea of selectively targeting nociceptive transmission at the level of the peripheral nervous system is attractive from multiple perspectives, particularly the potential lack of non-specific (non-targeted) CNS side effects. Out of the multiple TRP channels involved in nociception, TRPV1 is a strong candidate based on its biophys. conductance properties and its expression in inflammation-sensitive dorsal root ganglion neurons and their axons and central and peripheral nerve terminals. While TRPV1 antagonists have undergone extensive medicinal chem. and pharmaceutical investigation, for TRPV1 agonists nature has provided an optimized compd. in RTX. RTX is not suitable for systemic administration, but it is highly adaptable to a variety of pain problems when used by local administration. This can include routes as diverse as s.c., intraganglionic or intrathecal (CSF space around the spinal cord). The present review focuses on the mol. and preclin. animal expts. that form the underpinnings of our clin. trial of intrathecal RTX for pain in advanced cancer. As such this represents a new approach to pain control that emerges from a long line of research on capsaicin and other vanilloids, their physiol. actions, and the mol. biol. of the capsaicin receptor TRPV1.

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Yang, B. H., Piao, Z. G., Kim, Y. B., Lee, C. H., Lee, J. K., Park, K., Kim, J. S., and Oh, S. B. (2003) (2003) Activation of vanilloid receptor 1 (VR1) by eugenol J. Dent. Res. 82, 781– 785

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Activation of vanilloid receptor 1 (VR1) by eugenol

Yang, B. H.; Piao, Z. G.; Kim, Y.-B.; Lee, C.-H.; Lee, J. K.; Park, K.; Kim, J. S.; Oh, S. B.

Journal of Dental Research (2003), 82 (10), 781-785CODEN: JDREAF; ISSN:0022-0345. (International Association for Dental Research)

The structural similarity of eugenol with capsaicin suggests that these two agents may share mol. mechanisms to produce their effects. The authors investigated the effects of eugenol in comparison with those of capsaicin using whole-cell patch clamp and Fura-2-based calcium-imaging techniques in a heterologous expression system and with sensory neurons. In vanilloid receptor 1 (VR1)-expressing human embryonic kidney (HEK) 293 cells and trigeminal ganglion (TG) neurons, eugenol activated inward currents, whereas capsazepine, a competitive VR antagonist, and ruthenium red (RR), a functional VR antagonist, completely blocked eugenol-induced inward currents. Moreover, eugenol caused elevation of [Ca2+]i, and this was completely abolished by both capsazepine and ruthenium red in VR1-expressing HEK 293 cells and TG neurons. The authors' results provide strong evidence that eugenol produces its effects, at least in part, via VR1 expressed by the sensory nerve endings in the teeth.

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Behrendt, H. J., Germann, T., Gillen, C., Hatt, H., and Jostock, R. (2004) Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay Br. J. Pharmacol. 141, 737– 45

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Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay

Behrendt, H.-J.; Germann, T.; Gillen, C.; Hatt, H.; Jostock, R.

British Journal of Pharmacology (2004), 141 (4), 737-745CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)

TRPM8 (CMR1) is a Ca2+-permeable channel, which can be activated by low temps., menthol, eucalyptol and icilin. It belongs to the transient receptor potential (TRP) family, and therefore is related to vanilloid receptor type-1 (VR1, TRPV1). We tested whether substances which are structurally related to menthol, or which produce a cooling sensation, could activate TRPM8, and compared the responses of TRPM8 and VR1 to these ligands. The effects of 70 odorants and menthol-related substances on recombinant mouse TRPM8 (mTRPM8), expressed in HEK293 cells, were examd. using a FLIPR assay. In all, 10 substances (linalool, geraniol, hydroxycitronellal, WS-3, WS-23, FrescolatMGA, FrescolatML, PMD38, CoolactP and Cooling Agent 10) were found to be agonists. The EC50 values of the agonists defined their relative potencies: icilin (0.2 ± 0.1 μM) > FrescolatML (3.3 ± 1.5 μM) > WS-3 (3.7 ± 1.7 μM) (-)menthol (4.1 ± 1.3 μM) frescolatMAG (4.8 ± 1.1 μM) > cooling agent 10 (6 ± 2.2 μM) (+)menthol (14.4 ± 1.3 μM) > PMD38 (31 ± 1.1 μM) > WS-23 (44 ± 7.3 μM) > Coolact P (66 ± 20 μM) > geraniol (5.9 ± 1.6 mM) > linalool (6.7 ± 2.0 mM) > eucalyptol (7.7 ± 2.0 mM) > hydroxycitronellal (19.6 ± 2.2 mM). Known VR1 antagonists (BCTC, thio-BCTC and capsazepine) were also able to block the response of TRPM8 to menthol (IC50: 0.8 ± 1.0, 3.5 ± 1.1 and 18 ± 1.1 μM, resp.). The Ca2+ response of hVR1-transfected HEK293 cells to the endogenous VR1 agonist N-arachidonoyl-dopamine was potentiated by low pH. In contrast, menthol- and icilin-activated TRPM8 currents were suppressed by low pH. In conclusion, in the present study, we identified 10 new agonists and three antagonists of TRPM8. We found that, in contrast to VR1, TRPM8 is inhibited rather than potentiated by protons.

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McNamara, F. N., Randall, A., and Gunthorpe, M. J. (2005) Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1) Br. J. Pharmacol. 144, 781– 790

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Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1)

McNamara, Fergal N.; Randall, Andrew; Gunthorpe, Martin J.

British Journal of Pharmacology (2005), 144 (6), 781-790CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)

1. We have characterized the effects of piperine, a pungent alkaloid found in black pepper, on the human vanilloid receptor TRPV1 using whole-cell patch-clamp electrophysiol. 2. Piperine produced a clear agonist activity at the human TRPV1 receptor yielding rapidly activating whole-cell currents that were antagonized by the competitive TRPV1 antagonist capsazepine and the non-competitive TRPV1 blocker ruthenium red. 3. The current-voltage relationship of piperine-activated currents showed pronounced outward rectification (25±4-fold between -70 and +70 mV) and a reversal potential of 0.0±0.4 mV, which was indistinguishable from that of the prototypical TRPV1 agonist capsaicin. 4. Although piperine was a less potent agonist (EC50=37.9±1.9 μM) than capsaicin (EC50=0.29±0.05 μM), it demonstrated a much greater efficacy (approx. two-fold) at TRPV1. 5. This difference in efficacy did not appear to be related to the proton-mediated regulation of the receptor since a similar degree of potentiation was obsd. for responses evoked by piperine (230±20%, n=11) or capsaicin (284±32%, n=8) upon acidification to pH 6.5. 6. The effects of piperine upon receptor desensitization were also unable to explain this effect since piperine resulted in more pronounced macroscopic desensitization (t1/2=9.9±0.7 s) than capsaicin (t1/2>20 s) and also caused greater tachyphylaxis in response to repetitive agonist applications. 7. Overall, our data suggest that the effects of piperine at human TRPV1 are similar to those of capsaicin except for its propensity to induce greater receptor desensitization and, rather remarkably, exhibit a greater efficacy than capsaicin itself. These results may provide insight into the TRPV1-mediated effects of piperine on gastrointestinal function.

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Bhardwaj, R. K., Glaeser, H., Becquemont, L., Klotz, U., Gupta, S. K., and Fromm, M. F. (2002) Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4 J. Pharmacol. Exp. Ther. 302, 645– 650

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Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4

Bhardwaj, Rajinder K.; Glaeser, Hartmut; Becquemont, Laurent; Klotz, Ulrich; Gupta, Suresh K.; Fromm, Martin F.

Journal of Pharmacology and Experimental Therapeutics (2002), 302 (2), 645-650CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)

Dietary constituents (e.g., in grapefruit juice; NaCl) and phytochems. (e.g., St. John's wort) are important agents modifying drug metab. and transport and thereby contribute to interindividual variability in drug disposition. Most of these drug-food interactions are due to induction or inhibition of P-glycoprotein and/or CYP3A4. Preliminary data indicate that piperine, a major component of black pepper, inhibits drug-metabolizing enzymes in rodents and increases plasma concns. of several drugs, including P-glycoprotein substrates (phenytoin and rifampin) in humans. However, there are no direct data whether piperine is an inhibitor of human P-glycoprotein and/or CYP3A4. We therefore investigated the influence of piperine on P-glycoprotein-mediated, polarized transport of digoxin and cyclosporine in monolayers of Caco-2 cells. Moreover, by using human liver microsomes we detd. the effect of piperine on CYP3A4-mediated formation of the verapamil metabolites D-617 and norverapamil. Piperine inhibited digoxin and cyclosporine A transport in Caco-2 cells with IC50 values of 15.5 and 74.1 μM, resp. CYP3A4-catalyzed formation of D-617 and norverapamil was inhibited in a mixed fashion, with Ki values of 36±8 (liver 1)/49±6 (liver 2) and 44±10 (liver 1)/77±10 μM (liver 2), resp. In summary, we showed that piperine inhibits both the drug transporter P-glycoprotein and the major drug-metabolizing enzyme CYP3A4. Because both proteins are expressed in enterocytes and hepatocytes and contribute to a major extent to first-pass elimination of many drugs, our data indicate that dietary piperine could affect plasma concns. of P-glycoprotein and CYP3A4 substrates in humans, in particular if these drugs are administered orally.

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Bisogno, T., Hanus, L., De Petrocellis, L., Tchilibon, S., Ponde, D. E., Brandi, I., Moriello, A. S., Davis, J. B., Mechoulam, R., and Di Marzo, V. (2001) Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide Br. J. Pharmacol. 134, 845– 852

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Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

Bisogno, Tiziana; Hanus, Lumir; De Petrocellis, Luciano; Tchilibon, Susanna; Ponde, Datta E.; Brandi, Ines; Moriello, Aniello Schiano; Davis, John B.; Mechoulam, Raphael; Di Marzo, Vincenzo

British Journal of Pharmacology (2001), 134 (4), 845-852CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)

(-)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible mol. targets of this compd. We investigated whether CBD and some of its derivs. interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). CBD and its enantiomer, (+)-CBD, together with seven analogs, obtained by exchanging the C-7 Me group of CBD with a hydroxy-Me or a carboxyl function and/or the C-5' pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concns. in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalyzed by the fatty acid amide hydrolase. Both CBD and (+)-CBD, but not the other analogs, stimulated VR1 with EC50=3.2-3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67-70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compds. were not additive. (+)-5'-DMH-CBD and (+)-7-hydroxy-5'-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (-)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM). CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (-)-7-hydroxy-CBD (IC50=34 μM), but not the other analogs (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis. Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors. These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacol. effects of CBD and its analogs. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (-)-5'-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent.

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Xu, H., Blair, N. T., and Clapham, D. E. (2005) Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism J. Neurosci. 25, 8924– 8937

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Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism

Xu, Haoxing; Blair, Nathaniel T.; Clapham, David E.

Journal of Neuroscience (2005), 25 (39), 8924-8937CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)

Camphor is a naturally occurring compd. that is used as a major active ingredient of balms and liniments supplied as topical analgesics. Despite its long history of common medical use, the underlying mol. mechanism of camphor action is not understood. Capsaicin and menthol, two other topically applied agents widely used for similar purposes, are known to excite and desensitize sensory nerves by acting on two members of transient receptor potential (TRP) channel superfamily: heat-sensitive TRP vanilloid subtype 1 (TRPV1) and cold-sensitive TRP channel M8, resp. Camphor has recently been shown to activate TRPV3, and here we show that camphor also activates heterologously expressed TRPV1, requiring higher concns. than capsaicin. Activation was enhanced by phospholipase C-coupled receptor stimulation mimicking inflamed conditions. Similar camphor-activated TRPV1-like currents were obsd. in isolated rat DRG neurons and were strongly potentiated after activation of protein kinase C with phorbol-12-myristate-13-acetate. Camphor activation of rat TRPV1 was mediated by distinct channel regions from capsaicin, as indicated by camphor activation in the presence of the competitive inhibitor capsazepine and in a capsaicin-insensitive point mutant. Camphor did not activate the capsaicin-insensitive chicken TRPV1. TRPV1 desensitization is believed to contribute to the analgesic actions of capsaicin. We found that, although camphor activates TRPV1 less effectively, camphor application desensitized TRPV1 more rapidly and completely than capsaicin. Conversely, TRPV3 current sensitized after repeated camphor applications, which is inconsistent with the analgesic role of camphor. We also found that camphor inhibited several other related TRP channels, including ankyrin-repeat TRP 1 (TRPA1). The camphor-induced desensitization of TRPV1 and block of TRPA1 may underlie the analgesic effects of camphor.

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Pearce, L. V., Petukhov, P. A., Szabo, T., Kedei, N., Bizik, F., Kozikowski, A. P., and Blumberg, P. M. (2004) Evodiamine functions as an agonist for the vanilloid receptor TRPV1 Org. Biomol. Chem. 2, 2281– 2286

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Evodiamine functions as an agonist for the vanilloid receptor TRPV1

Pearce, Larry V.; Petukhov, Pavel A.; Szabo, Tamas; Kedei, Noemi; Bizik, Fero; Kozikowski, Alan P.; Blumberg, Peter M.

Organic & Biomolecular Chemistry (2004), 2 (16), 2281-2286CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)

Evodiamine, a quinozole alkaloid constituent of Evodia rutaecarpa, has been reported previously to induce several responses comparable to capsaicin in animal systems. Here, we characterize evodiamine as an agonist for rat TRPV1 expressed heterologously in CHO cells. Evodiamine bound to rat TRPV1 with a Ki of 5.95±0.87 μM, as measured by inhibition of [3H] RTX binding (capsaicin, Ki = 1.8±0.3 μM). Evodiamine was a full agonist for induction of 45Ca2+ uptake, with an EC50 of 856±43 nM (capsaicin, EC50 = 45±4 nM) and was competitively antagonized by capsazepine, as revealed by a Schild plot. The pattern of cellular response, as detd. by calcium imaging, was similar to that with capsaicin and yielded an EC50 of 1.03±0.21 μM. Mol. modeling suggested a consistent pattern of overlap between evodiamine and TRPV1 agonists. We conclude that evodiamine represents a novel class of agonists for rat TRPV1, albeit 3-19-fold less potent than capsaicin, and thus represents a new potential class of lead mols. for drug development.

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Morera, E., De Petrocellis, L., Morera, L., Moriello, A. S., Nalli, M., Di Marzo, V., and Ortar, G. (2012) Synthesis and biological evaluation of [6]-gingerol analogues as transient receptor potential channel TRPV1 and TRPA1 modulators Bioorg. Med. Chem. Lett. 22, 1674– 1677

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Xu, H., Delling, M., Jun, J. C., and Clapham, D. E. (2006) Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels Nat. Neurosci. 9, 628– 635

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Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels

Xu, Haoxing; Delling, Markus; Jun, Janice C.; Clapham, David E.

Nature Neuroscience (2006), 9 (5), 628-635CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)

Carvacrol, eugenol and thymol are major components of plants such as oregano, savory, clove and thyme. When applied to the tongue, these flavors elicit a warm sensation. They are also known to be skin sensitizers and allergens. The transient receptor potential channel (TRPV3) is a warm-sensitive Ca2+-permeable cation channel highly expressed in the skin, tongue and nose. Here we show that TRPV3 is strongly activated and sensitized by carvacrol, thymol and eugenol. Tongue and skin epithelial cells respond to carvacrol and eugenol with an increase in intracellular Ca2+ levels. We also show that this TRPV3 activity is strongly potentiated by phospholipase C-linked, G protein-coupled receptor stimulation. In addn., carvacrol activates and rapidly desensitizes TRPA1, which may explain the pungency of oregano. Our results support a role for temp.-sensitive TRP channels in chemesthesis in oral and nasal epithelium and suggest that TRPV3 may be a mol. target of plant-derived skin sensitizers.

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Andre, E., Campi, B., Trevisani, M., Ferreira, J., Malheiros, A., Yunes, R. A., Calixto, J. B., and Geppetti, P. (2006) Pharmacological characterisation of the plant sesquiterpenes polygodial and drimanial as vanilloid receptor agonists Biochem. Pharmacol. 71, 1248– 1254

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Iwasaki, Y., Tanabe, M., Kayama, Y., Abe, M., Kashio, M., Koizumi, K., Okumura, Y., Morimitsu, Y., Tominaga, M., Ozawa, Y., and Watanabe, T. (2009) Miogadial and miogatrial with alpha,beta-unsaturated 1,4-dialdehyde moieties—novel and potent TRPA1 agonists Life Sci. 85, 60– 69

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Lübbert, M., Kyereme, J., Schöbel, N., Beltrán, L., Wetzel, C. H., and Hatt, H. (2013) Transient receptor potential channels encode volatile chemicals sensed by rat trigeminal ganglion neurons PLoS One 8, e77998

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Trevisan, G., Rossato, M. F., Walker, C. I., Klafke, J. Z., Rosa, F., Oliveira, S. M., Tonello, R., Guerra, G. P., Boligon, A. A., Zanon, R. B., Athayde, M. L., and Ferreira, J. (2012) Identification of the plant steroid alpha-spinasterol as a novel transient receptor potential vanilloid 1 antagonist with antinociceptive properties J. Pharmacol. Exp. Ther. 343, 258– 269

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Identification of the plant steroid α-spinasterol as a novel transient receptor potential vanilloid 1 antagonist with antinociceptive properties

Trevisan, Gabriela; Rossato, Mateus Fortes; Walker, Cristiani Isabel Bandero; Klafke, Jonatas Zeni; Rosa, Fernanda; Oliveira, Sara Marchesan; Tonello, Raquel; Guerra, Gustavo Petri; Boligon, Aline Augusti; Zanon, Ricardo Basso; Athayde, Margareth Linde; Ferreira, Juliano

Journal of Pharmacology and Experimental Therapeutics (2012), 343 (2), 258-269CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)

The transient receptor potential vanilloid 1 (TRPV1) receptor is relevant to the perception of noxious information and has been studied as a therapeutic target for the development of new analgesics. The goal of this study was to perform in vivo and in vitro screens to identify novel, efficacious, and safe TRPV1 antagonists isolated from leaves of the medicinal plant Vernonia tweedieana Baker. All of the fractions and the hydroalcoholic ext. produced antinociception in mice during the capsaicin test, but the dichloromethane fraction also had antioedematogenic effect. Among the compds. isolated from the dichloromethane fraction, only α-spinasterol reduced the nociception and edema induced by capsaicin injection. Moreover, α-spinasterol demonstrated good oral absorption and high penetration into the brain and spinal cord of mice. α-Spinasterol was able to displace [3H]resiniferatoxin binding and diminish calcium influx mediated by capsaicin. Oral administration of the dichloromethane fraction and α-spinasterol also produced antinociceptive effect in the noxious heat-induced nociception test; however, they did not change the mech. threshold of naive mice. The treatment with α-spinasterol did not produce antinociceptive effect in mice systemically pretreated with resiniferatoxin. In addn., α-spinasterol and the dichloromethane fraction reduced the edema, mech., and heat hyperalgesia elicited by complete Freund's adjuvant paw injection. The dichloromethane fraction and α-spinasterol did not affect body temp. or locomotor activity. In conclusion, α-spinasterol is a novel efficacious and safe antagonist of the TRPV1 receptor with antinociceptive effect.

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Birnbaumer, L., Yildirim, E., and Abramowitz, J. (2003) A comparison of the genes coding for canonical TRP channels and their M, V and P relatives Cell Calcium 33, 419– 432

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Peier, A. M., Reeve, A. J., Andersson, D. A., Moqrich, A., Earley, T. J., Hergarden, A. C., Story, G. M., Colley, S., Hogenesch, J. B., McIntyre, P., Bevan, S., and Patapoutian, A. (2002) A heat-sensitive TRP channel expressed in keratinocytes Science 296, 2046– 2049

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Moqrich, A., Hwang, S. W., Earley, T. J., Petrus, M. J., Murray, A. N., Spencer, K. S., Andahazy, M., Story, G. M., and Patapoutian, A. (2005) Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin Science 307, 1468– 1472

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Impaired Thermosensation in Mice Lacking TRPV3, a Heat and Camphor Sensor in the Skin

Moqrich, Aziz; Hwang, Sun Wook; Earley, Taryn J.; Petrus, Matt J.; Murray, Amber N.; Spencer, Kathryn S. R.; Andahazy, Mary; Story, Gina M.; Patapoutian, Ardem

Science (Washington, DC, United States) (2005), 307 (5714), 1468-1472CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

Environmental temp. is thought to be directly sensed by neurons through their projections in the skin. A subset of the mammalian transient receptor potential (TRP) family of ion channels has been implicated in this process. These "thermoTRPs" are activated at distinct temp. thresholds and are typically expressed in sensory neurons. TRPV3 is activated by heat (>33°) and, unlike most thermoTRPs, is expressed in mouse keratinocytes. We found that TRPV3 null mice have strong deficits in responses to innocuous and noxious heat but not in other sensory modalities; hence, TRPV3 has a specific role in thermosensation. The natural compd. camphor, which modulates sensations of warmth in humans, proved to be a specific activator of TRPV3. Camphor activated cultured primary keratinocytes but not sensory neurons, and this activity was abolished in TRPV3 null mice. Therefore, heat-activated receptors in keratinocytes are important for mammalian thermosensation.

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Xu, H., Ramsey, I. S., Kotecha, S. A., Moran, M. M., Chong, J. A., Lawson, D., Ge, P., Lilly, J., Silos-Santiago, I., Xie, Y., DiStefano, P. S., Curtis, R., and Clapham, D. E. (2002) TRPV3 is a calcium-permeable temperature-sensitive cation channel Nature 418, 181– 186

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TRPV3 is a calcium-permeable temperature-sensitive cation channel

Xu, Haoxing; Ramsey, I. Scott; Kotecha, Suhas A.; Moran, Magdalene M.; Chong, Jayhong A.; Lawson, Deborah; Ge, Pei; Lilly, Jeremiah; Silos-Santiago, Inmaculada; Xie, Yu; DiStefano, Peter S.; Curtis, Rory; Clapham, David E.

Nature (London, United Kingdom) (2002), 418 (6894), 181-186CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

Transient receptor potential (TRP) proteins are cation-selective channels that function in processes as diverse as sensation and vasoregulation. Mammalian TRP channels that are gated by heat and capsaicin (>43°C; TRPV1 (ref. 1)), noxious heat (>52°C; TRPV2 (ref. 2)), and cooling (< 22°C; TRPM8 (refs 3, 4)) have been cloned; however, little is known about the mol. determinants of temp. sensing in the range between ∼22°C and 40°C. Here we have identified a member of the vanilloid channel family, human TRPV3 (hTRPV3) that is expressed in skin, tongue, dorsal root ganglion, trigeminal ganglion, spinal cord and brain. Increasing temp. from 22°C to 40°C in mammalian cells transfected with hTRPV3 elevated intracellular calcium by activating a nonselective cationic conductance. As in published recordings from sensory neurons, the current was steeply dependent on temp., sensitized with repeated heating, and displayed a marked hysteresis on heating and cooling. On the basis of these properties, we propose that hTRPV3 is thermosensitive in the physiol. range of temps. between TRPM8 and TRPV1.

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Smith, G. D., Gunthorpe, M. J., Kelsell, R. E., Hayes, P. D., Reilly, P., Facer, P., Wright, J. E., Jerman, J. C., Walhin, J. P., Ooi, L., Egerton, J., Charles, K. J., Smart, D., Randall, A. D., Anand, P., and Davis, J. B. (2002) TRPV3 is a temperature-sensitive vanilloid receptor-like protein Nature 418, 186– 190

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133
Gopinath, P., Wan, E., Holdcroft, A., Facer, P., Davis, J. B., Smith, G. D., Bountra, C., and Anand, P. (2005) Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain BMC Women’s Health 5, 2

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134
Facer, P., Casula, M. A., Smith, G. D., Benham, C. D., Chessell, I. P., Bountra, C., Sinisi, M., Birch, R., and Anand, P. (2007) Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy BMC Neurol. 7, 11

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Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy

Facer Paul; Casula Maria A; Smith Graham D; Benham Christopher D; Chessell Iain P; Bountra Chas; Sinisi Marco; Birch Rolfe; Anand Praveen

BMC neurology (2007), 7 (), 11 ISSN:.

BACKGROUND: Transient receptor potential (TRP) receptors expressed by primary sensory neurons mediate thermosensitivity, and may play a role in sensory pathophysiology. We previously reported that human dorsal root ganglion (DRG) sensory neurons co-expressed TRPV1 and TRPV3, and that these were increased in injured human DRG. Related receptors TRPV4, activated by warmth and eicosanoids, and TRPM8, activated by cool and menthol, have been characterised in pre-clinical models. However, the role of TRPs in common clinical sensory neuropathies needs to be established. METHODS: We have studied TRPV1, TRPV3, TRPV4, and TRPM8 in nerves (n = 14) and skin from patients with nerve injury, avulsed dorsal root ganglia (DRG) (n = 11), injured spinal nerve roots (n = 9), diabetic neuropathy skin (n = 8), non-diabetic neuropathic nerve biopsies (n = 6), their respective control tissues, and human post mortem spinal cord, using immunohistological methods. RESULTS: TRPV1 and TRPV3 were significantly increased in injured brachial plexus nerves, and TRPV1 in hypersensitive skin after nerve repair, whilst TRPV4 was unchanged. TRPM8 was detected in a few medium diameter DRG neurons, and was unchanged in DRG after avulsion injury, but was reduced in axons and myelin in injured nerves. In diabetic neuropathy skin, TRPV1 expressing sub- and intra-epidermal fibres were decreased, as was expression in surviving fibres. TRPV1 was also decreased in non-diabetic neuropathic nerves. Immunoreactivity for TRPV3 was detected in basal keratinocytes, with a significant decrease of TRPV3 in diabetic skin. TRPV1-immunoreactive nerves were present in injured dorsal spinal roots and dorsal horn of control spinal cord, but not in ventral roots, while TRPV3 and TRPV4 were detected in spinal cord motor neurons. CONCLUSION: The accumulation of TRPV1 and TRPV3 in peripheral nerves after injury, in spared axons, matches our previously reported changes in avulsed DRG. Reduction of TRPV1 levels in nerve fibres in diabetic neuropathy skin may result from the known decrease of nerve growth factor (NGF) levels. The role of TRPs in keratinocytes is unknown, but a relationship to changes in NGF levels, which is produced by keratinocytes, deserves investigation. TRPV1 represents a more selective therapeutic target than other TRPs for pain and hypersensitivity, particularly in post-traumatic neuropathy.

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Huang, S. M., Lee, H., Chung, M. K., Park, U., Yu, Y. Y., Bradshaw, H. B., Coulombe, P. A., Walker, J. M., and Caterina, M. J. (2008) Overexpressed transient receptor potential vanilloid 3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2 J. Neurosci. 28, 13727– 13737

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Overexpressed transient receptor potential vanilloid 3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2

Huang, Susan M.; Lee, Hyosang; Chung, Man-Kyo; Park, Una; Yu, Yin Yin; Bradshaw, Heather B.; Coulombe, Pierre A.; Walker, J. Michael; Caterina, Michael J.

Journal of Neuroscience (2008), 28 (51), 13727-13737CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)

The ability to sense changes in the environment is essential for survival because it permits responses such as withdrawal from noxious stimuli and regulation of body temp. Keratinocytes, which occupy much of the skin epidermis, are situated at the interface between the external environment and the body's internal milieu, and have long been appreciated for their barrier function against external insults. The recent discovery of temp.-sensitive transient receptor potential vanilloid (TRPV) ion channels in keratinocytes has raised the possibility that these cells also actively participate in acute temp. and pain sensation. To address this notion, the authors generated and characterized transgenic mice that overexpress TRPV3 in epidermal keratinocytes under the control of the keratin 14 promoter. Compared with wild-type controls, keratinocytes overexpressing TRPV3 exhibited larger currents as well as augmented prostaglandin E2 (PGE2) release in response to two TRPV3 agonists, 2-aminoethoxydiphenyl borate (2APB) and heat. Thermal selection behavior and heat-evoked withdrawal behavior of naive mice overexpressing TRPV3 were not consistently altered. Upon selective pharmacol. inhibition of TRPV1 with JNJ-7203212, however, the keratinocyte-specific TRPV3 transgenic mice showed increased escape responses to noxious heat relative to their wild-type littermates. Coadministration of the cyclooxygenase inhibitor, ibuprofen, with the TRPV1 antagonist decreased inflammatory thermal hyperalgesia in transgenic but not wild-type animals. The authors' results reveal a previously undescribed mechanism for keratinocyte participation in thermal pain transduction through keratinocyte TRPV3 ion channels and the intercellular messenger PGE2.

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Hammarstrom, S., Hamberg, M., Samuelsson, B., Duell, E. A., Stawiski, M., and Voorhees, J. J. (1975) Increased concentrations of nonesterified arachidonic acid, 12L-hydroxy-5,8,10,14-eicosatetraenoic acid, prostaglandin E2, and prostaglandin F2alpha in epidermis of psoriasis Proc. Natl. Acad. Sci. U.S.A. 72, 5130– 5134

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137
Brash, A. R. (2001) Arachidonic acid as a bioactive molecule J. Clin. Invest. 107, 1339– 1345

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Arachidonic acid as a bioactive molecule

Brash, Alan R.

Journal of Clinical Investigation (2001), 107 (11), 1339-1345CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)

A review, with 46 refs., of the biol. activity of arachidonic acid. Before dealing with bioactivity, the authors consider the soly. properties of the mol., which are crucial to understanding the availability within the cell of endogenous and exogenous arachidonic acid. This is followed by a discussion of two controversial issues, arachidonic acid transport into cells and the accessibility of added arachidonic acid to endogenous cellular compartments, and finally selected biol. actions of this lipid. The enzymes of arachidonic acid release have been well covered in specialized reviews and are introduced here only in passing.

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Mandadi, S., Sokabe, T., Shibasaki, K., Katanosaka, K., Mizuno, A., Moqrich, A., Patapoutian, A., Fukumi-Tominaga, T., Mizumura, K., and Tominaga, M. (2009) TRPV3 in keratinocytes transmits temperature information to sensory neurons via ATP Pfluegers Arch. 458, 1093– 2002

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TRPV3 in keratinocytes transmits temperature information to sensory neurons via ATP

Mandadi, Sravan; Sokabe, Takaaki; Shibasaki, Koji; Katanosaka, Kimiaki; Mizuno, Atsuko; Moqrich, Aziz; Patapoutian, Ardem; Fukumi-Tominaga, Tomoko; Mizumura, Kazue; Tominaga, Makoto

Pfluegers Archiv (2009), 458 (6), 1093-1102CODEN: PFLABK; ISSN:0031-6768. (Springer GmbH)

Transient receptor potential V3 (TRPV3) and TRPV4 are heat-activated cation channels expressed in keratinocytes. It has been proposed that heat-activation of TRPV3 and/or TRPV4 in the skin may release diffusible mols. which would then activate termini of neighboring dorsal root ganglion (DRG) neurons. Here we show that ATP is such a candidate mol. released from keratinocytes upon heating in the co-culture systems. Using TRPV1-deficient DRG neurons, we found that increase in cytosolic Ca2+-concn. in DRG neurons upon heating was obsd. only when neurons were co-cultured with keratinocytes, and this increase was blocked by P2 purinoreceptor antagonists, PPADS and suramin. In a co-culture of keratinocytes with HEK293 cells (transfected with P2X2 cDNA to serve as a bio-sensor), we obsd. that heat-activated keratinocytes secretes ATP, and that ATP release is compromised in keratinocytes from TRPV3-deficient mice. This study provides evidence that ATP is a messenger mol. for mainly TRPV3-mediated thermotransduction in skin.

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Xiao, R., Tang, J., Wang, C., Colton, C. K., Tian, J., and Zhu, M. X. (2008) Calcium plays a central role in the sensitization of TRPV3 channel to repetitive stimulations J. Biol. Chem. 283, 6162– 6174

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Imura, K. (2007) Influence of TRPV3 mutation on hair growth cycle in mice Biochem. Biophys. Res. Commun. 363, 479– 483

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141
Asakawa, M., Yoshioka, T., Matsutani, T., Hikita, I., Suzuki, M., Oshima, I., Tsukahara, K., Arimura, A., Horikawa, T., Hirasawa, T., and Sakata, T. (2006) Association of a mutation in TRPV3 with defective hair growth in rodents J. Invest. Dermatol. 126, 2664– 2672

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Macpherson, L. J., Hwang, S. W., Miyamoto, T., Dubin, A. E., Patapoutian, A., and Story, G. M. (2006) More than cool: promiscuous relationships of menthol and other sensory compounds Mol. Cell Neurosci. 32, 335– 343

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142
More than cool: Promiscuous relationships of menthol and other sensory compounds

Macpherson, Lindsey J.; Hwang, Sun Wook; Miyamoto, Takashi; Dubin, Adrienne E.; Patapoutian, Ardem; Story, Gina M.

Molecular and Cellular Neuroscience (2006), 32 (4), 335-343CODEN: MOCNED; ISSN:1044-7431. (Elsevier)

Several temp.-activated transient receptor potential (thermoTRP) ion channels are the mol. receptors of natural compds. that evoke thermal and pain sensations. Menthol, popularly known for its cooling effect, activates TRPM8 - a cold-activated thermoTRP ion channel. However, human physiol. studies demonstrate a paradoxical role of menthol in modulation of warm sensation, and here, we show that menthol also activates heat-activated TRPV3. We further show that menthol inhibits TRPA1, potentially explaining the use of menthol as an analgesic. Similar to menthol, both camphor and cinnamaldehyde (initially reported to be specific activators of TRPV3 and TRPA1, resp.) also modulate other thermoTRPs. Therefore, we find that many "sensory compds." presumed to be specific have a promiscuous relationship with thermoTRPs.

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Moussaieff, A., Rimmerman, N., Bregman, T., Straiker, A., Felder, C. C., Shoham, S., Kashman, Y., Huang, S. M., Lee, H., Shohami, E., Mackie, K., Caterina, M. J., Walker, J. M., Fride, E., and Mechoulam, R. (2008) Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain FASEB J. 22, 3024– 3034

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144
De Petrocellis, L., Orlando, P., Moriello, A. S., Aviello, G., Stott, C., Izzo, A. A., and Di Marzo, V. (2012) Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation Acta Physiol. 204, 255– 266

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Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation

De Petrocellis, L.; Orlando, P.; Moriello, A. Schiano; Aviello, G.; Stott, C.; Izzo, A. A.; Di Marzo, V.

Acta Physiologica (2012), 204 (2), 255-266CODEN: APCHC4; ISSN:1748-1708. (Wiley-Blackwell)

Aim: Plant cannabinoids, like Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), activate/desensitize thermosensitive transient receptor potential (TRP) channels of vanilloid type-1 or -2 (TRPV1 or TRPV2). We investigated whether cannabinoids also activate/desensitize two other "thermo-TRP's", the TRP channels of vanilloid type-3 or -4 (TRPV3 or TRPV4), and if the TRPV-inactive cannabichromene (CBC) modifies the expression of TRPV1-4 channels in the gastrointestinal tract. Methods: TRP activity was assessed by evaluating elevation of [Ca2+]i in rat recombinant TRPV3- and TRPV4-expressing HEK-293 cells. TRP channel mRNA expression was measured by quant. RT-PCR in the jejunum and ileum of mice treated with vehicle or the pro-inflammatory agent croton oil. Results: (i) CBD and tetrahydrocannabivarin (THCV) stimulated TRPV3-mediated [Ca2+]i with high efficacy (50-70% of the effect of ionomycin) and potency (EC50∼3.7 μM), whereas cannabigerovarin (CBGV) and cannabigerolic acid (CBGA) were significantly more efficacious at desensitizing this channel to the action of carvacrol than at activating it; (ii) cannabidivarin and THCV stimulated TRPV4-mediated [Ca2+]i with moderate-high efficacy (30-60% of the effect of ionomycin) and potency (EC50 0.9-6.4 μM), whereas CBGA, CBGV, cannabinol and cannabigerol were significantly more efficacious at desensitizing this channel to the action of 4-α-phorbol 12,13-didecanoate (4α-PDD) than at activating it; (iii) CBC reduced TRPV1β, TRPV3 and TRPV4 mRNA in the jejunum, and TRPV3 and TRPV4 mRNA in the ileum of croton oil-treated mice. Conclusions: Cannabinoids can affect both the activity and the expression of TRPV1-4 channels, with various potential therapeutic applications, including in the gastrointestinal tract.

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Strotmann, R., Harteneck, C., Nunnenmacher, K., Schultz, G., and Plant, T. D. (2000) OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity Nat. Cell Biol. 2, 695– 702

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OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity

Strotmann, Rainer; Harteneck, Christian; Nunnenmacher, Karin; Schultz, Gunter; Plant, Tim D.

Nature Cell Biology (2000), 2 (10), 695-702CODEN: NCBIFN; ISSN:1465-7392. (Nature Publishing Group)

Ca2+-permeable channels that are involved in the responses of mammalian cells to changes in extracellular osmolarity have not been characterized at the mol. level. Here we identify a new TRP (transient receptor potential)-like channel protein, OTRPC4, that is expressed at high levels in the kidney, liver and heart. OTRPC4 forms Ca2+-permeable, nonselective cation channels that exhibit spontaneous activity in isotonic media and are rapidly activated by decreases in, and are inhibited by increases in, extracellular osmolarity. Changes in osmolarity of as little as 10% result in significant changes in intracellular Ca2+ concn. We propose that OTRPC4 is a candidate for a mol. sensor that confers osmosensitivity on mammalian cells.

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Watanabe, H., Davis, J. B., Smart, D., Jerman, J. C., Smith, G. D., Hayes, P., Vriens, J., Cairns, W., Wissenbach, U., Prenen, J., Flockerzi, V., Droogmans, G., Benham, C. D., and Nilius, B. (2002) Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives J. Biol. Chem. 277, 13569– 13577

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Suzuki, M., Mizuno, A., Kodaira, K., and Imai, M. (2003) Impaired pressure sensation in mice lacking TRPV4 J. Biol. Chem. 278, 22664– 22668

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148
Nilius, B., Droogmans, G., and Wondergem, R. (2003) Transient receptor potential channels in endothelium: solving the calcium entry puzzle? Endothelium 10, 5– 15

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148
Transient Receptor Potential Channels in Endothelium: Solving the Calcium Entry Puzzle?

Nilius, Bernd; Droogmans, Guy; Wondergem, Robert

Endothelium (2003), 10 (1), 5-15CODEN: ENDTE9; ISSN:1062-3329. (Taylor & Francis Ltd.)

A review. Many endothelial cell (EC) functions depend on influx of extracellular Ca2+, which is triggered by a variety of mech. and chem. signals. Here, we discuss possible pathways for this Ca2+ entry. The superfamily of cation channels derived from the "transient receptor potential" (TRP) channels is introduced. Several members of this family are expressed in ECs, and they provide pathways for Ca2+ entry. All TRP subfamilies may contribute to the Ca2+ entry channels or to the regulation of Ca2+ entry in EC. Members of Ca2+ entry channels in endothelium probably belong to the canonical TRP subfamily, TRPC. All TRPC1-6 have been discussed as Ca2+ entry channels that might be store-operated and/or receptor-operated. More importantly, knockout models of TRPC4 have proven that this channel is functionally involved in the regulation of endothelial-dependent vasorelaxation and in the control of EC barrier function. TRPC1 might be an important candidate for involvement of endothelial growth factors. TRPC3 is unequivocally important for a sustained EC Ca2+ entry. ECs express different patterns of TRPCs, which may increase the variability of TRPC channel function by formation of different multiheteromers. Among the two other TRP subfamilies, TRPMV and TRPM, at least TRPV4 and TRPM4 are EC channels. TRPV4 is a Ca2+ entry channel that is activated by an increase in cell vol., which might be involved in mechano-sensing, by an increase in temp., and perhaps by ligand-activation. TRPM4 is a nonselective cation channel, which is not Ca2+ permeable. It is probably modulated by NO and might be essential for regulating the inward driving force for Ca2+ entry. Possible modes of TRP channel regulation are described, involving (a) activation via the phospholipase (PL)Cβ and PLCγ pathways; (b) activation by lipids (diacylglycerol [DAG], arachidonic acid); (c) Ca2+ depletion of Ca2+ stores in the endoplasmic reticulum; (d) shear stress; and (e) radicals.

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Kohler, R., Heyken, W. T., Heinau, P., Schubert, R., Si, H., Kacik, M., Busch, C., Grgic, I., Maier, T., and Hoyer, J. (2006) Evidence for a functional role of endothelial transient receptor potential V4 in shear stress-induced vasodilatation Arterioscler., Thromb., Vasc. Biol. 26, 1495– 15502

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Evidence for a functional role of endothelial transient receptor potential V4 in shear stress-induced vasodilatation

Kohler Ralf; Heyken Willm-Thomas; Heinau Philipp; Schubert Rudolf; Si Han; Kacik Michael; Busch Christoph; Grgic Ivica; Maier Tanja; Hoyer Joachim

Arteriosclerosis, thrombosis, and vascular biology (2006), 26 (7), 1495-502 ISSN:.

OBJECTIVE: Ca2+-influx through transient receptor potential (TRP) channels was proposed to be important in endothelial function, although the precise role of specific TRP channels is unknown. Here, we investigated the role of the putatively mechanosensitive TRPV4 channel in the mechanisms of endothelium-dependent vasodilatation. METHODS AND RESULTS: Expression and function of TRPV4 was investigated in rat carotid artery endothelial cells (RCAECs) by using in situ patch-clamp techniques, single-cell RT-PCR, Ca2+ measurements, and pressure myography in carotid artery (CA) and Arteria gracilis. In RCAECs in situ, TRPV4 currents were activated by the selective TRPV4 opener 4alpha-phorbol-12,13-didecanoate (4alphaPDD), arachidonic acid, moderate warmth, and mechanically by hypotonic cell swelling. Single-cell RT-PCR in endothelial cells demonstrated mRNA expression of TRPV4. In FURA-2 Ca2+ measurements, 4alphaPDD increased [Ca2+]i by &140 nmol/L above basal levels. In pressure myograph experiments in CAs and A gracilis, 4alphaPDD caused robust endothelium-dependent and strictly endothelium-dependent vasodilatations by &80% (K(D) 0.3 microL), which were suppressed by the TRPV4 blocker ruthenium red (RuR). Shear stress-induced vasodilatation was similarly blocked by RuR and also by the phospholipase A2 inhibitor arachidonyl trifluoromethyl ketone (AACOCF3). 4alphaPDD produced endothelium-derived hyperpolarizing factor (EDHF)-type responses in A gracilis but not in rat carotid artery. Shear stress did not produce EDHF-type vasodilatation in either vessel type. CONCLUSIONS: Ca2+ entry through endothelial TRPV4 channels triggers NO- and EDHF-dependent vasodilatation. Moreover, TRPV4 appears to be mechanistically important in endothelial mechanosensing of shear stress.

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Watanabe, H., Vriens, J., Suh, S. H., Benham, C. D., Droogmans, G., and Nilius, B. (2002) Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells J. Biol. Chem. 277, 47044– 47051

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Watanabe, H., Vriens, J., Prenen, J., Droogmans, G., Voets, T., and Nilius, B. (2003) Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels Nature 424, 434– 438

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152
Loukin, S. H., Su, Z., and Kung, C. (2009) Hypotonic shocks activate rat TRPV4 in yeast in the absence of polyunsaturated fatty acids FEBS Lett. 583, 754– 758

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Cao, D. S., Yu, S. Q., and Premkumar, L. S. (2009) Modulation of transient receptor potential Vanilloid 4-mediated membrane currents and synaptic transmission by protein kinase C Mol. Pain 5, 5

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Modulation of transient receptor potential Vanilloid 4-mediated membrane currents and synaptic transmission by protein kinase C

Cao De-Shou; Yu Shuang-Quan; Premkumar Louis S

Molecular pain (2009), 5 (), 5 ISSN:.

BACKGROUND: Transient receptor potential Vanilloid (TRPV) receptors are involved in nociception and are expressed predominantly in sensory neurons. TRPV1, a non-selective cation channel has been extensively studied and is responsible for inflammatory thermal hypersensitivity. In this study, the expression and function of TRPV4 have been characterized and compared with those of TRPV1. RESULTS: Immunohistochemical studies revealed that both TRPV1 and TRPV4 were co-expressed in dorsal root ganglion (DRG) neuronal cell bodies and in the central terminals of laminae I and II of the spinal dorsal horn (DH). In Ca2+ fluorescence imaging and whole-cell patch-clamp experiments, TRPV1- and TRPV4-mediated responses were observed in a population of the same DRG neurons. Sensitization of TRPV1 has been shown to be involved in inflammatory pain conditions. Incubation with phorbol 12, 13-dibutyrate (PDBu), a PKC activator, resulted in a significant potentiation of TRPV4 currents in DRG neurons. In TRPV4 expressing HEK 293T cells, PDBu increased 4alpha-phorbol 12, 13-didecanoate (4alpha-PDD)-induced single-channel activity in cell-attached patches, which was abrogated by bisindolylmaleimide (BIM), a selective PKC inhibitor. TRPV4 is also expressed at the central terminals of sensory neurons. Activation of TRPV4 by 4alpha-PDD increased the frequency of miniature excitatory post synaptic currents (mEPSCs) in DRG-DH neuronal co-cultures. 4alpha-PDD-induced increase in the frequency of mEPSCs was further enhanced by PDBu. The expression of TRP channels has been shown in other areas of the CNS; application of 4alpha-PDD significantly increased the mEPSC frequency in cultured hippocampal neurons, which was further potentiated by PDBu, whereas, TRPV1 agonist capsaicin did not modulate synaptic transmission. CONCLUSION: These results indicate that TRPV4 and TRPV1 are co-expressed in certain DRG neurons and TRPV4 can be sensitized by PKC not only in DRG neuronal cell bodies, but also in the central sensory and non-sensory nerve terminals. Co-expression of TRPV1 and TRPV4 ion channels, their modulation of synaptic transmission and their sensitization by PKC may synergistically play a role in nociception.

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Matthews, B. D., Thodeti, C. K., Tytell, J. D., Mammoto, A., Overby, D. R., and Ingber, D. E. (2010) Ultra-rapid activation of TRPV4 ion channels by mechanical forces applied to cell surface beta1 integrins Integr. Biol. 2, 435– 442

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Ultra-rapid activation of TRPV4 ion channels by mechanical forces applied to cell surface β1 integrins

Matthews, Benjamin D.; Thodeti, Charles K.; Tytell, Jessica D.; Mammoto, Akiko; Overby, Darryl R.; Ingber, Donald E.

Integrative Biology (2010), 2 (9), 435-442CODEN: IBNIFL; ISSN:1757-9694. (Royal Society of Chemistry)

Integrins are ubiquitous transmembrane mechanoreceptors that elicit changes in intracellular biochem. in response to mech. force application, but these alterations generally proceed over seconds to minutes. Stress-sensitive ion channels represent another class of mechanoreceptors that are activated much more rapidly (within msec), and recent findings suggest that calcium influx through Transient Receptor Potential Vanilloid-4 (TRPV4) channels expressed in the plasma membrane of bovine capillary endothelial cells is required for mech. strain-induced changes in focal adhesion assembly, cell orientation and directional migration. However, whether mech. stretching a cell's extracellular matrix (ECM) adhesions might directly activate cell surface ion channels remains unknown. Here we show that forces applied to β1 integrins result in ultra-rapid (within 4 ms) activation of calcium influx through TRPV4 channels. The TRPV4 channels were specifically activated by mech. strain in the cytoskeletal backbone of the focal adhesion, and not by deformation of the lipid bilayer or submembranous cortical cytoskeleton alone. This early-immediate calcium signaling response required the distal region of the β1 integrin cytoplasmic tail that contains a binding site for the integrin-assocd. transmembrane CD98 protein, and external force application to CD98 within focal adhesions activated the same ultra-rapid calcium signaling response. Local direct strain-dependent activation of TRPV4 channels mediated by force transfer from integrins and CD98 may therefore enable compartmentalization of calcium signaling within focal adhesions that is crit. for mech. control of many cell behaviors that underlie cell and tissue development.

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Alessandri-Haber, N., Dina, O. A., Joseph, E. K., Reichling, D. B., and Levine, J. D. (2008) Interaction of transient receptor potential vanilloid 4, integrin, and SRC tyrosine kinase in mechanical hyperalgesia J. Neurosci. 28, 1046– 1057

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155
Interaction of transient receptor potential vanilloid 4, integrin, and Src tyrosine kinase in mechanical hyperalgesia

Alessandri-Haber, Nicole; Dina, Olayinka A.; Joseph, Elizabeth K.; Reichling, David B.; Levine, Jon D.

Journal of Neuroscience (2008), 28 (5), 1046-1057CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)

Although the transient receptor potential vanilloid 4 (TRPV4) has been implicated in the process of osmomech. transduction, it appears to make little contribution to the normal somatosensory detection of mech. stimuli. However, evidence suggests that it may play an important role in mech. hyperalgesia. In the present study, we examd. the common requirement for TRPV4 in mech. hyperalgesia assocd. with diverse pain models and investigated whether the very close assocn. obsd. between TRPV4 and mech. hyperalgesia, regardless of etiol., reflects a close functional connection of TRPV4 with other mols. implicated in mech. transduction. In models of painful peripheral neuropathy assocd. with vincristine chemotherapy, alcoholism, diabetes, and human immunodeficiency virus/acquired immune deficiency syndrome therapy, mech. hyperalgesia was markedly reduced by spinal intra-thecal administration of oligodeoxynucleotides antisense to TRPV4. Similarly, mech. hyperalgesia induced by paclitaxel, vincristine, or diabetes was strongly reduced in TRPV4 knock-out mice. We also show that α2β1 integrin and Src tyrosine kinase, which have been implicated in mech. transduction, are important for the development of mech. hyperalgesia, and that their contribution requires TRPV4. Furthermore, we establish a direct interaction between TRPV4, α2 integrin, and the Src tyrosine kinase Lyn in sensory neurons. We suggest that TRPV4 plays a role in mechanotransduction, as a component of a mol. complex that functions only in the setting of inflammation or nerve injury.

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Chen, X., Alessandri-Haber, N., and Levine, J. D. (2007) Marked attenuation of inflammatory mediator-induced C-fiber sensitization for mechanical and hypotonic stimuli in TRPV4–/– mice Mol. Pain 3, 31

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Marked attenuation of inflammatory mediator-induced C-fiber sensitization for mechanical and hypotonic stimuli in TRPV4-/- mice

Chen Xiaojie; Alessandri-Haber Nicole; Levine Jon D

Molecular pain (2007), 3 (), 31 ISSN:.

Inflammatory mediators can directly sensitize primary afferent nociceptors to mechanical and osmotic stimuli. Sensitized nociceptors have a lowered threshold of activation and increased spontaneous activity, which result in symptoms of hyperalgesia and pain, respectively. The transient receptor potential vanilloid 4 (TRPV4) ligand-gated ion channel has been implicated in the hyperalgesia for mechanical and osmotic stimuli associated with inflammatory states. To investigate whether TRPV4 directly contributes to the mechanisms of inflammatory mediator sensitization of C-fiber nociceptors, we compared the effect of the injection of simplified inflammatory soup (prostaglandin E2 and serotonin) into the mechanical receptive fields of C-fibers in TRPV4+/+ and TRPV4-/- mice in vivo. Following the injection of the soup, the percentage of C-fibers responding to a hypotonic stimulus and the magnitude of the response was significantly greater in TRPV4+/+ mice compared to TRPV4-/- mice. Moreover, in response to simplified inflammatory soup only C-fibers from TRPV4+/+ mice exhibited increased spontaneous activity and decreased mechanical threshold. These marked impairments in the response of C-fibers in TRPV4-/- mice demonstrate the importance of TRPV4 in nociceptor sensitization; we suggest that TRPV4, as TRPV1, underlies the nociceptive effects of multiple inflammatory mediators on primary afferent.

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Alessandri-Haber, N., Yeh, J. J., Boyd, A. E., Parada, C. A., Chen, X., Reichling, D. B., and Levine, J. D. (2003) Hypotonicity induces TRPV4-mediated nociception in rat Neuron 39, 497– 511

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158
Alessandri-Haber, N., Joseph, E., Dina, O. A., Liedtke, W., and Levine, J. D. (2005) TRPV4 mediates pain-related behavior induced by mild hypertonic stimuli in the presence of inflammatory mediator Pain 118, 70– 79

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Smith, P. L., Maloney, K. N., Pothen, R. G., Clardy, J., and Clapham, D. E. (2006) Bisandrographolide from Andrographis paniculata activates TRPV4 channels J. Biol. Chem. 281, 29897– 29904

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Figure 1

Figure 1. TRPA1 agonists (phytochemicals, synthetic chemicals, and endogenous molecules). Allicin, 2-propene-1-sulfinothioic acid S-2-propenyl ester; allylisothiocyanate (AITC), 3-isothiocyanato-1-propene, is an organosulfur compound; cinnamaldehyde, (2E)-3-phenylprop-2-enal; Δ⁹-tetrahydrocannabinol, (−)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol; umbellulone, 1-isopropyl-4-methylbicyclo[3.1.0]hex-3-en-2-one; ligustilide, (3Z)-3-butylidene-4,5-dihydro-2-benzofuran-1(3H)-one; methyl salicylate, methyl 2-hydroxybenzoate; icilin, 1-(2-hydroxyphenyl)-4-(3-nitrophenyl)-3,6-dihydropyrimidin-2-one; N-methylmaleimide (oxidizing agent); 4-hydroxynonenal, 4-hydroxy-2-nonenal, an α,β-unsaturated hydroxyalkenal produced by lipid peroxidation, is an endogenous agonist; methylglyoxal, an aldehyde from pyruvic acid, acts both as an aldehyde and ketone, and reacts with free amino acids such as lysine, arginine and thiol groups of cysteine. MG is an endogenous agonist.

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Figure 2

Figure 2. Other TRP channel activators. Hyperforin, (1R,5S,6R,7S)-4-hydroxy-5-isobutyryl-6-methyl-1,3,7-tris(3-methyl-2-buten-1-yl)-6-(4-methyl-3-penten-1-yl)bicyclo[3.3.1]non-3-ene-2,9-dione (TRPC6); bisandrographolide, 3-{(E)-2-[6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylenedecahydro-1-naphthalenyl]vinyl}-5-{6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylene-1-[2-(2-oxo-2,5-dihydro-3-furanyl)ethyl]decahydro-1-naphthalenyl}-2(5H)-furanone (TRPV4); paclitaxel, (2α,5β,7β,10β,13α)-4,10-diacetoxy-13-{[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate (TRPA1, TRPV4); dicentrine, (7aS)-10,11-dimethoxy-7-methyl-6,7,7a,8-tetrahydro-5H-[1,3]benzodioxolo[6,5,4-de]benzo[g]quinoline (TRPA1).

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Figure 3

Figure 3. TRPM8 agonists. Menthol, (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol; eucalyptol, 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane; icilin, 1-(2-hydroxyphenyl)-4-(3-nitrophenyl)-3,6-dihydropyrimidin-2-one.

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Figure 4

Figure 4. TRPV1 agonists. Vanillin, has the vanillyl moiety, that is essential for activating TRPV1 channels; Capsaicin, (E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methyl-6-nonenamide, has a vanilloid and an aceyl moiety; dihydrocapsaicin, the structure of which is a 6,7-dihydro derivative of capsaicin; resiniferatoxin, has a complex structure, but shares a homovanillyl group, which is necessary for the activity of all vanilloids; eugenol, 2-methoxy-4-(2-propenyl)phenol and is a member of the allylbenzene class of chemical compounds; Cannabidiol, 2-[(1R,6R)-6-isopropenyl-3-methyl-3-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol; anandamide or arachidonylethanolamide or arachidonic acid N-(hydroxyethyl)amide consists of the acyl moiety and is an edogenous ligand of TRPV1 and cannabinoid receptor 1 (CB1).

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References

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This article references 159 other publications.
1. 1
  Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D., and Julius, D. (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway Nature 389, 816– 824
  
  1
  The capsaicin receptor: a heat-activated ion channel in the pain pathway
  
  Caterina, Michael J.; Schumacher, Mark A.; Tominaga, Makoto; Rosen, Tobias A.; Levine, Jon D.; Julius, David
  
  Nature (London) (1997), 389 (6653), 816-824CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)
  
  Capsaicin, the main pungent ingredient in 'hot' chili peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. The authors have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons. This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels. The cloned capsaicin receptor is also activated by increases in temp. in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.
  
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2. 2
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  Montell, C. and Rubin, G. M. (1989) Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction Neuron 2, 1313– 1323
  
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  Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction
  
  Montell, Craig; Rubin, Gerald M.
  
  Neuron (1989), 2 (4), 1313-23CODEN: NERNET; ISSN:0896-6273.
  
  Recent studies suggest that the fly uses the inositol lipid signaling system for visual exitation and that the Drosophila transient receptor potential (trp) mutation disrupts this process subsequent to the prodn. of IP3. This paper shows that trp encodes a novel 1275 amino acid protein with eight putative transmembrane segments. Immunolocalization indicates that the trp protein is expressed predominantly in the rhabdomeric membranes of the photoreceptor cells.
  
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4. 4
  Montell, C. (2005) The TRP superfamily of cation channels Sci. STKE re3
  
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5. 5
  Story, G. M., Peier, A. M., Reeve, A. J., Eid, S. R., Mosbacher, J., Hricik, T. R., Earley, T. J., Hergarden, A. C., Andersson, D. A., Hwang, S. W., McIntyre, P., Jegla, T., Bevan, S., and Patapoutian, A. (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures Cell 112, 819– 829
  
  5
  ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures
  
  Story, Gina M.; Peier, Andrea M.; Reeve, Alison J.; Eid, Samer R.; Mosbacher, Johannes; Hricik, Todd R.; Earley, Taryn J.; Hergarden, Anne C.; Andersson, David A.; Hwang, Sun Wook; McIntyre, Peter; Jegla, Tim; Bevan, Stuart; Patapoutian, Ardem
  
  Cell (Cambridge, MA, United States) (2003), 112 (6), 819-829CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
  
  Mammals detect temp. with specialized neurons in the peripheral nervous system. Four TRPV-class channels have been implicated in sensing heat, and one TRPM-class channel in sensing cold. The combined range of temps. that activate these channels covers a majority of the relevant physiol. spectrum sensed by most mammals, with a significant gap in the noxious cold range. Here, we describe the characterization of ANKTM1, a cold-activated channel with a lower activation temp. compared to the cold and menthol receptor, TRPM8. ANKTM1 is a distant family member of TRP channels with very little amino acid similarity to TRPM8. It is found in a subset of nociceptive sensory neurons where it is coexpressed with TRPV1/VR1 (the capsaicin/heat receptor) but not TRPM8. Consistent with the expression of ANKTM1, we identify noxious cold-sensitive sensory neurons that also respond to capsaicin but not to menthol.
  
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6. 6
  Jordt, S. E., Bautista, D. M., Chuang, H. H., McKemy, D. D., Zygmunt, P. M., Hogestatt, E. D., Meng, I. D., and Julius, D. (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1 Nature 427, 260– 265
  
  6
  Mustard oils and cannabinoids excite sensory nerve fibers through the TRP channel ANKTM1
  
  Jordt, Sven-Eric; Bautista, Diana M.; Chuang, Huai-hu; McKemy, David D.; Zygmunt, Peter M.; Hoegestaett, Edward D.; Meng, Ian D.; Julius, David
  
  Nature (London, United Kingdom) (2004), 427 (6971), 260-265CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  
  Wasabi, horseradish and mustard owe their pungency to isothiocyanate compds. Topical application of mustard oil (allyl isothiocyanate) to the skin activates underlying sensory nerve endings, thereby producing pain, inflammation and robust hypersensitivity to thermal and mech. stimuli. Despite their widespread use in both the kitchen and the lab., the mol. mechanism through which isothiocyanates mediate their effects remains unknown. Here we show that mustard oil depolarizes a subpopulation of primary sensory neurons that are also activated by capsaicin, the pungent ingredient in chilli peppers, and by Δ9-tetrahydrocannabinol (THC), the psychoactive component of marijuana. Both allyl isothiocyanate and THC mediate their excitatory effects by activating ANKTM1, a member of the TRP ion channel family recently implicated in the detection of noxious cold. These findings identify a cellular and mol. target for the pungent action of mustard oils and support an emerging role for TRP channels as ionotropic cannabinoid receptors.
  
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7. 7
  Peier, A. M., Moqrich, A., Hergarden, A. C., Reeve, A. J., Andersson, D. A., Story, G. M., Earley, T. J., Dragoni, I., McIntyre, P., Bevan, S., and Patapoutian, A. (2002) A TRP channel that senses cold stimuli and menthol Cell 108, 705– 715
  
  7
  A TRP channel that senses cold stimuli and menthol
  
  Peier, Andrea M.; Moqrich, Aziz; Hergarden, Anne C.; Reeve, Alison J.; Andersson, David A.; Story, Gina M.; Earley, Taryn J.; Dragoni, Ilaria; McIntyre, Peter; Bevan, Stuart; Patapoutian, Ardem
  
  Cell (Cambridge, MA, United States) (2002), 108 (5), 705-715CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
  
  A distinct subset of sensory neurons are thought to directly sense changes in thermal energy through their termini in the skin. Very little is known about the mols. that mediate thermoreception by these neurons. Vanilloid receptor 1 (VR1), a member of the TRP family of channels, is activated by noxious heat. Here the authors describe the cloning and characterization of TRPM8, a distant relative of VR1. TRPM8 is specifically expressed in a subset of pain- and temp.-sensing neurons. Cells overexpressing the TRPM8 channel can be activated by cold temps. and by a cooling agent, menthol. The identification of a cold-sensing TRP channel in a distinct subpopulation of sensory neurons implicates an expanded role for this family of ion channels in somatic sensory detection.
  
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8. 8
  McKemy, D. D., Neuhausser, W. M., and Julius, D. (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation Nature 416, 52– 58
  
  8
  Identification of a cold receptor reveals a general role for TRP channels in thermosensation
  
  McKemy, David D.; Neuhausser, Werner M.; Julius, David
  
  Nature (London, United Kingdom) (2002), 416 (6876), 52-58CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  
  The cellular and mol. mechanisms that enable us to sense cold are not well understood. Insights into this process have come from the use of pharmacol. agents, such as menthol, that elicit a cooling sensation. Here we have characterized and cloned a menthol receptor from trigeminal sensory neurons that is also activated by thermal stimuli in the cool to cold range. This cold- and menthol-sensitive receptor, CMR1, is a member of the TRP family of excitatory ion channels, and we propose that it functions as a transducer of cold stimuli in the somatosensory system. These findings, together with our previous identification of the heat-sensitive channels VR1 and VRL-1, demonstrate that TRP channels detect temps. over a wide range and are the principal sensors of thermal stimuli in the mammalian peripheral nervous system.
  
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9. 9
  Cao, E., Liao, M., Cheng, Y., and Julius, D. (2013) TRPV1 structures in distinct conformations reveal activation mechanisms Nature 504, 113– 118
  
  9
  TRPV1 structures in distinct conformations reveal activation mechanisms
  
  Cao, Erhu; Liao, Maofu; Cheng, Yifan; Julius, David
  
  Nature (London, United Kingdom) (2013), 504 (7478), 113-118CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  
  Transient receptor potential (TRP) channels are polymodal signal detectors that respond to a wide range of phys. and chem. stimuli. Elucidating how these channels integrate and convert physiol. signals into channel opening is essential to understanding how they regulate cell excitability under normal and pathophysiol. conditions. Here we exploit pharmacol. probes (a peptide toxin and small vanilloid agonists) to det. structures of two activated states of the capsaicin receptor, TRPV1. A domain (consisting of transmembrane segments 1-4) that moves during activation of voltage-gated channels remains stationary in TRPV1, highlighting differences in gating mechanisms for these structurally related channel superfamilies. TRPV1 opening is assocd. with major structural rearrangements in the outer pore, including the pore helix and selectivity filter, as well as pronounced dilation of a hydrophobic constriction at the lower gate, suggesting a dual gating mechanism. Allosteric coupling between upper and lower gates may account for rich physiol. modulation exhibited by TRPV1 and other TRP channels.
  
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10. 10
  Liao, M., Cao, E., Julius, D., and Cheng, Y. (2013) Structure of the TRPV1 ion channel determined by electron cryo-microscopy Nature 504, 107– 112
  
  10
  Structure of the TRPV1 ion channel determined by electron cryo-microscopy
  
  Liao, Maofu; Cao, Erhu; Julius, David; Cheng, Yifan
  
  Nature (London, United Kingdom) (2013), 504 (7478), 107-112CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  
  Transient receptor potential (TRP) channels are sensors for a wide range of cellular and environmental signals, but elucidating how these channels respond to phys. and chem. stimuli has been hampered by a lack of detailed structural information. Here, the authors exploited advances in electron cryo-microscopy to det. the structure of a mammalian TRP channel, TRPV1, at 3.4 Å resoln., breaking the side-chain resoln. barrier for membrane proteins without crystn. Like voltage-gated channels, TRPV1 exhibited 4-fold symmetry around a central ion pathway formed by transmembrane segments 5-6 (S5-S6) and the intervening pore loop, which was flanked by S1-S4 voltage-sensor-like domains. TRPV1 had a wide extracellular 'mouth' with a short selectivity filter. The conserved 'TRP domain' interacted with the S4-S5 linker, consistent with its contribution to allosteric modulation. Subunit organization was facilitated by interactions among cytoplasmic domains, including N-terminal ankyrin repeats. These observations provide a structural blueprint for understanding unique aspects of TRP channel function.
  
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11. 11
  Bikman, B. T., Zheng, D., Pories, W. J., Chapman, W., Pender, J. R., Bowden, R. C., Reed, M. A., Cortright, R. N., Tapscott, E. B., Houmard, J. A., Tanner, C. J., Lee, J., and Dohm, G. L. (2008) Mechanism for improved insulin sensitivity after gastric bypass surgery J. Clin. Endocrinol. Metab. 93, 4656– 4663
  
  11
  Mechanism for improved insulin sensitivity after gastric bypass surgery
  
  Bikman, Benjamin T.; Zheng, Donghai; Pories, Walter J.; Chapman, William; Pender, John R.; Bowden, Rita C.; Reed, Melissa A.; Cortright, Ronald N.; Tapscott, Edward B.; Houmard, Joseph A.; Tanner, Charles J.; Lee, Jihyun; Dohm, G. Lynis
  
  Journal of Clinical Endocrinology and Metabolism (2008), 93 (12), 4656-4663CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)
  
  Surgical treatments of obesity were shown to induce rapid and prolonged improvements in insulin sensitivity. The aim of the study was to investigate the effects of gastric bypass surgery and the mechanisms that explain the improvement in insulin sensitivity. The authors performed a cross-sectional, nonrandomized, controlled study. This study was conducted jointly between the Departments of Exercise Science and Physiol. at East Carolina University in Greenville, North Carolina. Subjects were recruited into 4 groups: 1) lean [body mass index (BMI < 25 kg/m2; n = 93]; 2) wt.-matched (BMI = 25 to 35 kg/m2; n = 310); 3) morbidly obese (BMI > 35 kg/m2; n = 43); and 4) postsurgery patients (BMI ≈ 30 kg/m2; n = 40)]. Postsurgery patients were wt. stable 1 yr after surgery. Whole-body insulin sensitivity, muscle glucose transport, and muscle insulin signaling were assessed. Postsurgery subjects had insulin sensitivity index values that were similar to the lean and higher than morbidly obese and wt.-matched control subjects. Glucose transport was higher in the postsurgery vs. morbidly obese and wt.-matched groups. IRS1-pSer312 in the postsurgery group was lower than morbidly obese and wt.-matched groups. Inhibitor κBα was higher in the postsurgery vs. the morbidly obese and wt.-matched controls, indicating reduced inhibitor of κB kinase β activity. Insulin sensitivity and glucose transport are greater in the postsurgery patients than predicted from the wt.-matched group, suggesting that improved insulin sensitivity after bypass is due to something other than, or in addn. to, wt. loss. Improved insulin sensitivity is related to reduced inhibitor of κB kinase β activity and enhanced insulin signaling in muscle.
  
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12. 12
  Corey, D. P., Garcia-Anoveros, J., Holt, J. R., Kwan, K. Y., Lin, S. Y., Vollrath, M. A., Amalfitano, A., Cheung, E. L., Derfler, B. H., Duggan, A., Geleoc, G. S., Gray, P. A., Hoffman, M. P., Rehm, H. L., Tamasauskas, D., and Zhang, D. S. (2004) TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells Nature 432, 723– 730
  
  There is no corresponding record for this reference.
13. 13
  Bandell, M., Story, G. M., Hwang, S. W., Viswanath, V., Eid, S. R., Petrus, M. J., Earley, T. J., Patapoutian, A., Bautista, D. M., Movahed, P., Hinman, A., Axelsson, H. E., Sterner, O., Hogestatt, E. D., Julius, D., Jordt, S. E., and Zygmunt, P. M. (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin Neuron 41, 849– 857
  
  13
  Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin
  
  Bandell, Michael; Story, Gina M.; Hwang, Sun Wook; Viswanath, Veena; Eid, Samer R.; Petrus, Matt J.; Earley, Taryn J.; Patapoutian, Ardem
  
  Neuron (2004), 41 (6), 849-857CODEN: NERNET; ISSN:0896-6273. (Cell Press)
  
  Six members of the mammalian transient receptor potential (TRP) ion channels respond to varied temp. thresholds. The natural compds. capsaicin and menthol activate noxious heat-sensitive TRPV1 and cold-sensitive TRPM8, resp. The burning and cooling perception of capsaicin and menthol demonstrate that these ion channels mediate thermosensation. The authors show that, in addn. to noxious cold, pungent natural compds. present in cinnamon oil, wintergreen oil, clove oil, mustard oil, and ginger all activate TRPA1 (ANKTM1). Bradykinin, an inflammatory peptide acting through its G protein-coupled receptor, also activates TRPA1. The authors further show that phospholipase C is an important signaling component for TRPA1 activation. Cinnamaldehyde, the most specific TRPA1 activator, excites a subset of sensory neurons highly enriched in cold-sensitive neurons and elicits nociceptive behavior in mice. Collectively, these data demonstrate that TRPA1 activation elicits a painful sensation and provide a potential mol. model for why noxious cold can paradoxically be perceived as burning pain.
  
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14. 14
  Bautista, D. M., Movahed, P., Hinman, A., Axelsson, H. E., Sterner, O., Hogestatt, E. D., Julius, D., Jordt, S. E., and Zygmunt, P. M. (2005) Pungent products from garlic activate the sensory ion channel TRPA1 Proc. Natl. Acad. Sci. U.S.A. 102, 12248– 12252
  
  14
  Pungent products from garlic activate the sensory ion channel TRPA1
  
  Bautista, Diana M.; Movahed, Pouya; Hinman, Andrew; Axelsson, Helena E.; Sterner, Olov; Hogestatt, Edward D.; Julius, David; Jordt, Sven-Eric; Zygmunt, Peter M.
  
  Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (34), 12248-12252CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  
  Garlic belongs to the Allium family of plants that produce organosulfur compds., such as allicin and diallyl disulfide (DADS), which account for their pungency and spicy aroma. Many health benefits have been ascribed to Allium exts., including hypotensive and vasorelaxant activities. However, the mol. mechanisms underlying these effects remain unknown. Intriguingly, allicin and DADS share structural similarities with allyl isothiocyanate, the pungent ingredient in wasabi and other mustard plants that induces pain and inflammation by activating TRPA1, an excitatory ion channel on primary sensory neurons of the pain pathway. Here we show that allicin and DADS excite an allyl isothiocyanate-sensitive subpopulation of sensory neurons and induce vasodilation by activating capsaicin-sensitive perivascular sensory nerve endings. Moreover, allicin and DADS activate the cloned TRPA1 channel when expressed in heterologous systems. These and other results suggest that garlic excites sensory neurons primarily through activation of TRPA1. Thus different plant genera, including Allium and Brassica, have developed evolutionary convergent strategies that target TRPA1 channels on sensory nerve endings to achieve chem. deterrence.
  
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15. 15
  Macpherson, L. J., Geierstanger, B. H., Viswanath, V., Bandell, M., Eid, S. R., Hwang, S., and Patapoutian, A. (2005) The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin Curr. Biol. 15, 929– 934
  
  15
  The Pungency of Garlic: Activation of TRPA1 and TRPV1 in Response to Allicin
  
  Macpherson, Lindsey J.; Geierstanger, Bernhard H.; Viswanath, Veena; Bandell, Michael; Eid, Samer R.; Hwang, SunWook; Patapoutian, Ardem
  
  Current Biology (2005), 15 (10), 929-934CODEN: CUBLE2; ISSN:0960-9822. (Cell Press)
  
  A review. Summary: Garlic's pungent flavor has made it a popular ingredient in cuisines around the world and throughout history. Garlic's health benefits have been elevated from folklore to clin. study [1-5]. Although there is some controversy as to the efficacy of garlic, garlic products are one of the most popular herbal supplements in the U.S. [6]. Chem. complex, garlic contains different assortments of sulfur compds. depending on whether the cloves are intact, crushed, cooked, or raw [7]. Raw garlic, when cut and placed on the tongue or lips, elicits painful burning and prickling sensations through unknown mechanisms. Here, we show that raw but not baked garlic activates TRPA1 and TRPV1, two temp.-activated ion channels that belong to the transient receptor potential (TRP) family [8-12]. These thermoTRPs are present in the pain-sensing neurons that innervate the mouth. We further show that allicin, an unstable component of fresh garlic, is the chem. responsible for TRPA1 and TRPV1 activation and is therefore likely to cause garlic's pungency.
  
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16. 16
  Kwan, K. Y., Allchorne, A. J., Vollrath, M. A., Christensen, A. P., Zhang, D. S., Woolf, C. J., and Corey, D. P. (2006) TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction Neuron 50, 277– 289
  
  There is no corresponding record for this reference.
17. 17
  Andersson, D. A., Gentry, C., Moss, S., and Bevan, S. (2008) Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress J. Neurosci. 28, 2485– 2494
  
  17
  Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress
  
  Andersson, David A.; Gentry, Clive; Moss, Sian; Bevan, Stuart
  
  Journal of Neuroscience (2008), 28 (10), 2485-2494CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
  
  Transient receptor potential A1 (TRPA1) is expressed in a subset of nociceptive sensory neurons where it acts as a sensor for environmental irritants, including acrolein, and some pungent plant ingredients such as allyl isothiocyanate and cinnamaldehyde. These exogenous compds. activate TRPA1 by covalent modification of cysteine residues. We have used electrophysiol. methods and measurements of intracellular calcium concn. ([Ca2+]i) to show that TRPA1 is activated by several classes of endogenous thiolreactive mols. TRPA1 was activated by hydrogen peroxide (H2O2; EC50, 230 μM), by endogenously occurring alkenyl aldehydes (EC50: 4-hydroxynonenal 19.9 μM, 4-oxo-nonenal 1.9 μM, 4-hydroxyhexenal 38.9 μM) and by the cyclopentenone prostaglandin, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, EC50: 5.6 μM). The effect of H2O2 was reversed by treatment with dithiothreitol indicating that H2O2 acts by promoting the formation of disulfide bonds whereas the actions of the alkenyl aldehydes and 15d-PGJ2 were not reversed, suggesting that these agents form Michael adducts. H2O2 and the naturally occurring alkenyl aldehydes and 15d-PGJ2 acted on a subset of isolated rat and mouse sensory neurons [∼25% of rat dorsal root ganglion (DRG) and ∼50% of nodose ganglion neurons] to evoke a depolarizing inward current and an increase in [Ca2+]i in TRPA1 expressing neurons. The abilities of H2O2, alkenyl aldehydes and 15d-PGJ2 to raise [Ca2+]i in mouse DRG neurons were greatly reduced in neurons from trpa1-/- mice. Furthermore, intraplantar injection of either H2O2 or 15d-PGJ2 evoked a nocifensive/pain response in wild-type mice, but not in trpa1-/- mice. These data demonstrate that multiple agents produced during episodes of oxidative stress can activate TRPA1 expressed in sensory neurons.
  
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18. 18
  Bessac, B. F., Sivula, M., von Hehn, C. A., Escalera, J., Cohn, L., and Jordt, S. E. (2008) TRPA1 is a major oxidant sensor in murine airway sensory neurons J. Clin. Invest. 118, 1899– 1910
  
  18
  TRPA1 is a major oxidant sensor in murine airway sensory neurons
  
  Bessac, Bret F.; Sivula, Michael; von Hehn, Christian A.; Escalera, Jasmine; Cohn, Lauren; Jordt, Sven-Eric
  
  Journal of Clinical Investigation (2008), 118 (5), 1899-1910CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)
  
  Sensory neurons in the airways are finely tuned to respond to reactive chems. threatening airway function and integrity. Nasal trigeminal nerve endings are particularly sensitive to oxidants formed in polluted air and during oxidative stress as well as to chlorine, which is frequently released in industrial and domestic accidents. Oxidant activation of airway neurons induces respiratory depression, nasal obstruction, sneezing, cough, and pain. While normally protective, chemosensory airway reflexes can provoke severe complications in patients affected by inflammatory airway conditions like rhinitis and asthma. Here, we showed that both hypochlorite, the oxidizing mediator of chlorine, and hydrogen peroxide, a reactive oxygen species, activated Ca2+ influx and membrane currents in an oxidant-sensitive subpopulation of chemosensory neurons. These responses were absent in neurons from mice lacking TRPA1, an ion channel of the transient receptor potential (TRP) gene family. TRPA1 channels were strongly activated by hypochlorite and hydrogen peroxide in primary sensory neurons and heterologous cells. In tests of respiratory function, Trpa1-/- mice displayed profound deficiencies in hypochlorite- and hydrogen peroxide-induced respiratory depression as well as decreased oxidant-induced pain behavior. Our results indicate that TRPA1 is an oxidant sensor in sensory neurons, initiating neuronal excitation and subsequent physiol. responses in vitro and in vivo.
  
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19. 19
  Cao, D. S., Zhong, L., Hsieh, T. H., Abooj, M., Bishnoi, M., Hughes, L., and Premkumar, L. S. (2012) Expression of transient receptor potential ankyrin 1 (TRPA1) and its role in insulin release from rat pancreatic beta cells PloS One 7, e38005
  
  There is no corresponding record for this reference.
20. 20
  Brownlee, M. (2001) Biochemistry and molecular cell biology of diabetic complications Nature 414, 813– 820
  
  20
  Biochemistry and molecular cell biology of diabetic complications
  
  Brownlee, Michael
  
  Nature (London, United Kingdom) (2001), 414 (6865), 813-820CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  
  A review. Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main mol. mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycemia-induced process of overprodn. of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.
  
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21. 21
  Nagata, K., Duggan, A., Kumar, G., and Garcia-Anoveros, J. (2005) Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing J. Neurosci. 25, 4052– 4061
  
  21
  Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing
  
  Nagata, Keiichi; Duggan, Anne; Kumar, Gagan; Garcia-Anoveros, Jaime
  
  Journal of Neuroscience (2005), 25 (16), 4052-4061CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
  
  Mechanosensory channels of sensory cells mediate the sensations of hearing, touch, and some forms of pain. The TRPA1 (a member of the TRP family of ion channel proteins) channel is activated by pain-producing chems., and its inhibition impairs hair cell mechanotransduction. As shown here and previously, TRPA1 is expressed by hair cells as well as by most nociceptors (small neurons of dorsal root, trigeminal, and nodose ganglia) and localizes to their sensory terminals (mechanosensory stereocilia and peripheral free nerves, resp.). Thus, TRPA1 channels are proposed to mediate transduction in both hair cells and nociceptors. Accordingly, we find that heterologously expressed TRPA1 display channel behaviors expected for both auditory and nociceptive transducers. First, TRPA1 and the hair cell transducer share a unique set of pore properties not described for any other channel (block by gadolinium, amiloride, gentamicin, and ruthenium red, a ranging conductance of ∼100 pS that is reduced to 54% by calcium, permeating calcium-induced potentiation followed by closure, and reopening by depolarization), supporting a direct role of TRPA1 as a pore-forming subunit of the hair cell transducer. Second, TRPA1 channels inactivate in hyperpolarized cells but remain open in depolarized cells. This property provides a mechanism for the lack of desensitization, coincidence detection, and allodynia that characterize pain by allowing a sensory neuron to respond constantly to sustained stimulation that is suprathreshold (i.e., noxious) and yet permitting the same cell to ignore sustained stimulation that is subthreshold (i.e., innocuous). Our results support a TRPA1 role in both nociceptor and hair cell transduction.
  
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22. 22
  Obata, K., Katsura, H., Mizushima, T., Yamanaka, H., Kobayashi, K., Dai, Y., Fukuoka, T., Tokunaga, A., Tominaga, M., and Noguchi, K. (2005) TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury J. Clin. Invest. 115, 2393– 2401
  
  There is no corresponding record for this reference.
23. 23
  Hinman, A., Chuang, H. H., Bautista, D. M., and Julius, D. (2006) TRP channel activation by reversible covalent modification Proc. Natl. Acad. Sci. U.S.A. 103, 19564– 19568
  
  23
  TRP channel activation by reversible covalent modification
  
  Hinman, Andrew; Chuang, Huai-hu; Bautista, Diana M.; Julius, David
  
  Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (51), 19564-19568CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  
  Allyl isothiocyanate, the pungent principle of wasabi and other mustard oils, produces pain by activating TRPA1, an excitatory ion channel on sensory nerve endings. Isothiocyanates are membrane--permeable electrophiles that form adducts with thiols and primary amines, suggesting that covalent modification, rather than classical lock-and-key binding, accounts for their agonist properties. Indeed, we show that the thio1 reactive compds. of diverse structure activate TRPA1 in a manner that relies on covalent modification of cysteine residues within the cytoplasmic N terminus of the channel. These findings suggest an unusual paradigm whereby natural products activate a receptor through direct, reversible, and covalent protein modification.
  
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24. 24
  Raisinghani, M., Zhong, L., Jeffry, J. A., Bishnoi, M., Pabbidi, R. M., Pimentel, F., Cao, D. S., Evans, M. S., and Premkumar, L. S. (2011) Activation characteristics of transient receptor potential ankyrin 1 and its role in nociception Am. J. Physiol.: Cell Physiol. 301, C587– 600
  
  There is no corresponding record for this reference.
25. 25
  Premkumar, L. S. and Raisinghani, M. (2006) Nociceptors in cardiovascular functions: complex interplay as a result of cyclooxygenase inhibition Mol. Pain 2, 26
  
  25
  Nociceptors in cardiovascular functions: complex interplay as a result of cyclooxygenase inhibition
  
  Premkumar Louis S; Raisinghani Manish
  
  Molecular pain (2006), 2 (), 26 ISSN:.
  
  Prostaglandins (PGs) are requisite components of inflammatory pain as indicated by the efficacy of cyclooxygenase 1/2 (COX1/2) inhibitors. PGs do not activate nociceptive ion channels directly, but sensitize them by downstream mechanisms linked to G-protein coupled receptors. Antiinflammatory effects are purported to arise from inhibition of synthesis and/or release of proinflammatory agents. Release of these agents from peripheral and central terminals of sensory neurons modulates nociceptive input from the periphery and synaptic transmission at the first sensory synapse, respectively. Heart and blood vessels are densely innervated by sensory nerve endings that express chemo-, mechano-, and thermo-sensitive receptors. Activation of these receptors mediates synthesis and/or release of vasoactive agents by virtue of their Ca2+permeability. In this article, we discuss that inhibition of COX2 reduces PG synthesis and renders beneficial effects by preventing sensitization of nociceptors, but at the same time, it might contribute to deleterious cardiovascular effects by compromising the synthesis and/or release of vasoactive agents.
  
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26. 26
  Khan, A., Safdar, M., Ali Khan, M. M., Khattak, K. N., and Anderson, R. A. (2003) Cinnamon improves glucose and lipids of people with type 2 diabetes Diabetes Care 26, 3215– 3218
  
  26
  Cinnamon improves glucose and lipids of people with type 2 diabetes
  
  Khan Alam; Safdar Mahpara; Ali Khan Mohammad Muzaffar; Khattak Khan Nawaz; Anderson Richard A
  
  Diabetes care (2003), 26 (12), 3215-8 ISSN:0149-5992.
  
  OBJECTIVE: The objective of this study was to determine whether cinnamon improves blood glucose, triglyceride, total cholesterol, HDL cholesterol, and LDL cholesterol levels in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 60 people with type 2 diabetes, 30 men and 30 women aged 52.2 +/- 6.32 years, were divided randomly into six groups. Groups 1, 2, and 3 consumed 1, 3, or 6 g of cinnamon daily, respectively, and groups 4, 5, and 6 were given placebo capsules corresponding to the number of capsules consumed for the three levels of cinnamon. The cinnamon was consumed for 40 days followed by a 20-day washout period. RESULTS: After 40 days, all three levels of cinnamon reduced the mean fasting serum glucose (18-29%), triglyceride (23-30%), LDL cholesterol (7-27%), and total cholesterol (12-26%) levels; no significant changes were noted in the placebo groups. Changes in HDL cholesterol were not significant. CONCLUSIONS: The results of this study demonstrate that intake of 1, 3, or 6 g of cinnamon per day reduces serum glucose, triglyceride, LDL cholesterol, and total cholesterol in people with type 2 diabetes and suggest that the inclusion of cinnamon in the diet of people with type 2 diabetes will reduce risk factors associated with diabetes and cardiovascular diseases.
  
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27. 27
  Hlebowicz, J., Darwiche, G., Bjorgell, O., and Almer, L. O. (2007) Effect of cinnamon on postprandial blood glucose, gastric emptying, and satiety in healthy subjects Am. J. Clin. Nutr. 85, 1552– 1556
  
  27
  Effect of cinnamon on postprandial blood glucose, gastric emptying, and satiety in healthy subjects
  
  Hlebowicz, Joanna; Darwiche, Gassan; Bjoergell, Ola; Almer, Lars-Olof
  
  American Journal of Clinical Nutrition (2007), 85 (6), 1552-1556CODEN: AJCNAC; ISSN:0002-9165. (American Society for Nutrition)
  
  Background: Previous studies of patients with type 2 diabetes showed that cinnamon lowers fasting serum glucose, triacylglycerol, and LDL- and total cholesterol concns. Objective: We aimed to study the effect of cinnamon on the rate of gastric emptying, the postprandial blood glucose response, and satiety in healthy subjects. Design: The gastric emptying rate (GER) was measured by using standardized real-time ultrasonog. Fourteen healthy subjects were assessed by using a crossover trial. The subjects were examd. after an 8-h fast if they had normal fasting blood glucose concns. GER was calcd. as the percentage change in the antral cross-sectional area 15-90 min after ingestion of 300 g rice pudding (GER1) or 300 g rice pudding and 6 g cinnamon (GER2). Results: The median value of GER1 was 37%, and that of GER2 was 34.5%. The addn. of cinnamon to the rice pudding significantly delayed gastric emptying and lowered the postprandial glucose response (P < 0.05 for both). The redn. in the postprandial blood glucose concn. was much more noticeable and pronounced than was the lowering of the GER. The effect of cinnamon on satiety was not significant. Conclusions: The intake of 6 g cinnamon with rice pudding reduces postprandial blood glucose and delays gastric emptying without affecting satiety. Inclusion of cinnamon in the diet lowers the postprandial glucose response, a change that is at least partially explained by a delayed GER.
  
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28. 28
  Lissiman, E., Bhasale, A. L., and Cohen, M. (2009) Garlic for the common cold Cochrane Database Syst. Rev. 3, CD006206
  
  There is no corresponding record for this reference.
29. 29
  Lissiman, E., Bhasale, A. L., and Cohen, M. (2012) Garlic for the common cold Cochrane Database Syst. Rev. 14, CD006206
  
  There is no corresponding record for this reference.
30. 30
  Cutler, R. R., Odent, M., Hajj-Ahmad, H., Maharjan, S., Bennett, N. J., Josling, P. D., Ball, V., Hatton, P., and Dall’Antonia, M. (2009) In vitro activity of an aqueous allicin extract and a novel allicin topical gel formulation against Lancefield group B streptococci J. Antimicrob. Chemother. 63, 151– 154
  
  30
  In vitro activity of an aqueous allicin extract and a novel allicin topical gel formulation against Lancefield group B streptococci
  
  Cutler, Ronald R.; Odent, Michel; Hajj-Ahmad, Hussein; Maharjan, Sunil; Bennett, Norman J.; Josling, Peter D.; Ball, Vanessa; Hatton, Paulette; Dall'Antonia, Martino
  
  Journal of Antimicrobial Chemotherapy (2009), 63 (1), 151-154CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
  
  Background Studies have shown the efficacy of intra-partum antibiotics in preventing early-onset group B streptococcal sepsis. This approach results in a high intra-partum antibiotic use. The same antibiotics used in prophylaxis are also first-line treatment for neonatal sepsis, and antibiotic exposure in the peri-natal period has been shown to be a risk factor for late-onset serious bacterial infections and allergic disease. Antibiotic exposure in the peri-natal period is becoming a major public health issue; alternative strategies are needed. Garlic has been traditionally used to treat vaginal infections. Allicin is the main antibacterial agent isolated from garlic. The aim of the study was to investigate the in vitro activity of a novel allicin ext. in aq. and gel formulation against 76 clin. isolates of Lancefield group B streptococci (GBS). MICs and MBCs of allicin were detd. for 76 GBS isolates by agar diln. and microtiter plate methods. Killing kinetics were detd. for a selected 16 of the 76 strains. Agar diffusion tests were compared for allicin liq. and gel (500 mg/L). Results and conclusions MICs and MBCs of allicin liq. were 35 to 95 mg/L and 75 to 315 mg/L, resp. Time/dose kill curves produced a 2-3 log redn. in cfu/mL within 3 h and no detectable growth at 8 and 24 h. A novel 500 mg/L allicin gel produced an av. zone size of 23 ± 6 mm compared with 21 ± 6 mm for allicin in water. Aq. allicin is bactericidal against GBS isolates and maintains activity in a novel gel formulation.
  
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31. 31
  Khanum, F., Anilakumar, K. R., and Viswanathan, K. R. (2004) Anticarcinogenic properties of garlic: a review Crit. Rev. Food. Sci. Nutr. 44, 479– 488
  
  There is no corresponding record for this reference.
32. 32
  Shenoy, N. R. and Choughuley, A. S. (1992) Inhibitory effect of diet related sulphydryl compounds on the formation of carcinogenic nitrosamines Cancer Lett. 65, 227– 232
  
  32
  Inhibitory effect of diet related sulfhydryl compounds on the formation of carcinogenic nitrosamines
  
  Shenoy, Narmada R.; Choughuley, Ahmed S. U.
  
  Cancer Letters (Shannon, Ireland) (1992), 65 (3), 227-32CODEN: CALEDQ; ISSN:0304-3835.
  
  The authors studied the modifying effect of sulfhydryl compd. viz., cysteine (CE), cystine (CI), glutathione (GU), cysteamine (CEA), cystamine (CEI), cysteic acid (CIA) and thioglycolic acid (TGA) on the nitrosation of model amines viz., pyrrolidine (PYR), piperidine (NPIP) and morpholine (NMOR). The present work also describes the inhibitory effect of onion and garlic juices on the nitrosation reactions. Most of these compds. behave as antinitrosating agents and their inhibitory activity towards formation of carcinogenic nitrosamines, under different conditions is described.
  
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33. 33
  Koizumi, K., Iwasaki, Y., Narukawa, M., Iitsuka, Y., Fukao, T., Seki, T., Ariga, T., and Watanabe, T. (2009) Diallyl sulfides in garlic activate both TRPA1 and TRPV1 Biochem. Biophys. Res. Commun. 382, 545– 548
  
  There is no corresponding record for this reference.
34. 34
  Leamy, A. W., Shukla, P., McAlexander, M. A., Carr, M. J., and Ghatta, S. (2011) Curcumin ((E,E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) activates and desensitizes the nociceptor ion channel TRPA1 Neurosci. Lett. 503, 157– 162
  
  There is no corresponding record for this reference.
35. 35
  Gupta, S. C., Patchva, S., and Aggarwal, B. B. (2013) Therapeutic roles of curcumin: lessons learned from clinical trials AAPS J. 15, 195– 218
  
  35
  Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials
  
  Gupta, Subash C.; Patchva, Sridevi; Aggarwal, Bharat B.
  
  AAPS Journal (2013), 15 (1), 195-218CODEN: AJAOB6; ISSN:1550-7416. (Springer)
  
  A review. Extensive research over the past half century has shown that curcumin (diferuloylmethane), a component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling pathways. Extensive clin. trials over the past quarter century have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects have been obsd. in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn's disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis. Curcumin has also shown protection against hepatic conditions, chronic arsenic exposure, and alc. intoxication. Dose-escalating studies have indicated the safety of curcumin at doses as high as 12 g/day over 3 mo. Curcumin's pleiotropic activities emanate from its ability to modulate numerous signaling mols. such as pro-inflammatory cytokines, apoptotic proteins, NF-κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E2, prostate-specific antigen, adhesion mols., phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1, creatinine, HO-1, AST, and ALT in human participants. In clin. trials, curcumin has been used either alone or in combination with other agents. Various formulations of curcumin, including nanoparticles, liposomal encapsulation, emulsions, capsules, tablets, and powder, have been examd. In this review, we discuss in detail the various human diseases in which the effect of curcumin has been investigated.
  
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36. 36
  Song, Y., Sonawane, N. D., Salinas, D., Qian, L., Pedemonte, N., Galietta, L. J., and Verkman, A. S. (2004) Evidence against the rescue of defective DeltaF508-CFTR cellular processing by curcumin in cell culture and mouse models J. Biol. Chem. 279, 40629– 40633
  
  There is no corresponding record for this reference.
37. 37
  Gao, J., Zhou, H., Lei, T., Zhou, L., Li, W., Li, X., and Yang, B. (2011) Curcumin inhibits renal cyst formation and enlargement in vitro by regulating intracellular signaling pathways Eur. J. Pharmacol. 654, 92– 99
  
  37
  Curcumin inhibits renal cyst formation and enlargement in vitro by regulating intracellular signaling pathways
  
  Gao, Jinsheng; Zhou, Hong; Lei, Tianluo; Zhou, Li; Li, Weidong; Li, Xuejun; Yang, Baoxue
  
  European Journal of Pharmacology (2011), 654 (1), 92-99CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)
  
  Autosomal dominant polycystic kidney disease, a common inherited disease affecting about 1/1000 and 1/400 live births, is characterized by massive enlargement of fluid-filled cysts and eventually causes renal failure. The purpose of this study is to identify the inhibitory effect of curcumin on renal cyst development and to investigate the inhibitory mechanism. Madin-Darby canine kidney (MDCK) cyst model and murine embryonic kidney cyst model were used to evaluate inhibitory activity. Cell viability, proliferation, apoptosis, CFTR function and expression, and signaling pathways in MDCK cells were detd. to explore the mechanism of cyst inhibition. Curcumin was found to significantly inhibit MDCK cyst development. At max. dose curcumin caused 62% inhibition of the cyst formation (IC50 was 0.12 μM). Curcumin slowed cyst enlargement in both MDCK cyst model and embryonic kidney cyst model with dose-response relationship. Curcumin neither induced cytotoxicity nor apoptosis in MDCK cells at < 100 μM. Curcumin failed to affect the chloride transporter CFTR expression and function. Interestingly, curcumin inhibited forskolin-promoted cell proliferation and promoted the tubule formation in MDCK cells, which indicates curcumin promotes MDCK cell differentiation. Furthermore, curcumin reduced the intracellular signaling proteins Ras, B-raf, p-MEK, p-ERK, c-fos, Egr-1, but increased Raf-1 and NAB2 in MDCK cells exposed to forskolin. These results define that curcumin inhibits renal cyst formation and enlargement and suggest that curcumin might be developed as a candidate drug for polycystic kidney disease.
  
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38. 38
  Sohma, Y., Yu, Y. C., and Hwang, T. C. (2013) Curcumin and genistein: the combined effects on disease-associated CFTR mutants and their clinical implications Curr. Pharm. Des. 19, 3521– 3528
  
  38
  Curcumin and genistein: the combined effects on disease-associated CFTR mutants and their clinical implications
  
  Sohma, Yoshiro; Yu, Ying-Chun; Hwang, Tzyh-Chang
  
  Current Pharmaceutical Design (2013), 19 (19), 3521-3528CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
  
  A review. Genistein and curcumin are major components of Asian foods, soybean and curry turmeric resp. These compds. have been intensively investigated for their chem. and biol. features conferring their anti-cancer activity. Genistein and curcumin have also been investigated for their potentiation effects on disease-assocd. CFTR mutants such as ΔF508 and G551D. Recently, we investigated the combined effect of genistein and curcumin on G551D-CFTR, which exhibits gating defects without abnormalities in protein synthesis or trafficking using the patch-clamp technique. We found that genistein and curcumin showed additive effects on their potentiation of G551D-CFTR in high concn. range and also, more importantly, showed a significant synergistic effect in their min. concn. ranges. These results are consistent with the idea that multiple mechanisms are involved in the action of these CFTR potentiators. In this review, we revisit the pharmacol. of genistein and curcumin on CFTR and also propose new pharmaceutical implications of combined use of these compds. in the development of drugs for CF pharmacotherapy.
  
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39. 39
  Nassini, R., Materazzi, S., Vriens, J., Prenen, J., Benemei, S., De Siena, G., la Marca, G., Andre, E., Preti, D., Avonto, C., Sadofsky, L., Di Marzo, V., De Petrocellis, L., Dussor, G., Porreca, F., Taglialatela-Scafati, O., Appendino, G., Nilius, B., and Geppetti, P. (2012) The ‘headache tree’ via umbellulone and TRPA1 activates the trigeminovascular system Brain 135, 376– 390
  
  There is no corresponding record for this reference.
40. 40
  Zhong, J., Pollastro, F., Prenen, J., Zhu, Z., Appendino, G., and Nilius, B. (2011) Ligustilide: a novel TRPA1 modulator Pfluegers Arch. 462, 841– 849
  
  40
  Ligustilide: a novel TRPA1 modulator
  
  Zhong, Jian; Pollastro, Federica; Prenen, Jean; Zhu, Zhiming; Appendino, Giovanni; Nilius, Bernd
  
  Pfluegers Archiv (2011), 462 (6), 841-849CODEN: PFLABK; ISSN:0031-6768. (Springer GmbH)
  
  TRPA1 is activated by electrophilic compds. such as mustard oil (MO). Here, we demonstrate a bimodal sensitivity of TRPA1 to ligustilide (Lig), an electrophilic volatile dihydrophthalide of dietary and medicinal relevance. Lig is a potent TRPA1 activator and is also capable to induce a modest block of MO activated currents. Aromatization to dehydroligustilide (DH-Lig), as occurs during aging of its botanical sources, reversed this profile, enhancing TRPA1 inhibition and reducing activation. Mutation of the reactive cysteines in mouseTRPA1 (C622S, C642S, C666S) dramatically reduced activation by MO and significantly reduced that by Lig, but had an almost negligible effect on the action of DH-Lig, whose activation mechanism of TRPA1 is therefore largely independent from the alkylation of cysteine residues. Taken together, these observations show that the phthalide structural motif is a versatile platform to investigate the modulation of TRPA1 by small mols., being tunable in terms of activation/inhibition profile and mechanism of interaction. Finally, the action of Lig on TRPA1 may contribute to the gustatory effects of celery, its major dietary source, and to the pharmacol. action of important plants from the Chinese and native American traditional medicines.
  
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41. 41
  Materazzi, S., Fusi, C., Benemei, S., Pedretti, P., Patacchini, R., Nilius, B., Prenen, J., Creminon, C., Geppetti, P., and Nassini, R. (2012) TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism Pfluegers Arch. 463, 561– 569
  
  41
  TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism
  
  Materazzi, Serena; Fusi, Camilla; Benemei, Silvia; Pedretti, Pamela; Patacchini, Riccardo; Nilius, Bernd; Prenen, Jean; Creminon, Christophe; Geppetti, Pierangelo; Nassini, Romina
  
  Pfluegers Archiv (2012), 463 (4), 561-569CODEN: PFLABK; ISSN:0031-6768. (Springer GmbH)
  
  Paclitaxel produces a sensory neuropathy, characterized by mech. and cold hypersensitivity, which are abated by antioxidants. The transient receptor potential vanilloid 4 (TRPV4) channel was reported to contribute to paclitaxel-evoked allodynia in rodents. We recently showed that TRP ankyrin 1 (TRPA1) channel mediates oxaliplatin-evoked cold and mech. allodynia, and the drug targets TRPA1 via generation of oxidative stress. Here, we have explored whether TRPA1 activation contributes to paclitaxel-induced mech. and cold hypersensitivity and whether this activation is mediated by oxidative stress generation. Paclitaxel-evoked mech. allodynia was reduced partially by the TRPA1 antagonist, HC-030031, and the TRPV4 antagonist, HC-067047, and was completely abated by the combination of the 2 antagonists. The reduced paclitaxel-evoked mech. allodynia, obsd. in TRPA1-deficient mice, was completely abolished when mice were treated with HC-067047. Cold allodynia was abated completely by HC-030031 and in TRPA1-deficient mice. Exposure to paclitaxel of slices of mouse esophagus released the sensory neuropeptide, calcitonin gene-related peptide (CGRP). This effect was abolished by capsaicin desensitization and in calcium-free medium (indicating neurosecretion from sensory nerve terminals), partially reduced by either HC-030031 or HC-067047, and completely abated in the presence of glutathione (GSH). Finally, the reduced CGRP release, obsd. in esophageal slices of TRPA1-deficient mice, was further inhibited by GSH. Paclitaxel via oxygen radical formation targets TRPA1 and TRPV4, and both channels are key for the delayed development of mech. allodynia. Cold allodynia is, however, entirely dependent on TRPA1.
  
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42. 42
  De Petrocellis, L., Vellani, V., Schiano-Moriello, A., Marini, P., Magherini, P. C., Orlando, P., and Di Marzo, V. (2008) Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8 J. Pharmacol. Exp. Ther. 325, 1007– 1015
  
  42
  Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8
  
  De Petrocellis, Luciano; Vellani, Vittorio; Schiano-Moriello, Aniello; Marini, Pietro; Magherini, Pier Cosimo; Orlando, Pierangelo; Di Marzo, Vincenzo
  
  Journal of Pharmacology and Experimental Therapeutics (2008), 325 (3), 1007-1015CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
  
  The plant cannabinoids (phytocannabinoids), cannabidiol (CBD), and Δ9-tetrahydrocannabinol (THC) were previously shown to activate transient receptor potential channels of both vanilloid type 1 (TRPV1) and ankyrin type 1 (TRPA1), resp. Furthermore, the endocannabinoid anandamide is known to activate TRPV1 and was recently found to antagonize the menthol- and icilin-sensitive transient receptor potential channels of melastatin type 8 (TRPM8). In this study, we investigated the effects of six phytocannabinoids [i.e., CBD, THC, CBD acid, THC acid, cannabichromene (CBC), and cannabigerol (CBG)] on TRPA1- and TRPM8-mediated increase in intracellular Ca2+ in either HEK-293 cells overexpressing the two channels or rat dorsal root ganglia (DRG) sensory neurons. All of the compds. tested induced TRPA1-mediated Ca2+ elevation in HEK-293 cells with efficacy comparable with that of mustard oil isothiocyanates (MO), the most potent being CBC (EC50 = 60 nM) and the least potent being CBG and CBD acid (EC50 = 3.4-12.0 μM). CBC also activated MO-sensitive DRG neurons, although with lower potency (EC50 = 34.3 μM). Furthermore, although none of the compds. tested activated TRPM8-mediated Ca2+ elevation in HEK-293 cells, they all, with the exception of CBC, antagonized this response when it was induced by either menthol or icilin. CBD, CBG, THC, and THC acid were equipotent (IC50 = 70-160 nM), whereas CBD acid was the least potent compd. (IC50 = 0.9-1.6 μM). CBG inhibited Ca2+ elevation also in icilin-sensitive DRG neurons with potency (IC50 = 4.5 μM) similar to that of anandamide (IC50 = 10 μM). Our findings suggest that phytocannabinoids and cannabis exts. exert some of their pharmacol. actions also by interacting with TRPA1 and TRPM8 channels, with potential implications for the treatment of pain and cancer.
  
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43. 43
  Montrucchio, D. P., Cordova, M. M., and Santos, A. R. (2013) Plant derived aporphinic alkaloid S-(+)-dicentrine induces antinociceptive effect in both acute and chronic inflammatory pain models: evidence for a role of TRPA1 channels PloS One 8, e67730
  
  There is no corresponding record for this reference.
44. 44
  Talavera, K., Gees, M., Karashima, Y., Meseguer, V. M., Vanoirbeek, J. A., Damann, N., Everaerts, W., Benoit, M., Janssens, A., Vennekens, R., Viana, F., Nemery, B., Nilius, B., and Voets, T. (2009) Nicotine activates the chemosensory cation channel TRPA1 Nat. Neurosci. 12, 1293– 1299
  
  44
  Nicotine activates the chemosensory cation channel TRPA1
  
  Talavera, Karel; Gees, Maarten; Karashima, Yuji; Meseguer, Victor M.; Vanoirbeek, Jeroen A. J.; Damann, Nils; Everaerts, Wouter; Benoit, Melissa; Janssens, Annelies; Vennekens, Rudi; Viana, Felix; Nemery, Benoit; Nilius, Bernd; Voets, Thomas
  
  Nature Neuroscience (2009), 12 (10), 1293-1299CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
  
  Topical application of nicotine, as used in nicotine replacement therapies, causes irritation of the mucosa and skin. This reaction has been attributed to activation of nicotinic acetylcholine receptors (nAChRs) in chemosensory neurons. In contrast with this view, the chemosensory cation channel transient receptor potential A1 (TRPA1) is crucially involved in nicotine-induced irritation. Micromolar concns. of nicotine activated heterologously expressed mouse and human TRPA1. Nicotine acted in a membrane-delimited manner, stabilizing the open state(s) and destabilizing the closed state(s) of the channel. In the presence of the general nAChR blocker hexamethonium, nociceptive neurons showed nicotine-induced responses that were strongly reduced in TRPA1-deficient mice. Finally, TRPA1 mediated the mouse airway constriction reflex to nasal instillation of nicotine. The identification of TRPA1 as a nicotine target suggests that existing models of nicotine-induced irritation should be revised and may facilitate the development of smoking cessation therapies with less adverse effects.
  
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45. 45
  Riera, C. E., Menozzi-Smarrito, C., Affolter, M., Michlig, S., Munari, C., Robert, F., Vogel, H., Simon, S. A., and Le Coutre, J. (2009) Compounds from Sichuan and Melegueta peppers activate, covalently and non-covalently, TRPA1 and TRPV1 channels Br. J. Pharmacol. 157, 1398– 1409
  
  45
  Compounds from Sichuan and Melegueta peppers activate, covalently and non-covalently, TRPA1 and TRPV1 channels
  
  Riera, C. E.; Menozzi-Smarrito, C.; Affolter, M.; Michlig, S.; Munari, C.; Robert, F.; Vogel, H.; Simon, S. A.; Le Coutre, J.
  
  British Journal of Pharmacology (2009), 157 (8), 1398-1409CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)
  
  Background and purpose: Oily exts. of Sichuan and Melegueta peppers evoke pungent sensations mediated by different alkylamides [mainly hydroxy-α-sanshool (α-SOH)] and hydroxyarylalkanones (6-shogaol and 6-paradol). We assessed how transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (TRPV1), two chemosensory ion channels, participate in these pungent sensations. Exptl. approach: The structure-activity relationships of these mols. on TRPA1 and TRPV1 was measured by testing natural and synthetic analogs using calcium and voltage imaging on dissocd. dorsal root ganglia neurons and human embryonic kidney 293 cells expressing the wild-type channels or specific cysteine mutants using glutathione trapping as a model to probe TRPA1 activation. In addn., using Trpv1 knockout mice, the compds.' aversive responses were measured in a taste brief-access test. Key results: For TRPA1 activation, the cis C6 double bond in the polyenic chain of α-SOH was crit., whereas no structural specificity was required for activation of TRPV1. Both 6-shogaol and 6-paradol were found to activate TRPV1 and TRPA1 channels, whereas linalool, an abundant terpene in Sichuan pepper, activated TRPA1 but not TRPV1 channels. Alkylamides and 6-shogaol act on TRPA1 by covalent bonding whereas none of these compds. activated TRPV1 through such interactions. Finally, TRPV1 mutant mice retained sensitivity to 6-shogaol but were not responsive to α-SOH. Conclusions and implications: The pungent nature of components of Sichuan and Melegueta peppers was mediated via interactions with TRPA1 and TRPV1 channels and may explain the aversive properties of these compds.
  
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46. 46
  Vazquez, G., Wedel, B. J., Aziz, O., Trebak, M., and Putney, J. W., Jr. (2004) The mammalian TRPC cation channels Biochim. Biophys. Acta 1742, 21– 36
  
  46
  The mammalian TRPC cation channels
  
  Vazquez, Guillermo; Wedel, Barbara J.; Aziz, Omar; Trebak, Mohamed; Putney, James W.
  
  Biochimica et Biophysica Acta, Molecular Cell Research (2004), 1742 (1-3), 21-36CODEN: BBAMCO; ISSN:0167-4889. (Elsevier B.V.)
  
  A review. Transient Receptor Potential-Canonical (TRPC) channels are mammalian homologs of Transient Receptor Potential (TRP), a Ca2+-permeable channel involved in the phospholipase C-regulated photoreceptor activation mechanism in Drosophila. The seven mammalian TRPCs constitute a family of channels which have been proposed to function as store-operated as well as second messenger-operated channels in a variety of cell types. TRPC channels, together with other more distantly related channel families, make up the larger TRP channel superfamily. This review summarizes recent findings on the structure, regulation and function of the apparently ubiquitous TRPC cation channels.
  
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47. 47
  Birnbaumer, L. (2009) The TRPC class of ion channels: a critical review of their roles in slow, sustained increases in intracellular Ca(2+) concentrations Annu. Rev. Pharmacol. Toxicol. 49, 395– 426
  
  There is no corresponding record for this reference.
48. 48
  Leuner, K., Kazanski, V., Muller, M., Essin, K., Henke, B., Gollasch, M., Harteneck, C., and Muller, W. E. (2007) Hyperforin--a key constituent of St. John’s wort specifically activates TRPC6 channels FASEB J. 21, 4101– 4111
  
  There is no corresponding record for this reference.
49. 49
  Sikand, P. and Premkumar, L. S. (2007) Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse J. Physiol. 581, 631– 647
  
  49
  Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse
  
  Sikand, Parul; Premkumar, Louis S.
  
  Journal of Physiology (Oxford, United Kingdom) (2007), 581 (2), 631-647CODEN: JPHYA7; ISSN:0022-3751. (Blackwell Publishing Ltd.)
  
  Sensory input from the periphery to the CNS is critically dependent on the strength of synaptic transmission at the first sensory synapse formed between primary afferent dorsal root ganglion (DRG) and superficial dorsal horn (DH) neurons of the spinal cord. Transient receptor potential vanilloid 1 (TRPV1) expressed on a subset of sensory neurons plays an important role in chronic inflammatory thermal nociception. Activation of protein kinase C (PKC) sensitizes TRPV1, which may contribute to the pathophysiol. of chronic pain conditions. In this study, the authors have examd. the modulation of TRPV1-mediated enhancement of excitatory synaptic transmission in response to PKC activation. Miniature excitatory postsynaptic currents (mEPSCs) from embryonic rat DRG-DH neuronal cocultures were recorded by patch clamping DH neurons. Capsaicin potently increased the frequency but not the amplitude of mEPSCs in a calcium-dependent manner, suggesting TRPV1-mediated glutamate release from presynaptic terminals of sensory neurons. Continued or repeated applications of capsaicin reduced the frequency of mEPSCs over time. The PKC activator phorbol 12,13-dibutyrate (PDBu) alone increased mEPSC events to a certain extent in a reversible manner but capsaicin further synergistically enhanced the frequency of mEPSCs. The PKC inhibitor bisindolylmaleimide (BIM) abolished PDBu-mediated potentiation of TRPV1-dependent increases in mEPSC frequency, suggesting modulation of TRPV1 by PKC-induced phosphorylation. In addn., at normal body temps. (∼37°) PKC-mediated enhancement of mEPSC frequency is significantly decreased by a specific TRPV1 antagonist, suggesting a physiol. role of TRPV1 at the central terminals. Furthermore, bradykinin (BK) significantly potentiated TRPV1-modulated synaptic responses by activating the PLC-PKC pathway. The authors' results indicate that TRPV1 activation can modulate excitatory synaptic transmission at the first sensory synapse and its effects can further be augmented by activation of PKC. Increased gain of sensory input by TRPV1-induced enhancement of glutamate release and its potentiation by various inflammatory mediators may contribute to persistent pain conditions. Selective targeting of TRPV1 expressed on the central terminals of sensory neurons may serve as a strategy to alleviate chronic intractable pain conditions.
  
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50. 50
  Cao, D. S., Yu, S. Q., and Premkumar, L. S. (2009) Modulation of transient receptor potential Vanilloid 4-mediated membrane currents and synaptic transmission by protein kinase C Mol. Pain 5, 5
  
  50
  Modulation of transient receptor potential Vanilloid 4-mediated membrane currents and synaptic transmission by protein kinase C
  
  Cao De-Shou; Yu Shuang-Quan; Premkumar Louis S
  
  Molecular pain (2009), 5 (), 5 ISSN:.
  
  BACKGROUND: Transient receptor potential Vanilloid (TRPV) receptors are involved in nociception and are expressed predominantly in sensory neurons. TRPV1, a non-selective cation channel has been extensively studied and is responsible for inflammatory thermal hypersensitivity. In this study, the expression and function of TRPV4 have been characterized and compared with those of TRPV1. RESULTS: Immunohistochemical studies revealed that both TRPV1 and TRPV4 were co-expressed in dorsal root ganglion (DRG) neuronal cell bodies and in the central terminals of laminae I and II of the spinal dorsal horn (DH). In Ca2+ fluorescence imaging and whole-cell patch-clamp experiments, TRPV1- and TRPV4-mediated responses were observed in a population of the same DRG neurons. Sensitization of TRPV1 has been shown to be involved in inflammatory pain conditions. Incubation with phorbol 12, 13-dibutyrate (PDBu), a PKC activator, resulted in a significant potentiation of TRPV4 currents in DRG neurons. In TRPV4 expressing HEK 293T cells, PDBu increased 4alpha-phorbol 12, 13-didecanoate (4alpha-PDD)-induced single-channel activity in cell-attached patches, which was abrogated by bisindolylmaleimide (BIM), a selective PKC inhibitor. TRPV4 is also expressed at the central terminals of sensory neurons. Activation of TRPV4 by 4alpha-PDD increased the frequency of miniature excitatory post synaptic currents (mEPSCs) in DRG-DH neuronal co-cultures. 4alpha-PDD-induced increase in the frequency of mEPSCs was further enhanced by PDBu. The expression of TRP channels has been shown in other areas of the CNS; application of 4alpha-PDD significantly increased the mEPSC frequency in cultured hippocampal neurons, which was further potentiated by PDBu, whereas, TRPV1 agonist capsaicin did not modulate synaptic transmission. CONCLUSION: These results indicate that TRPV4 and TRPV1 are co-expressed in certain DRG neurons and TRPV4 can be sensitized by PKC not only in DRG neuronal cell bodies, but also in the central sensory and non-sensory nerve terminals. Co-expression of TRPV1 and TRPV4 ion channels, their modulation of synaptic transmission and their sensitization by PKC may synergistically play a role in nociception.
  
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51. 51
  Jeffry, J. A., Yu, S. Q., Sikand, P., Parihar, A., Evans, M. S., and Premkumar, L. S. (2009) Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia PloS One 4, e7021
  
  There is no corresponding record for this reference.
52. 52
  Evans, M. S., Cheng, X., Jeffry, J. A., Disney, K. E., and Premkumar, L. S. (2012) Sumatriptan inhibits TRPV1 channels in trigeminal neurons Headache 52, 773– 784
  
  There is no corresponding record for this reference.
53. 53
  Zhou, J., Du, W., Zhou, K., Tai, Y., Yao, H., Jia, Y., and Ding, Y. (2008) Critical role of TRPC6 channels in the formation of excitatory synapses Nat. Neurosci. 11, 741– 743
  
  53
  Critical role of TRPC6 channels in the formation of excitatory synapses
  
  Zhou, Jian; Du, Wanlu; Zhou, Kechun; Tai, Yilin; Yao, Hailan; Jia, Yichang; Ding, Yuqiang; Wang, Yizheng
  
  Nature Neuroscience (2008), 11 (7), 741-743CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
  
  TRPC6 promotes the formation of synapses in a CaMKIV-CREB-dependent manner. TRPC6-expressing transgenic animals showed increased nos. of spines and demonstrated enhanced learning on behavioral tasks. TRPC6 promotes the formation of synapses in a CaMKIV-CREB-dependent manner. TRPC6-expressing transgenic animals showed increased nos. of spines and demonstrated enhanced learning on behavioral tasks. The transient receptor potential canonical (TRPC) channels are Ca2+-permeable, nonselective cation channels with different biol. functions, but their roles in brain are largely unknown. Here we report that TRPC6 was localized to excitatory synapses and promoted their formation via a CaMKIV-CREB-dependent pathway. TRPC6 transgenic mice showed enhancement in spine formation, and spatial learning and memory in Morris water maze. These results reveal a previously unknown role of TRPC6 in synaptic and behavioral plasticity.
  
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54. 54
  Nilius, B. and Owsianik, G. (2011) The transient receptor potential family of ion channels Genome Biol. 12, 218
  
  54
  The transient receptor potential family of ion channels
  
  Nilius, Bernd; Owsianik, Grzegorz
  
  Genome Biology (2011), 12 (), 218CODEN: GNBLFW; ISSN:1474-760X. (BioMed Central Ltd.)
  
  A review. The transient receptor potential (TRP) multigene superfamily encodes integral membrane proteins that function as ion channels. Members of this family are conserved in yeast, invertebrates and vertebrates. The TRP family is subdivided into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin) and TRPN (NOMPC-like); the latter is found only in invertebrates and fish. TRP ion channels are widely expressed in many different tissues and cell types, where they are involved in diverse physiol. processes, such as sensation of different stimuli or ion homeostasis. Most TRPs are non-selective cation channels, only few are highly Ca2+ selective, some are even permeable for highly hydrated Mg2+ ions. This channel family shows a variety of gating mechanisms, with modes of activation ranging from ligand binding, voltage and changes in temp. to covalent modifications of nucleophilic residues. Activated TRP channels cause depolarization of the cellular membrane, which in turn activates voltage-dependent ion channels, resulting in a change of intracellular Ca2+ concn.; they serve as gatekeeper for transcellular transport of several cations (such as Ca2+ and Mg2+), and are required for the function of intracellular organelles (such as endosomes and lysosomes). Because of their function as intracellular Ca2+ release channels, they have an important regulatory role in cellular organelles. Mutations in several TRP genes have been implicated in diverse pathol. states, including neurodegenerative disorders, skeletal dysplasia, kidney disorders and pain, and ongoing research may help find new therapies for treatments of related diseases.
  
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55. 55
  Carakostas, M. C., Curry, L. L., Boileau, A. C., and Brusick, D. J. (2008) Overview: the history, technical function and safety of rebaudioside A, a naturally occurring steviol glycoside, for use in food and beverages Food Chem. Toxicol. 46 (Suppl 7) S1– S10
  
  There is no corresponding record for this reference.
56. 56
  Medler, K. F. (2011) Multiple roles for TRPs in the taste system: not your typical TRPs Adv. Exp. Med. Biol. 704, 831– 846
  
  There is no corresponding record for this reference.
57. 57
  Sprous, D. and Palmer, K. R. (2010) The T1R2/T1R3 sweet receptor and TRPM5 ion channel taste targets with therapeutic potential Prog. Mol. Biol. Transl. Sci. 91, 151– 208
  
  57
  The T1R2/T1R3 sweet receptor and TRPM5 ion channel: taste targets with therapeutic potential
  
  Sprous, Dennis; Palmer, Kyle R.
  
  Progress in Molecular Biology and Translational Science (2010), 91 (Membrane Proteins as Drug Targets), 151-208CODEN: PNARC5 ISSN:. (Elsevier Inc.)
  
  A review. A review on the hypothesis of gastrointestinal taste signaling and the potential for T1R2/T1R3 and TRPM5 as targets of therapeutic intervention in obesity and diabetes. Topics covered include ingestive behaviors as therapeutic endpoints, taste signaling proteins as targets for the drug discovery approach, obesity and diabetes, T1R2/T1R3 sweet receptor, TRPM5 ion channel, morphol. and functional characteristics of type II taste cells, morphol. and functional characteristics of gut chemosensory cells, taste signaling in the gut, type II taste cells are not secretory cells, discovery of useful ligands for sweet receptors and TRPM5, creating focused libraries through chemoinformatics, computational and chemoinformatics methods, and directions for drug discovery.
  
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58. 58
  Palmer, R. K. (2007) The pharmacology and signaling of bitter, sweet, and umami taste sensing Mol. Interv. 7, 87– 98
  
  There is no corresponding record for this reference.
59. 59
  Depoortere, I. (2014) Taste receptors of the gut: emerging roles in health and disease Gut 63, 179– 190
  
  There is no corresponding record for this reference.
60. 60
  Kaji, I., Karaki, S. I., and Kuwahara, A. (2014) Taste Sensing in the Colon Curr. Pharm. Des. 20, 2766– 2774
  
  60
  Taste Sensing in the Colon
  
  Kaji, Izumi; Karaki, Shin-ichiro; Kuwahara, Atsukazu
  
  Current Pharmaceutical Design (2014), 20 (16), 2766-2774CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
  
  The colonic lumen is continually exposed to many compds., including beneficial and harmful compds. that are produced by colonic microflora. The intestinal epithelia form a barrier between the internal and luminal (external) environments. Chem. receptors that sense the luminal environment are thought to play important roles as sensors and as modulators of epithelial cell functions. The recent mol. identification of various membrane receptor proteins has revealed the sensory role of intestinal epithelial cells. Nutrient sensing by these receptors in the small intestine is implicated in nutrient absorption and metab. However, little is known about the physiol. roles of chemosensors in the large intestine. Since 1980s, researchers have examd. the effects of short-chain fatty acids (SCFA), the primary products of commensal bacteria, on gut motility, secretion, and incretin release, for example. In this decade, the SCFA receptor genes and their expression were identified in the mammalian colon. Furthermore, many other chem. receptors, including taste and olfactory receptors have been found in colonic epithelial cells. These findings indicate that the large intestinal epithelia express chemosensors that detect the luminal contents, particularly bacterial metabolites, and induce the host defense systems and the modulation of systemic metab. via incretin release. In this review, we describe the local effects of chem. stimuli on the lumen assocd. with the expression pattern of sensory receptors. We propose that sensory receptors expressed in the colonic mucosa play important roles in luminal chemosensing to maintain homeostasis.
  
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61. 61
  Premkumar, L. S., Raisinghani, M., Pingle, S. C., Long, C., and Pimentel, F. (2005) Downregulation of transient receptor potential melastatin 8 by protein kinase C-mediated dephosphorylation J. Neurosci. 25, 11322– 11329
  
  61
  Downregulation of transient receptor potential melastatin 8 by protein kinase C-mediated dephosphorylation
  
  Premkumar Louis S; Raisinghani Manish; Pingle Sandeep C; Long Cheng; Pimentel Fatima
  
  The Journal of neuroscience : the official journal of the Society for Neuroscience (2005), 25 (49), 11322-9 ISSN:.
  
  Transient receptor potential melastatin 8 (TRPM8) and transient receptor potential vanilloid 1 (TRPV1) are ion channels that detect cold and hot sensations, respectively. Their activation depolarizes the peripheral nerve terminals resulting in action potentials that propagate to brain via the spinal cord. These receptors also play a significant role in synaptic transmission between dorsal root ganglion (DRG) and dorsal horn (DH) neurons. Here, we show that TRPM8 is functionally downregulated by activation of protein kinase C (PKC) resulting in inhibition of membrane currents and increases in intracellular Ca2+ compared with upregulation of TRPV1 in cloned and native receptors. Bradykinin significantly downregulates TRPM8 via activation of PKC in DRG neurons. Activation of TRPM8 or TRPV1 at first sensory synapse between DRG and DH neurons leads to a robust increase in frequency of spontaneous/miniature EPSCs. PKC activation blunts TRPM8- and facilitates TRPV1-mediated synaptic transmission. Significantly, downregulation is attributable to PKC-mediated dephosphorylation of TRPM8 that could be reversed by phosphatase inhibitors. These findings suggest that inflammatory thermal hyperalgesia mediated by TRPV1 may be further aggravated by downregulation of TRPM8, because the latter could mediate the much needed cool/soothing sensation.
  
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62. 62
  Tsuzuki, K., Xing, H., Ling, J., and Gu, J. G. (2004) Menthol-induced Ca2+ release from presynaptic Ca2+ stores potentiates sensory synaptic transmission J. Neurosci. 24, 762– 771
  
  62
  Menthol-induced Ca2+ release from presynaptic Ca2+ stores potentiates sensory synaptic transmission
  
  Tsuzuki, Kenzo; Xing, Hong; Ling, Jennifer; Gu, Jianguo G.
  
  Journal of Neuroscience (2004), 24 (3), 762-771CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
  
  Menthol and many of its derivs. produce profound sensory and mental effects. The receptor for menthol has been cloned and named cold- and menthol-sensitive receptor-1 (CMR1) or transient receptor potential channel M8 (TRPM8) receptor. Using a dorsal root ganglion (DRG) and dorsal horn (DH) coculture system as a model for the first sensory synapse in the CNS, we studied menthol effects on sensory synaptic transmission and the underlying mechanisms. We found that menthol increased the frequency of miniature EPSCs (mEPSCs). The effects persisted under an extracellular Ca2+-free condition but were abolished by intracellular BAPTA and pretreatment with thapsigargin. Menthol-induced increases of mEPSC frequency were blocked by 2-aminoethoxydiphenylborane (2-APB) but not affected by the phospholipase C inhibitor U73122 or by the cADP receptor inhibitor 8-bromo-cADPR (8Br-cADPR). Double-patch recordings from DRG-DH pairs showed that menthol could potentiate evoked EPSCs (eEPSCs) and change the paired-pulse ratio of eEPSCs. A Ca2+ imaging study on DRG neurons demonstrated that menthol could directly release Ca2+ from intracellular Ca2+ stores. Menthol-induced Ca2+ release was abolished by 2-APB but not affected by U73122 or 8Br-cADPR. Taken together, our results indicate that menthol can act directly on presynaptic Ca2+ stores of sensory neurons to release Ca2+, resulting in a facilitation of glutamate release and a modulation of neuronal transmission at sensory synapses. Expression of TRPM8 receptor on presynaptic Ca2+ stores, a novel localization for this ligand-gated ion channel, is also strongly suggested.
  
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63. 63
  Tsavaler, L., Shapero, M. H., Morkowski, S., and Laus, R. (2001) Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins Cancer Res. 61, 3760– 3769
  
  63
  Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins
  
  Tsavaler, Larisa; Shapero, Michael H.; Morkowski, Stan; Laus, Reiner
  
  Cancer Research (2001), 61 (9), 3760-3769CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
  
  The authors have identified and cloned a novel gene, trp-p8, by screening a prostate-specific subtracted cDNA library. The 5694-bp cDNA has a 3312-bp open reading frame, which codes for a 1104 amino acid putative protein with seven transmembrane domains. The predicted protein revealed significant homol. with the transient receptor potential (trp) family of Ca2+ channel proteins. Northern blot anal. indicated that trp-p8 expression within normal human tissues is mostly restricted to prostate epithelial cells. In situ hybridization anal. showed that trp-p8 mRNA expression was at moderate levels in normal prostate tissue and appears to be elevated in prostate cancer. Notably, trp-p8 mRNA was also expressed in a no. of nonprostatic primary tumors of breast, colon, lung, and skin origin, whereas transcripts encoding trp-p8 were hardly detected or not detected in the corresponding normal human tissues.
  
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64. 64
  Uhl, G. R., Walther, D., Behm, F. M., and Rose, J. E. (2011) Menthol preference among smokers: association with TRPA1 variants Nicotine Tob. Res. 13, 1311– 1315
  
  64
  Menthol Preference Among Smokers: Association With TRPA1 Variants
  
  Uhl, George R.; Walther, Donna; Behm, Frederique M.; Rose, Jed E.
  
  Nicotine & Tobacco Research (2011), 13 (12), 1311-1315CODEN: NTREF6; ISSN:1462-2203. (Oxford University Press)
  
  Introduction: Preference for smoking menthol cigarettes differs from individual to individual and population to population in ways that may provide higher levels of nicotine intake and contribute to smoking's morbidity and mortality. Menthol acts at sites that include the transient receptor potential (TRP) A1 channel that is expressed by nociceptors in the lung and airways, suggesting that individual and population differences in TRPA1 sequences might contribute to obsd. differences in menthol preference among smokers. Methods: We have thus sought assocn. between menthol preference and common variants in the TRPA1 gene in heavier and lighter European-American smokers. Smokers were recruited for studies of smoking cessation in North Carolina and of substance abuse genetics in Maryland. Results: A common TRPA1 haplotype is defined by 1 missense and 10 intronic single nucleotide polymorphisms that display significant (.006 < p < .05; χ2) assocn. with preference for mentholated cigarettes in heavy smokers (odds ratio ca. 1.3). There are smaller trends in the same direction in lighter smokers. Conclusions: This TRPA1 haplotype provides a novel biol. basis for individual differences in menthol preference and possibly for actions of other agents that act at TRPA1.
  
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65. 65
  Hans, M., Wilhelm, M., and Swandulla, D. (2012) Menthol suppresses nicotinic acetylcholine receptor functioning in sensory neurons via allosteric modulation Chem. Senses 37, 463– 469
  
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  Menthol Suppresses Nicotinic Acetylcholine Receptor Functioning in Sensory Neurons via Allosteric Modulation
  
  Hans, M.; Wilhelm, M.; Swandulla, D.
  
  Chemical Senses (2012), 37 (5), 463-469CODEN: CHSED8; ISSN:0379-864X. (Oxford University Press)
  
  In this study, we have investigated how the function of native and recombinant nicotinic acetylcholine receptors (nAChRs) is modulated by the monoterpenoid alc. from peppermint (-) menthol. In trigeminal neurons (TG), we found that nicotine (75 μM)-activated whole-cell currents through nAChRs were reversibly reduced by menthol in a concn.-dependent manner with an IC50 of 111 μM. To analyze the mechanism underlying menthol's action in more detail, we used single channel and whole-cell recordings from recombinant human α4β2 nAChR expressed in HEK tsA201 cells. Here, we found a shortening of channel open time and a prolongation of channel closed time, and an increase in single channel amplitude leading in summary to a redn. in single channel current. Furthermore, menthol did not affect nicotine's EC50 value for currents through recombinant human α4β2 nAChRs but caused a significant redn. in nicotine's efficacy. Taken together, these findings indicate that menthol is a neg. allosteric modulator of nAChRs.
  
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66. 66
  Willis, D. N., Liu, B., Ha, M. A., Jordt, S. E., and Morris, J. B. (2011) Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants FASEB J. 25, 4434– 4444
  
  66
  Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants
  
  Willis, Daniel N.; Liu, Boyi; Ha, Michael A.; Jordt, Sven-Eric; Morris, John B.
  
  FASEB Journal (2011), 25 (12), 4434-4444, 10.1096/fj.11-188383CODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)
  
  Menthol, the cooling agent in peppermint, is added to almost all com. available cigarettes. Menthol stimulates olfactory sensations, and interacts with transient receptor potential melastatin 8 (TRPM8) ion channels in cold-sensitive sensory neurons, and transient receptor potential ankyrin 1 (TRPA1), an irritant-sensing channel. It is highly controversial whether menthol in cigarette smoke exerts pharmacol. actions affecting smoking behavior. Using plethysmog., we investigated the effects of menthol on the respiratory sensory irritation response in mice elicited by smoke irritants (acrolein, acetic acid, and cyclohexanone). Menthol, at a concn. (16 ppm) lower than in smoke of mentholated cigarettes, immediately abolished the irritation response to acrolein, an agonist of TRPA1, as did eucalyptol (460 ppm), another TRPM8 agonist. Menthol's effects were reversed by a TRPM8 antagonist, AMTB. Menthol's effects were not specific to acrolein, as menthol also attenuated irritation responses to acetic acid, and cyclohexanone, an agonist of the capsaicin receptor, TRPV1. Menthol was efficiently absorbed in the respiratory tract, reaching local concns. sufficient for activation of sensory TRP channels. These expts. demonstrate that menthol and eucalyptol, through activation of TRPM8, act as potent counterirritants against a broad spectrum of smoke constituents. Through suppression of respiratory irritation, menthol may facilitate smoke inhalation and promote nicotine addiction and smoking-related morbidities.
  
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67. 67
  Leuenroth, S. J., Okuhara, D., Shotwell, J. D., Markowitz, G. S., Yu, Z., Somlo, S., and Crews, C. M. (2007) Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease Proc. Natl. Acad. Sci. U.S.A. 104, 4389– 4394
  
  There is no corresponding record for this reference.
68. 68
  Szallasi, A. and Blumberg, P. M. (1999) Vanilloid (Capsaicin) receptors and mechanisms Pharmacol. Rev. 51, 159– 212
  
  68
  Vanilloid (capsaicin) receptors and mechanisms
  
  Szallasi, Arpad; Blumberg, Peter M.
  
  Pharmacological Reviews (1999), 51 (2), 159-211CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)
  
  A review with 560 refs. Topics discussed include the targets and actions of capsaicin; direct evidence for a vanilloid (capsaicin) receptor (VR); anatomical localization and tissue specificity of VRs; evidence for multiple VRs; biochem. pharmacol. of VRs; requirements for ligand recognition by VRs; vanilloid mechanisms; diverse biol. actions of vanilloids; species-related differences in vanilloid actions; question on the existence of endogenous vanilloids; vanilloids in clin. practice; and the question on whether vanilloids are carcinogens, anticarcinogens or neither.
  
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69. 69
  Vennekens, R., Owsianik, G., and Nilius, B. (2008) Vanilloid transient receptor potential cation channels: an overview Curr. Pharm. Des. 14, 18– 31
  
  69
  Vanilloid transient receptor potential cation channels: an overview
  
  Vennekens, Rudi; Owsianik, Grzegorz; Nilius, Bernd
  
  Current Pharmaceutical Design (2008), 14 (1), 18-31CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
  
  A review. The mammalian branch of the transient receptor potential (TRP) superfamily of cation channels consists of 28 members. They can be subdivided in six main subfamilies: the TRPC ('canonical'), TRPV ('vanilloid'), TRPM ('melastatin'), TRPP ('polycystin'), TRPML ('mucolipin'), and TRPA ('ankyrin') groups. The TRPV subfamily comprises channels that are critically involved in nociception and thermo-sensing (TRPV1, TRPV2, TRPV3, TRPV4) as well as highly Ca2+ selective channels involved in Ca2+ absorption/resorption in mammals (TRPV5, TRPV6). In this review we summarize fundamental physiol. properties of all TRPV members in the light of various cellular functions of these channels and their significance in the systemic context of the mammalian organism.
  
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70. 70
  Vriens, J., Nilius, B., and Vennekens, R. (2008) Herbal compounds and toxins modulating TRP channels Curr. Neuropharmacol. 6, 79– 96
  
  70
  Herbal compounds and toxins modulating TRP channels
  
  Vriens, Joris; Nilius, Bernd; Vennekens, Rudi
  
  Current Neuropharmacology (2008), 6 (1), 79-96CODEN: CNUEAN; ISSN:1875-6190. (Bentham Science Publishers Ltd.)
  
  A review. Although the benefits are sometimes obvious, traditional or herbal medicine is regarded with skepticism, because the mechanism through which plant compds. exert their powers are largely elusive. Recent studies have shown however that many of these plant compds. interact with specific ion channels and thereby modulate the sensing mechanism of the human body. Esp. members of the Transient Receptor Potential (TRP) channels have drawn large attention lately as the receptors for plant-derived compds. such as capsaicin and menthol. TRP channels constitute a large and diverse family of channel proteins that can serve as versatile sensors that allow individual cells and entire organisms to detect changes in their environment. For this family, a striking no. of empirical views have turned into mechanism-based actions of natural compds. In this review we will give an overview of herbal compds. and toxins, which modulate TRP channels.
  
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71. 71
  Hellwig, N., Albrecht, N., Harteneck, C., Schultz, G., and Schaefer, M. (2005) Homo- and heteromeric assembly of TRPV channel subunits J. Cell Sci. 118, 917– 928
  
  71
  Homo- and heteromeric assembly of TRPV channel subunits
  
  Hellwig, Nicole; Albrecht, Nadine; Harteneck, Christian; Schultz, Guenter; Schaefer, Michael
  
  Journal of Cell Science (2005), 118 (5), 917-928CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
  
  The vanilloid receptor-related TRP channels (TRPV1-6) mediate thermosensation, pain perception and epithelial Ca2+ entry. As the specificity of TRPV channel heteromerization and determinants governing the assembly of TRPV subunits were largely elusive, we investigated the TRPV homo- and heteromultimerization. To analyze the assembly of TRPV subunits in living cells, we generated fluorescent fusion proteins or FLAG-tagged TRPV channel subunits. The interaction between TRPV subunits was assessed by anal. of the subcellular colocalization, fluorescence resonance energy transfer and coimmunopptn. Our results demonstrate that TRPV channel subunits do not combine arbitrarily. With the exception of TRPV5 and TRPV6, TRPV channel subunits preferentially assemble into homomeric complexes. Truncation of TRPV1, expression of cytosolic termini of TRPV1 or TRPV4 and construction of chimeric TRPV channel subunits revealed that the specificity and the affinity of the subunit interaction is synergistically provided by interaction modules located in the transmembrane domains and in the cytosolic termini. The relative contribution of intramolecularly linked interaction modules presumably controls the overall affinity and the specificity of TRPV channel assembly.
  
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72. 72
  Tominaga, M., Caterina, M. J., Malmberg, A. B., Rosen, T. A., Gilbert, H., Skinner, K., Raumann, B. E., Basbaum, A. I., and Julius, D. (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli Neuron 21, 531– 543
  
  72
  The cloned capsaicin receptor integrates multiple pain-producing stimuli
  
  Tominaga, Makoto; Caterina, Michael J.; Malmberg, Annika B.; Rosen, Tobias A.; Gilbert, Heather; Skinner, Kate; Raumann, Brigitte; Basbaum, Allan I.; Julius, David
  
  Neuron (1998), 21 (3), 531-543CODEN: NERNET; ISSN:0896-6273. (Cell Press)
  
  Capsaicin, the main pungent ingredient in "hot" chili peppers, elicits burning pain by activating specific (vanilloid) receptors on sensory nerve endings. The cloned vanilloid receptor (VR1) is a cation channel that is also activated by noxious heat. Here, anal. of heat-evoked single channel currents in excised membrane patches suggests that heat gates VR1 directly. We also show that protons decrease the temp. threshold for VR1 activation such that even moderately acidic conditions (pH≤5.9) activate VR1 at room temp. VR1 can therefore be viewed as a mol. integrator of chem. and phys. stimuli that elicit pain. Immunocytochem. anal. indicates that the receptor is located in a neurochem. heterogeneous population of small diam. primary afferent fibers. A role for VR1 in injury-induced hypersensitivity at the level of the sensory neuron is presented.
  
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73. 73
  Nakatsuka, T., Furue, H., Yoshimura, M., and Gu, J. G. (2002) Activation of central terminal vanilloid receptor-1 receptors and alpha beta-methylene-ATP-sensitive P2X receptors reveals a converged synaptic activity onto the deep dorsal horn neurons of the spinal cord J. Neurosci. 22, 1228– 1237
  
  73
  Activation of central terminal vanilloid receptor-1 receptors and αβ-methylene-ATP-sensitive P2X receptors reveals a converged synaptic activity onto the deep dorsal horn neurons of the spinal cord
  
  Nakatsuka, Terumasa; Furue, Hidemasa; Yoshimura, Megumu; Gu, Jianguo G.
  
  Journal of Neuroscience (2002), 22 (4), 1228-1237CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
  
  The excitatory and inhibitory circuits connecting to lamina V neurons after the activation of afferent central terminal vanilloid receptor-1 (VR1) receptors and P2X receptors were examd. using a spinal cord slice prepn. and patch-clamp recordings from spinal cord dorsal horn neurons. The single neurons in lamina V often received excitatory inputs from two chem. defined afferent pathways, one of which was polysynaptic from capsaicin-sensitive afferent terminals. In this pathway, the capsaicin-sensitive afferent input first activated interneurons in superficial laminas, and then the excitatory activity was transmitted onto lamina V neurons. The second excitatory input was monosynaptic from αβm-ATP-sensitive/capsaicin-insensitive afferent terminals. Both capsaicin-sensitive and αβm-ATP-sensitive/capsaicin-insensitive pathways also recruited polysynaptic inhibitory inputs to lamina V neurons. The simultaneous activation of both capsaicin-sensitive afferent pathways and αβm-ATP-sensitive/capsaicin-insensitive pathways could generate a temporal summation of excitatory inputs onto single lamina V neurons. These convergent pathways may provide a mechanism of sensory integration for two chem. defined sensory inputs and may have implications in different sensory states.
  
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74. 74
  Baccei, M. L., Bardoni, R., and Fitzgerald, M. (2003) Development of nociceptive synaptic inputs to the neonatal rat dorsal horn: glutamate release by capsaicin and menthol J. Physiol. 549, 231– 242
  
  74
  Development of nociceptive synaptic inputs to the neonatal rat dorsal horn: Glutamate release by capsaicin and menthol
  
  Baccei, Mark L.; Bardoni, Rita; Fitzgerald, Maria
  
  Journal of Physiology (Cambridge, United Kingdom) (2003), 549 (1), 231-242CODEN: JPHYA7; ISSN:0022-3751. (Cambridge University Press)
  
  To study the postnatal development of nociceptive synaptic inputs in the superficial dorsal horn of the neonatal rat spinal cord, we examd. the effect of capsaicin and menthol on glutamatergic mEPSCs in postnatal day (P) 0-1, P5-6 and P9-11 slices of spinal cord. Capsaicin (100 nM to 2 μM) increased the mEPSC frequency in a concn.-dependent manner at all ages tested, with a significant enhancement of the effect between P5 and P10. This effect was sensitive to vanilloid receptor (VR) antagonists. The elevation in mEPSC frequency occurred at concns. of capsaicin (100 nM) that did not alter the distribution of mEPSC amplitudes and was abolished by a dorsal rhizotomy, demonstrating that capsaicin acts via presynaptic VR1 receptors localized on primary afferents. Menthol significantly increased the mEPSC frequency with a similar developmental pattern to capsaicin without consistently affecting mEPSC amplitude. The increase in mEPSC frequency following capsaicin did not depend on transmembrane calcium influx since it persisted in zero [Ca2+]o. The facilitation of spontaneous glutamate release by capsaicin was sufficient to evoke action potentials in neonatal dorsal horn neurons but was accompanied by a block of EPSCs evoked by elec. stimulation of the dorsal root. These results indicate that VR1-expressing nociceptive primary afferents form functional synaptic connections in the superficial dorsal horn from birth and that activation of the VR1 receptor increases spontaneous glutamate release via an undetd. mechanism. In addn., the data suggest that immature primary afferents express functional menthol receptors that are capable of modulating transmitter release. These results have important functional implications for infant pain processing.
  
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75. 75
  Kim, Y. H., Back, S. K., Davies, A. J., Jeong, H., Jo, H. J., Chung, G., Na, H. S., Bae, Y. C., Kim, S. J., Kim, J. S., Jung, S. J., and Oh, S. B. (2012) TRPV1 in GABAergic interneurons mediates neuropathic mechanical allodynia and disinhibition of the nociceptive circuitry in the spinal cord Neuron 74, 640– 647
  
  There is no corresponding record for this reference.
76. 76
  Doyle, M. W., Bailey, T. W., Jin, Y. H., and Andresen, M. C. (2002) Vanilloid receptors presynaptically modulate cranial visceral afferent synaptic transmission in nucleus tractus solitarius J. Neurosci. 22, 8222– 8229
  
  76
  Vanilloid receptors presynaptically modulate cranial visceral afferent synaptic transmission in nucleus tractus solitarius
  
  Doyle, Mark W.; Bailey, Timothy W.; Jin, Young-Ho; Andresen, Michael C.
  
  Journal of Neuroscience (2002), 22 (18), 8222-8229CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
  
  Though the central terminals of cranial visceral afferents express vanilloid receptor 1 (VR1), little is known about their functional properties at this first synapse within the nucleus tractus solitarius (NTS). Here, we examd. whether VR1 modulates afferent synaptic transmission. In horizontal brainstem slices, solitary tract (ST) activation evoked EPSCs. Monosynaptic EPSCs had low synaptic jitter (SD of latency to successive shocks) averaging 84.03+3.74 μsec (n = 72) and were completely blocked by the non-NMDA antagonist 2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline (NBQX). Sustained exposure to the VR1 agonist capsaicin (CAP; 100 nM) blocked ST EPSCs (CAP-sensitive) in some neurons but not others (CAP-resistant). CAP-sensitive EPSCs had longer latencies than CAP-resistant EPSCs (4.65±0.27 ms, n = 48 vs. 3.53±0.28 ms, n = 24, resp.; p = 0.011), but they had similar jitter. CAP evoked two transient responses in CAP-sensitive neurons: a rapidly developing inward current (Icap) (108.1±22.9 pA; n = 21) and an increase in spontaneous synaptic activity. After 3-5 min in CAP, Icap subsided and ST EPSCs disappeared. NBQX completely blocked Icap. The VR1 antagonist capsazepine (10-20 μM) attenuated CAP responses. Anatomically, second-order NTS neurons were identified by 4-(4-dihexadecylamino)styryl-N-methylpyridinium iodide transported from the cervical aortic depressor nerve (ADN) to stain central terminals. Neurons with fluorescent ADN contacts had CAP-sensitive EPSCs (n = 5) with latencies and jitter similar to those of unlabeled monosynaptic neurons. Thus, consistent with presynaptic VR1 localization, CAP selectively activates a subset of ST axons to release glutamate that acts on non-NMDA receptors. Because the CAP sensitivity of cranial afferents is exclusively assocd. with unmyelinated axons, VR1 identifies C-fiber afferent pathways within the brainstem.
  
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77. 77
  Marinelli, S., Di Marzo, V., Berretta, N., Matias, I., Maccarrone, M., Bernardi, G., and Mercuri, N. B. (2003) Presynaptic facilitation of glutamatergic synapses to dopaminergic neurons of the rat substantia nigra by endogenous stimulation of vanilloid receptors J. Neurosci. 23, 3136– 3144
  
  77
  Presynaptic facilitation of glutamatergic synapses to dopaminergic neurons of the rat substantia nigra by endogenous stimulation of vanilloid receptors
  
  Marinelli, Silvia; Di Marzo, Vincenzo; Berretta, Nicola; Matias, Isabel; Maccarrone, Mauro; Bernardi, Giorgio; Mercuri, Nicola B.
  
  Journal of Neuroscience (2003), 23 (8), 3136-3144CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
  
  Growing evidence regarding the function of vanilloid receptor-1 (VR1) in the brain suggests potential central roles of this receptor, previously described to occur primarily in peripheral sensory neurons. In the present study, the authors used electrophysiol. and biochem. techniques to investigate the function and the endogenous stimulation of VR1 in dopaminergic neurons of the substantia nigra pars compacta (SNc). The VR1 agonist capsaicin increased the frequency of both TTX-sensitive and -insensitive spontaneous EPSCs (sEPSCs) without affecting their amplitude, suggesting a presynaptic site of action. In contrast, no effect was detected with regard to GABAergic transmission. No increase in sEPSC frequency was obsd. in the presence of cadmium chloride, while the voltage-dependent calcium channel antagonist ω-conotoxin MVIIC did not prevent capsaicin action. The VR1 antagonists capsazepine and iodoresiniferatoxin (IRTX) blocked the effects of capsaicin. Importantly, IRTX per se reduced sEPSC frequency, suggesting a tonic activity of VR1. The endogenous VR1 agonist anandamide (AEA) produced an IRTX-sensitive increase in the frequency of sEPSCs on dopaminergic neurons that was more pronounced when protein kinase A had been activated. Furthermore, mass spectrometric analyses and binding expts. revealed high levels of endogenous AEA and specific binding of AEA to VR1 receptors in the SNc. These data suggest a tonic facilitation of glutamate release exerted by VR1 in the SNc through a stimulation of VR1 by endovanilloids, including anandamide. The increase in sEPSC frequency by VR1 onto midbrain dopaminergic neurons suggests the involvement of these receptors in motor and cognitive functions involving the dopaminergic system.
  
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78. 78
  Marinelli, S., Vaughan, C. W., Christie, M. J., and Connor, M. (2002) Capsaicin activation of glutamatergic synaptic transmission in the rat locus coeruleus in vitro J. Physiol. 543, 531– 540
  
  78
  Capsaicin activation of glutamatergic synaptic transmission in the rat locus coeruleus in vitro
  
  Marinelli, Silvia; Vaughan, Christopher W.; Christie, MacDonald J.; Connor, Mark
  
  Journal of Physiology (Cambridge, United Kingdom) (2002), 543 (2), 531-540CODEN: JPHYA7; ISSN:0022-3751. (Cambridge University Press)
  
  The vanilloid receptor protein (VR1) is a well-characterized integrator of noxious stimuli in peripheral sensory neurons. There is evidence for the presence of VR1 in the central nervous system, but little information as to its role there. In this study we have examd. the actions of agonists for VR1 receptors in the rat locus coeruleus (LC), using whole-cell patch-clamp recordings from acutely isolated neurons and neurons in slices. Superfusion with capsaicin resulted in a concn.-dependent increase in the frequency of isolated miniature excitatory postsynaptic currents (mEPSCs) in LC neurons. The mean amplitude of the mEPSCs was not affected by capsaicin. The effects of capsaicin (1 μM) were abolished by the VR1 receptor antagonists capsazepine (10 μM) and iodoresiniferatoxin (300 nM). Removal of extracellular Ca2+ abolished the capsaicin-induced increase in frequency of mEPSCs. Capsaicin superfusion had no consistent effects on evoked excitatory postsynaptic currents. Capsaicin superfusion also resulted in the release of an adrenoceptor agonist in the LC but did not affect the membrane currents of acutely isolated LC neurons. These data demonstrate that the VR1 receptor appears to be located presynaptically on afferents to the LC, and that activation of VR1 may serve to potentiate the release of glutamate and adrenaline/noradrenaline in this brain region.
  
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79. 79
  Gibson, H. E., Edwards, J. G., Page, R. S., Van Hook, M. J., and Kauer, J. A. (2008) TRPV1 channels mediate long-term depression at synapses on hippocampal interneurons Neuron 57, 746– 759
  
  There is no corresponding record for this reference.
80. 80
  Grueter, B. A., Brasnjo, G., and Malenka, R. C. (2010) Postsynaptic TRPV1 triggers cell type-specific long-term depression in the nucleus accumbens Nat. Neurosci. 13, 1519– 1525
  
  80
  Postsynaptic TRPV1 triggers cell type-specific long-term depression in the nucleus accumbens
  
  Grueter, Brad A.; Brasnjo, Gabor; Malenka, Robert C.
  
  Nature Neuroscience (2010), 13 (12), 1519-1525CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
  
  Synaptic modifications in the nucleus accumbens (NAc) are important for adaptive and pathol. reward-dependent learning. Medium spiny neurons (MSNs), the major cell type in the NAc, participate in two parallel circuits that subserve distinct behavioral functions, yet little is known about differences in their electrophysiol. and synaptic properties. Using bacterial artificial chromosome transgenic mice, we found that synaptic activation of group I metabotropic glutamate receptors in NAc MSNs in the indirect, but not direct, pathway led to the prodn. of endocannabinoids, which activated presynaptic CB1 receptors to trigger endocannabinoid-mediated long-term depression (eCB-LTD) as well as postsynaptic transient receptor potential vanilloid 1 (TRPV1) channels to trigger a form of LTD resulting from endocytosis of AMPA receptors. These results reveal a previously unknown action of TRPV1 channels and indicate that the postsynaptic generation of endocannabinoids can modulate synaptic strength in a cell type-specific fashion by activating distinct pre- and postsynaptic targets.
  
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81. 81
  Premkumar, L. S. and Ahern, G. P. (2000) Induction of vanilloid receptor channel activity by protein kinase C Nature 408, 985– 990
  
  There is no corresponding record for this reference.
82. 82
  Caterina, M. J. and Julius, D. (2001) The vanilloid receptor: a molecular gateway to the pain pathway Annu. Rev. Neurosci. 24, 487– 517
  
  82
  The vanilloid receptor: a molecular gateway to the pain pathway
  
  Caterina, Michael J.; Julius, David
  
  Annual Review of Neuroscience (2001), 24 (), 487-517CODEN: ARNSD5; ISSN:0147-006X. (Annual Reviews Inc.)
  
  A review with 163 refs. The detection of painful stimuli occurs primarily at the peripheral terminals of specialized sensory neurons called nociceptors. These small-diam. neurons transduce signals of a chem., mech., or thermal nature into action potentials and transmit this information to the central nervous system, ultimately eliciting a perception of pain or discomfort. Little is known about the proteins that detect noxious stimuli, esp. those of a phys. nature. Here, the authors review recent advances in the mol. characterization of the capsaicin (vanilloid) receptor, an excitatory ion channel expressed by nociceptors, which contributes to the detection and integration of pain-producing chem. and thermal stimuli. The anal. of vanilloid receptor gene knockout mice confirms the involvement of this channel in pain sensation, as well as in hypersensitivity to noxious stimuli following tissue injury. At the same time, these studies demonstrate the existence of redundant mechanisms for the sensation of heat-evoked pain.
  
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83. 83
  Minke, B. and Cook, B. (2002) TRP channel proteins and signal transduction Physiol. Rev. 82, 429– 472
  
  There is no corresponding record for this reference.
84. 84
  Clapham, D. E. (2003) TRP channels as cellular sensors Nature 426, 517– 524
  
  84
  TRP channels as cellular sensors
  
  Clapham, David E.
  
  Nature (London, United Kingdom) (2003), 426 (6966), 517-524CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  
  A review. TRP channels are the vanguard of our sensory systems, responding to temp., touch, pain, osmolarity, pheromones, taste and other stimuli. But their role is much broader than classical sensory transduction. They are an ancient sensory app. for the cell, not just the multicellular organism, and they have been adapted to respond to all manner of stimuli, from both within and outside the cell.
  
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85. 85
  Premkumar, L. S. and Bishnoi, M. (2011) Disease-related changes in TRPV1 expression and its implications for drug development Curr. Top. Med. Chem. 11, 2192– 2209
  
  85
  Disease-related changes in TRPV1 expression and its implications for drug development
  
  Premkumar, Louis S.; Bishnoi, Mahendra
  
  Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2011), 11 (17), 2192-2209CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
  
  A review. The transient receptor potential vanilloid 1(TRPV1) channel has been a topic of great interest, since its discovery in 1997. It is a homotetrameric non-selective cation channel predominantly expressed in a population of sensory neurons and its involvement in different modalities of pain has been extensively studied. However, TRPV1 has also been shown to be expressed in non-sensory neurons and non-neuronal cells. TRPV1 is considered as a potential target for drug development, based on its tissue distribution and its role in physiol. functions. Here, we summarize the evidence for disease-related alterations in TRPV1 expression and function and review the current perspectives for the therapeutic potential of TRPV1 agonists and antagonists in the treatment of a wide range of diseases.
  
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86. 86
  Julius, D. (2013) TRP channels and pain Annu. Rev. Cell Dev. Biol. 29, 355– 384
  
  There is no corresponding record for this reference.
87. 87
  Mezey, E., Toth, Z. E., Cortright, D. N., Arzubi, M. K., Krause, J. E., Elde, R., Guo, A., Blumberg, P. M., and Szallasi, A. (2000) Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human Proc. Natl. Acad. Sci. U.S.A. 97, 3655– 3660
  
  There is no corresponding record for this reference.
88. 88
  Huang, S. M., Bisogno, T., Trevisani, M., Al-Hayani, A., De Petrocellis, L., Fezza, F., Tognetto, M., Petros, T. J., Krey, J. F., Chu, C. J., Miller, J. D., Davies, S. N., Geppetti, P., Walker, J. M., and Di Marzo, V. (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors Proc. Natl. Acad. Sci. U.S.A. 99, 8400– 8405
  
  There is no corresponding record for this reference.
89. 89
  Mishra, S. K., Tisel, S. M., Orestes, P., Bhangoo, S. K., and Hoon, M. A. (2011) TRPV1-lineage neurons are required for thermal sensation EMBO J. 30, 582– 593
  
  There is no corresponding record for this reference.
90. 90
  Cavanaugh, D. J., Chesler, A. T., Braz, J. M., Shah, N. M., Julius, D., and Basbaum, A. I. (2011) Restriction of transient receptor potential vanilloid-1 to the peptidergic subset of primary afferent neurons follows its developmental downregulation in nonpeptidergic neurons J. Neurosci. 31, 10119– 10127
  
  90
  Restriction of transient receptor potential vanilloid-1 to the peptidergic subset of primary afferent neurons follows its developmental downregulation in nonpeptidergic neurons
  
  Cavanaugh, Daniel J.; Chesler, Alexander T.; Braz, Joao M.; Shah, Nirao M.; Julius, David; Basbaum, Allan I.
  
  Journal of Neuroscience (2011), 31 (28), 10119-10127CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
  
  Primary afferent "pain" fibers (nociceptors) are divided into subclasses based on distinct mol. and anatomical features, and these classes mediate noxious modality-specific contributions to behaviors evoked by painful stimuli. Whether the heat and capsaicin receptor transient receptor potential vanilloid-1 (TRPV1) is expressed heterogeneously across several sensory populations, or is selectively expressed by a unique nociceptor subclass, however, is unclear. Here we used two lines of Trpv1 reporter mice to investigate the primary afferent expression of TRPV1, both during development and in the adult. We demonstrate, using Cre-induced lineage tracing, that during development TRPV1 is transiently expressed in a wide range of dorsal root ganglion neurons, and that its expression is gradually refined, such that TRPV1 transcripts become restricted to a specific subset of peptidergic sensory neurons. Finally, the remarkable sensitivity that is characteristic of these reporter mice revealed an innervation of central and peripheral targets by TRPV1+ primary afferents in the adult that is considerably more extensive than has previously been appreciated.
  
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91. 91
  Lundberg, J. M., Martling, C. R., and Saria, A. (1983) Substance P and capsaicin-induced contraction of human bronchi Acta Physiol. Scand. 119, 49– 53
  
  There is no corresponding record for this reference.
92. 92
  Mitchell, J. A., Williams, F. M., Williams, T. J., and Larkin, S. W. (1997) Role of nitric oxide in the dilator actions of capsaicin-sensitive nerves in the rabbit coronary circulation Neuropeptides 31, 333– 338
  
  There is no corresponding record for this reference.
93. 93
  Zygmunt, P. M., Petersson, J., Andersson, D. A., Chuang, H., Sorgard, M., Di Marzo, V., Julius, D., Hogestatt, E. D., and Wang, Y. (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide Nature 400, 452– 457
  
  93
  Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide
  
  Zygmunt, Peter M.; Petersson, Jesper; Andersson, David A.; Chuang, Huai-Hu; Sorgard, Morten; Di Marzo, Vincenzo; Julius, David; Hogestatt, Edward D.
  
  Nature (London) (1999), 400 (6743), 452-457CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)
  
  The endogenous cannabinoid receptor agonist anandamide is a powerful vasodilator of isolated vascular prepns., but its mechanism of action is unclear. Here we show that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP). The selective CGRP-receptor antagonist 8-37 CGRP, but not the cannabinoid CB1 receptor blocker SR141716A, inhibited the vasodilator effect of anandamide. Other endogenous (2-arachidonylglycerol, palmitylethanolamide) and synthetic (HU 210, WIN 55,212-2, CP 55,940) CB1 and CB2 receptor agonists could not mimic the action of anandamide. The selective vanilloid receptor antagonist capsazepine inhibited anandamide-induced vasodilation and release of CGRP. In patch-clamp expts. on cells expressing the cloned vanilloid receptor (VR1), anandamide induced a capsazepine-sensitive current in whole cells and isolated membrane patches. Our results indicate that anandamide induces vasodilation by activating vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another mol. target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.
  
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94. 94
  Birder, L. A., Nakamura, Y., Kiss, S., Nealen, M. L., Barrick, S., Kanai, A. J., Wang, E., Ruiz, G., De Groat, W. C., Apodaca, G., Watkins, S., and Caterina, M. J. (2002) Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1 Nat. Neurosci. 5, 856– 860
  
  94
  Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1
  
  Birder, L. A.; Nakamura, Y.; Kiss, S.; Nealen, M. L.; Barrick, S.; Kanai, A. J.; Wang, E.; Ruiz, G.; de Groat, W. C.; Apodaca, G.; Watkins, S.; Caterina, M. J.
  
  Nature Neuroscience (2002), 5 (9), 856-860CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
  
  In the urinary bladder, the capsaicin-gated ion channel TRPV1 is expressed both within afferent nerve terminals and within the epithelial cells that line the bladder lumen. To det. the significance of this expression pattern, we analyzed bladder function in mice lacking TRPV1. Compared with wild-type littermates, trpv1-/- mice had a higher frequency of low-amplitude, non-voiding bladder contractions. This alteration was accompanied by redns. in both spinal cord signaling and reflex voiding during bladder filling (under anesthesia). In vitro, stretch-evoked ATP release and membrane capacitance changes were diminished in bladders excised from trpv1-/- mice, as was hypoosmolality-evoked ATP release from cultured trpv1-/- urothelial cells. These findings indicate that TRPV1 participates in normal bladder function and is essential for normal mech. evoked purinergic signaling by the urothelium.
  
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95. 95
  Cruz, F. and Dinis, P. (2007) Resiniferatoxin and botulinum toxin type A for treatment of lower urinary tract symptoms Neurourol. Urodyn. 26, 920– 927
  
  95
  Resiniferation and botulinum toxin type A for treatment of lower urinary tract symptoms
  
  Cruz, Francisco; Dinis, Paulo
  
  Neurourology and Urodynamics (2007), 26 (6, Suppl.), 920-927CODEN: NEUREM; ISSN:0733-2467. (Wiley-Liss, Inc.)
  
  A review. Resiniferatoxin (RTX) and botulinum toxin subtype A (BTX-A) are increasingly viewed as potential treatments for lower urinary tract symptoms (LUTS) refractory to conventional therapy. RTX, a capsaicin analog devoid of severe pungent properties, acts by desensitizing the transient receptor potential vanilloid type 1 (TRPV1) receptor and inactivating C-fibers. BTX-A cleaves sol. N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in afferent and efferent nerve endings, therefore impeding the fusion of synaptic vesicles with the neuronal membrane necessary for the release of neurotransmitters. In patients with neurogenic and idiopathic detrusor overactivity, RTX and BTX-A have been shown to increase the vol. to first detrusor contraction, increase bladder capacity, and improve urinary incontinence and quality of life. Recent data also suggest a role for these neurotoxins in treating urgency, the primary symptom in overactive bladder (OAB) syndrome. Furthermore, exptl. data strongly support the use of both neurotoxins in the treatment of pain and frequency in patients with interstitial cystitis/painful bladder syndrome (IC/PBS), although the results from available clin. trials for this use are still inconclusive. In spite of promising results overall, it should be made clear that the administration of these neurotoxins is still considered an exptl. procedure and that more clin. studies are necessary before a license for their use will be issued by health authorities.
  
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96. 96
  Varga, A., Nemeth, J., Szabo, A., McDougall, J. J., Zhang, C., Elekes, K., Pinter, E., Szolcsanyi, J., and Helyes, Z. (2005) Effects of the novel TRPV1 receptor antagonist SB366791 in vitro and in vivo in the rat Neurosci. Lett. 385, 137– 142
  
  There is no corresponding record for this reference.
97. 97
  Gavva, N. R. (2008) Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV1 Trends Pharmacol. Sci. 29, 550– 557
  
  There is no corresponding record for this reference.
98. 98
  Lehto, S. G., Tamir, R., Deng, H., Klionsky, L., Kuang, R., Le, A., Lee, D., Louis, J. C., Magal, E., Manning, B. H., Rubino, J., Surapaneni, S., Tamayo, N., Wang, T., Wang, J., Wang, J., Wang, W., Youngblood, B., Zhang, M., Zhu, D., Norman, M. H., and Gavva, N. R. (2008) Antihyperalgesic effects of (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluorom ethyl)phenyl)-acrylamide (AMG8562), a novel transient receptor potential vanilloid type 1 modulator that does not cause hyperthermia in rats J. Pharmacol. Exp. Ther. 326, 218– 229
  
  98
  Antihyperalgesic effects of (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)acrylamide (AMG8562), a novel transient receptor potential vanilloid type 1 modulator that does not cause hyperthermia in rats
  
  Lehto, Sonya G.; Tamir, Rami; Deng, Hong; Klionsky, Lana; Kuang, Rongzhen; Le, April; Lee, Doo; Louis, Jean-Claude; Magal, Ella; Manning, Barton H.; Rubino, John; Surapaneni, Sekhar; Tamayo, Nuria; Wang, Tingrong; Wang, Judy; Wang, Jue; Wang, Weiya; Youngblood, Brad; Zhang, Maosheng; Zhu, Dawn; Norman, Mark H.; Gavva, Narender R.
  
  Journal of Pharmacology and Experimental Therapeutics (2008), 326 (1), 218-229CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
  
  Antagonists of the vanilloid receptor TRPV1 (transient receptor potential vanilloid type 1) have been reported to produce antihyperalgesic effects in animal models of pain. These antagonists, however, also caused concomitant hyperthermia in rodents, dogs, monkeys, and humans. Antagonist-induced hyperthermia was not obsd. in TRPV1 knockout mice, suggesting that the hyperthermic effect is exclusively mediated through TRPV1. Since antagonist-induced hyperthermia is considered a hurdle for developing TRPV1 antagonists as therapeutics, we investigated the possibility of eliminating hyperthermia while maintaining antihyperalgesia. Here, we report four potent and selective TRPV1 modulators with unique in vitro pharmacol. profiles (profiles A through D) and their resp. effects on body temp. We found that profile C modulator, (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)acrylamide (AMG8562), blocks capsaicin activation of TRPV1, does not affect heat activation of TRPV1, potentiates pH 5 activation of TRPV1 in vitro, and does not cause hyperthermia in vivo in rats. We further profiled AMG8562 in an on-target (agonist) challenge model, rodent pain models, and tested for its side effects. We show that AMG8562 significantly blocks capsaicin-induced flinching behavior, produces statistically significant efficacy in complete Freund's adjuvant- and skin incision-induced thermal hyperalgesia, and acetic acid-induced writhing models, with no profound effects on locomotor activity. Based on the data shown here, we conclude that it is feasible to modulate TRPV1 in a manner that does not cause hyperthermia while maintaining efficacy in rodent pain models.
  
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99. 99
  Pabbidi, R. M., Yu, S. Q., Peng, S., Khardori, R., Pauza, M. E., and Premkumar, L. S. (2008) Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity Mol. Pain 4, 9
  
  99
  Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity
  
  Pabbidi Reddy M; Yu Shuang-Quan; Peng Siying; Khardori Romesh; Pauza Mary E; Premkumar Louis S
  
  Molecular pain (2008), 4 (), 9 ISSN:.
  
  A common complication associated with diabetes is painful or painless diabetic peripheral neuropathy (DPN). The mechanisms and determinants responsible for these peripheral neuropathies are poorly understood. Using both streptozotocin (STZ)-induced and transgene-mediated murine models of type 1 diabetes (T1D), we demonstrate that Transient Receptor Potential Vanilloid 1 (TRPV1) expression varies with the neuropathic phenotype. We have found that both STZ- and transgene-mediated T1D are associated with two distinct phases of thermal pain sensitivity that parallel changes in TRPV1 as determined by paw withdrawal latency (PWL). An early phase of hyperalgesia and a late phase of hypoalgesia are evident. TRPV1-mediated whole cell currents are larger and smaller in dorsal root ganglion (DRG) neurons collected from hyperalgesic and hypoalgesic mice. Resiniferatoxin (RTX) binding, a measure of TRPV1 expression is increased and decreased in DRG and paw skin of hyperalgesic and hypoalgesic mice, respectively. Immunohistochemical labeling of spinal cord lamina I and II, dorsal root ganglion (DRG), and paw skin from hyperalgesic and hypoalgesic mice reveal increased and decreased TRPV1 expression, respectively. A role for TRPV1 in thermal DPN is further suggested by the failure of STZ treatment to influence thermal nociception in TRPV1 deficient mice. These findings demonstrate that altered TRPV1 expression and function contribute to diabetes-induced changes in thermal perception.
  
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100. 100
  Van Buren, J. J., Bhat, S., Rotello, R., Pauza, M. E., and Premkumar, L. S. (2005) Sensitization and translocation of TRPV1 by insulin and IGF-I Mol. Pain 1, 17
  
  100
  Sensitization and translocation of TRPV1 by insulin and IGF-I
  
  Van Buren Jeremy J; Bhat Satyanarayan; Rotello Rebecca; Pauza Mary E; Premkumar Louis S
  
  Molecular pain (2005), 1 (), 17 ISSN:.
  
  Insulin and insulin-like growth factors (IGFs) maintain vital neuronal functions. Absolute or functional deficiencies of insulin or IGF-I may contribute to neuronal and vascular complications associated with diabetes. Vanilloid receptor 1 (also called TRPV1) is an ion channel that mediates inflammatory thermal nociception and is present on sensory neurons. Here we demonstrate that both insulin and IGF-I enhance TRPV1-mediated membrane currents in heterologous expression systems and cultured dorsal root ganglion neurons. Enhancement of membrane current results from both increased sensitivity of the receptor and translocation of TRPV1 from cytosol to plasma membrane. Receptor tyrosine kinases trigger a signaling cascade leading to activation of phosphatidylinositol 3-kinase (PI(3)K) and protein kinase C (PKC)-mediated phosphorylation of TRPV1, which is found to be essential for the potentiation. These findings establish a link between the insulin family of trophic factors and vanilloid receptors.
  
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101. 101
  Bishnoi, M., Bosgraaf, C. A., Abooj, M., Zhong, L., and Premkumar, L. S. (2011) Streptozotocin-induced early thermal hyperalgesia is independent of glycemic state of rats: role of transient receptor potential vanilloid 1(TRPV1) and inflammatory mediators Mol. Pain 7, 52
  
  101
  Streptozotocin-induced early thermal hyperalgesia is independent of glycemic state of rats: role of transient receptor potential vanilloid 1(TRPV1) and inflammatory mediators
  
  Bishnoi Mahendra; Bosgraaf Christine A; Abooj Mruvil; Zhong Linlin; Premkumar Louis S
  
  Molecular pain (2011), 7 (), 52 ISSN:.
  
  BACKGROUND: Streptozotocin (STZ) is used as a common tool to induce diabetes and to study diabetes-induced complications including diabetic peripheral neuropathy (DPN). Previously, we have reported that STZ induces a direct effect on neurons through expression and function of the Transient receptor potential vanilloid 1 (TRPV1) channel in sensory neurons resulting in thermal hyperalgesia, even in non-diabetic STZ-treated mice. In the present study, we investigated the role of expression and function of TRPV1 in the central sensory nerve terminals in the spinal cord in STZ-induced hyperalgesia in rats. RESULTS: We found that a proportion of STZ-treated rats were normoglycemic but still exhibited thermal hyperalgesia and mechanical allodynia. Immunohistochemical data show that STZ treatment, irrespective of glycemic state of the animal, caused microglial activation and increased expression of TRPV1 in spinal dorsal horn. Further, there was a significant increase in the levels of pro-inflammatory mediators (IL-1β, IL-6 and TNF-α) in spinal cord tissue, irrespective of the glycemic state. Capsaicin-stimulated release of calcitonin gene related peptide (CGRP) was significantly higher in the spinal cord of STZ-treated animals. Intrathecal administration of resiniferatoxin (RTX), a potent TRPV1 agonist, significantly attenuated STZ-induced thermal hyperalgesia, but not mechanical allodynia. RTX treatment also prevented the increase in TRPV1-mediated neuropeptide release in the spinal cord tissue. CONCLUSIONS: From these results, it is concluded that TRPV1 is an integral component of initiating and maintaining inflammatory thermal hyperalgesia, which can be alleviated by intrathecal administration of RTX. Further, the results suggest that enhanced expression and inflammation-induced sensitization of TRPV1 at the spinal cord may play a role in central sensitization in STZ-induced neuropathy.
  
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102. 102
  Akiba, Y., Kato, S., Katsube, K., Nakamura, M., Takeuchi, K., Ishii, H., and Hibi, T. (2004) Transient receptor potential vanilloid subfamily 1 expressed in pancreatic islet beta cells modulates insulin secretion in rats Biochem. Biophys. Res. Commun. 321, 219– 225
  
  There is no corresponding record for this reference.
103. 103
  Razavi, R., Chan, Y., Afifiyan, F. N., Liu, X. J., Wan, X., Yantha, J., Tsui, H., Tang, L., Tsai, S., Santamaria, P., Driver, J. P., Serreze, D., Salter, M. W., and Dosch, H. M. (2006) TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes Cell 127, 1123– 1135
  
  There is no corresponding record for this reference.
104. 104
  Wang, X., Miyares, R. L., and Ahern, G. P. (2005) Oleoylethanolamide excites vagal sensory neurones, induces visceral pain and reduces short-term food intake in mice via capsaicin receptor TRPV1 J. Physiol. 564, 541– 547
  
  104
  Oleoylethanolamide excites vagal sensory neurones, induces visceral pain and reduces short-term food intake in mice via capsaicin receptor TRPV1
  
  Wang, Xiangbin; Miyares, Rosa Linda; Ahern, Gerard P.
  
  Journal of Physiology (Oxford, United Kingdom) (2005), 564 (2), 541-547CODEN: JPHYA7; ISSN:0022-3751. (Blackwell Publishing Ltd.)
  
  Oleoylethanolamide (OEA) is an endogenous lipid that regulates feeding and body wt. Although the effects of OEA are believed to depend on activation of vagal sensory afferent neurons, the mechanisms involved in exciting these neurons are unclear. Here we show that OEA directly excited nodose ganglion neurons, the cell bodies of vagal afferents. OEA depolarized these neurons and evoked inward currents that were restricted to capsaicin-sensitive cells. These currents were fully blocked by the TRPV1 inhibitor, capsazepine, and no responses to OEA were obsd. in neurons cultured from TRPV1-null mice. Similarly, OEA induced a rise in Ca+ concn. in wild-type but not TRPV1-deficient neurons, and responses to OEA were greater at 37°C compared to room temp. Significantly, OEA administration in mice induced visceral pain-related behaviors that were inhibited by capsazepine and absent in TRPV1-null animals. Further, OEA reduced 30-min food intake in wild-type but not in TRPV1-null mice. Thus, the acute behavioral effects of OEA may result from visceral malaise via the activation of TRPV1.
  
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105. 105
  Ahern, G. P. (2013) Transient receptor potential channels and energy homeostasis Trends Endocrinol. Metab. 24, 554– 560
  
  105
  Transient receptor potential channels and energy homeostasis
  
  Ahern, Gerard P.
  
  Trends in Endocrinology and Metabolism (2013), 24 (11), 554-560CODEN: TENME4; ISSN:1043-2760. (Elsevier Ltd.)
  
  A review. Transient receptor potential (TRP) channels are members of an ancient class of ion channels that are present in most mammalian tissues. Consistent with their wide tissue distribution, TRPs are capable of influencing diverse physiol. processes including adipocyte function, energy intake and energy expenditure. TRPs function as transduction channels downstream of G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases, and some can also be direct sensors of chem. irritants that influence food intake or regulate body temp. and thermogenesis. TRP agonists were shown to reduce body wt. and adiposity, suggesting that they might be exploited as therapeutic targets. In this review I discuss the current knowledge of how TRP channels influence energy balance.
  
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106. 106
  Kindt, S., Vos, R., Blondeau, K., and Tack, J. (2009) Influence of intra-oesophageal capsaicin instillation on heartburn induction and oesophageal sensitivity in man Neurogastroenterol. Motil. 21, 1032– e1082
  
  106
  Influence of intra-esophageal capsaicin instillation on heartburn induction and esophageal sensitivity in man
  
  Kindt, S.; Vos, R.; Blondeau, K.; Tack, J.
  
  Neurogastroenterology & Motility (2009), 21 (10), 1032-1038CODEN: NMOTEK; ISSN:1350-1925. (Wiley-Blackwell)
  
  Heartburn is the most typical gastro-esophageal reflux disease (GERD) symptom. The transient receptor potential vanilloid receptor-1 (TRPV1) is a candidate mediator of heartburn. Exposure of TRPV1 to capsaicin is characterized by activation, followed by desensitization. Our aim was to investigate the effect of intra-esophageal capsaicin instillation on esophageal symptom perception (activation) and on sensitivity to esophageal acid perfusion and esophageal balloon distention (desensitization). In a first protocol (n = 10), saline or capsaicin soln. were instilled in the mid-esophagus and symptoms were rated at 5-min intervals for 60 min. In a second study (n = 10), esophageal 0.1 N hydrochloric acid perfusion was performed 60 min after pretreatment with saline, low or high dose capsaicin. In a third study (n = 10), sensitivity to esophageal balloon distention was detd. before and at 30-min intervals up to 90 min after pretreatment with saline, low or high dose capsaicin. Areas under the curve (AUC) for symptom intensities under different conditions were calcd. and compared with Kruskal-Wallis test. Esophageal capsaicin instillation induced transient symptoms of retrosternal and epigastric burning in a dose-dependent fashion. After esophageal capsaicin or saline instillation, there was no difference in symptom pattern and intensities induced by esophageal acid perfusion. After esophageal capsaicin or saline instillation, sensitivity to esophageal balloon distention and esophageal compliance were not significantly altered. Esophageal instillation of the TRPV1 receptor agonist capsaicin induces symptoms of retrosternal and epigastric burning in a dose-dependent fashion. Pretreatment with capsaicin does not desensitize the esophagus to acid perfusion or to balloon distention.
  
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107. 107
  Okumi, H., Tashima, K., Matsumoto, K., Namiki, T., Terasawa, K., and Horie, S. (2012) Dietary agonists of TRPV1 inhibit gastric acid secretion in mice Planta Med. 78, 1801– 1806
  
  There is no corresponding record for this reference.
108. 108
  Raisinghani, M., Pabbidi, R. M., and Premkumar, L. S. (2005) Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin J. Physiol. 567, 771– 786
  
  108
  Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin
  
  Raisinghani, Manish; Pabbidi, Reddy M.; Premkumar, Louis S.
  
  Journal of Physiology (Oxford, United Kingdom) (2005), 567 (3), 771-786CODEN: JPHYA7; ISSN:0022-3751. (Blackwell Publishing Ltd.)
  
  Transient receptor potential vanilloid 1 (TRPV1) is a Ca2+ permeable non-selective cation channel activated by phys. and chem. stimuli. Resiniferatoxin (RTX), an ultrapotent agonist of TRPV1, is under investigation for treatment of urinary bladder hyper-reflexia and chronic pain conditions. Here, we have detd. the characteristics of RTX-induced responses in cells expressing native and cloned rat TRPV1. Whole-cell currents increase with repeated application of submaximal concns. of RTX until a maximal response is attained and do not deactivate even after prolonged washout. Interestingly, the rate of activation and block by capsazepine of RTX-induced currents are significantly slower than for capsaicin-induced currents. RTX-induced whole-cell currents are outwardly rectifying, but to a lesser extent than capsaicin-induced currents. RTX-induced single channel currents exhibit multiple conductance states and outward rectification. The open probability (Po) of RTX-induced currents is higher at all potentials as compared to capsaicin-induced currents, which showed a strong voltage-dependent decrease at neg. potentials. Single-channel kinetic analyses reveal that open-time distribution of RTX-induced currents can be fitted with three exponential components at neg. and pos. potentials. The areas of distribution of the longer open time consts. are significantly larger than capsaicin-induced currents. The closed-time distribution of RTX-induced currents can be fitted with three exponential components as compared to capsaicin-induced currents, which require four exponential components. Current-clamp expts. reveal that low concns. of RTX caused a slow and sustained depolarization beyond threshold while generating few action potentials. Concns. of capsaicin required for the same extent of depolarization generated a significantly greater no. of action potentials. These properties of RTX may play a role in its clin. usefulness.
  
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109. 109
  Roberts, J. C., Davis, J. B., and Benham, C. D. (2004) [3H]Resiniferatoxin autoradiography in the CNS of wild-type and TRPV1 null mice defines TRPV1 (VR-1) protein distribution Brain Res. 995, 176– 183
  
  109
  [3H]Resiniferatoxin autoradiography in the CNS of wild-type and TRPV1 null mice defines TRPV1 (VR-1) protein distribution
  
  Roberts, Jennifer C.; Davis, John B.; Benham, Christopher D.
  
  Brain Research (2004), 995 (2), 176-183CODEN: BRREAP; ISSN:0006-8993. (Elsevier Science B.V.)
  
  Knowledge of the distribution and function of the vanilloid receptor (VR-1 or TRPV1) in the CNS lacks the detailed appreciation of its role in the peripheral nervous system. The radiolabeled vanilloid agonist [3H]resiniferatoxin (RTX) has been used to indicate the presence of TRPV1 receptor protein in the brain but low specific binding has complicated interpretation of this data. Recently, support for a more widespread CNS distribution of TRPV1 mRNA and protein has been provided by RT-PCR and antibody data. The authors have exploited the availability of TRPV1 null mice and used [3H]RTX autoradiog. in the CNS of TRPV1 wild-type and TRPV1 null mice to identify the component of [3H]RTX binding to TRPV1 receptor protein. In the brains of TRPV1+/+ mice, specific [3H]RTX binding was broadly localized with the greatest binding in the olfactory nuclei, the cerebral cortex, dentate gyrus, thalamus, hypothalamus, periaqueductal gray, superior colliculus, locus coeruleus and cerebellar cortex. Specific binding was also seen in the spinal cord and sensory (dorsal root and trigeminal) ganglia. This binding was much lower but not abolished in most regions in the TRPV1-/- mice. Nonspecific binding was low in all cases. The present study unequivocally demonstrates a widespread and discrete distribution pattern of the TRPV1 receptor protein in the rat central nervous system. The presence of TRPV1 receptors in several brain regions suggests that it may function as a cannabinoid-gated channel in the CNS.
  
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110. 110
  Chou, M. Z., Mtui, T., Gao, Y. D., Kohler, M., and Middleton, R. E. (2004) Resiniferatoxin binds to the capsaicin receptor (TRPV1) near the extracellular side of the S4 transmembrane domain Biochemistry 43, 2501– 2511
  
  There is no corresponding record for this reference.
111. 111
  Jung, J., Lee, S. Y., Hwang, S. W., Cho, H., Shin, J., Kang, Y. S., Kim, S., and Oh, U. (2002) Agonist recognition sites in the cytosolic tails of vanilloid receptor 1 J. Biol. Chem. 277, 44448– 44454
  
  There is no corresponding record for this reference.
112. 112
  Gavva, N. R., Klionsky, L., Qu, Y., Shi, L., Tamir, R., Edenson, S., Zhang, T. J., Viswanadhan, V. N., Toth, A., Pearce, L. V., Vanderah, T. W., Porreca, F., Blumberg, P. M., Lile, J., Sun, Y., Wild, K., Louis, J. C., and Treanor, J. J. (2004) Molecular determinants of vanilloid sensitivity in TRPV1 J. Biol. Chem. 279, 20283– 20295
  
  112
  Molecular determinants of vanilloid sensitivity in TRPV1
  
  Gavva, Narender R.; Klionsky, Lana; Qu, Yusheng; Shi, Licheng; Tamir, Rami; Edenson, Steve; Zhang, T. J.; Viswanadhan, Vellarkad N.; Toth, Attila; Pearce, Larry V.; Vanderah, Todd W.; Porreca, Frank; Blumberg, Peter M.; Lile, Jack; Sun, Yax; Wild, Ken; Louis, Jean-Claude; Treanor, James J. S.
  
  Journal of Biological Chemistry (2004), 279 (19), 20283-20295CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  
  Vanilloid receptor 1 (TRPV1), a membrane-assocd. cation channel, is activated by the pungent vanilloid from chili peppers, capsaicin, and the ultra potent vanilloid from Euphorbia resinifera, resiniferatoxin (RTX), as well as by phys. stimuli (heat and protons) and proposed endogenous ligands (anandamide, N-arachidonyldopamine, N-oleoyldopamine, and products of lipoxygenase). Only limited information is available in TRPV1 on the residues that contribute to vanilloid activation. Interestingly, rabbits have been suggested to be insensitive to capsaicin and have been shown to lack detectable [3H]RTX binding in membranes prepd. from their dorsal root ganglia. The authors have cloned rabbit TRPV1 (oTRPV1) and report that it exhibits high homol. to rat and human TRPV1. Like its mammalian orthologs, oTRPV1 is selectively expressed in sensory neurons and is sensitive to protons and heat activation but is 100-fold less sensitive to vanilloid activation than either rat or human. Here the authors identify key residues (Met547 and Thr550) in transmembrane regions 3 and 4 (TM3/4) of rat and human TRPV1 that confer vanilloid sensitivity, [3H]RTX binding and competitive antagonist binding to rabbit TRPV1. The authors also show that these residues differentially affect ligand recognition as well as the assays of functional response vs. ligand binding. Furthermore, these residues account for the reported pharmacol. differences of RTX, PPAHV (phorbol 12-phenyl-acetate 13-acetate 20-homovanillate) and capsazepine between human and rat TRPV1. Based on the authors' data the authors propose a model of the TM3/4 region of TRPV1 bound to capsaicin or RTX that may aid in the development of potent TRPV1 antagonists with utility in the treatment of sensory disorders.
  
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113. 113
  Brown, D. C., Iadarola, M. J., Perkowski, S. Z., Erin, H., Shofer, F., Laszlo, K. J., Olah, Z., and Mannes, A. J. (2005) Physiologic and antinociceptive effects of intrathecal resiniferatoxin in a canine bone cancer model Anesthesiology 103, 1052– 1059
  
  There is no corresponding record for this reference.
114. 114
  Iadarola, M. J. and Mannes, A. J. (2011) The vanilloid agonist resiniferatoxin for interventional-based pain control Curr. Top. Med. Chem. 11, 2171– 2179
  
  114
  The vanilloid agonist resiniferatoxin for interventional-based pain control
  
  Iadarola, Michael J.; Mannes, Andrew J.
  
  Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2011), 11 (17), 2171-2179CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
  
  A review. The idea of selectively targeting nociceptive transmission at the level of the peripheral nervous system is attractive from multiple perspectives, particularly the potential lack of non-specific (non-targeted) CNS side effects. Out of the multiple TRP channels involved in nociception, TRPV1 is a strong candidate based on its biophys. conductance properties and its expression in inflammation-sensitive dorsal root ganglion neurons and their axons and central and peripheral nerve terminals. While TRPV1 antagonists have undergone extensive medicinal chem. and pharmaceutical investigation, for TRPV1 agonists nature has provided an optimized compd. in RTX. RTX is not suitable for systemic administration, but it is highly adaptable to a variety of pain problems when used by local administration. This can include routes as diverse as s.c., intraganglionic or intrathecal (CSF space around the spinal cord). The present review focuses on the mol. and preclin. animal expts. that form the underpinnings of our clin. trial of intrathecal RTX for pain in advanced cancer. As such this represents a new approach to pain control that emerges from a long line of research on capsaicin and other vanilloids, their physiol. actions, and the mol. biol. of the capsaicin receptor TRPV1.
  
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115. 115
  Yang, B. H., Piao, Z. G., Kim, Y. B., Lee, C. H., Lee, J. K., Park, K., Kim, J. S., and Oh, S. B. (2003) (2003) Activation of vanilloid receptor 1 (VR1) by eugenol J. Dent. Res. 82, 781– 785
  
  115
  Activation of vanilloid receptor 1 (VR1) by eugenol
  
  Yang, B. H.; Piao, Z. G.; Kim, Y.-B.; Lee, C.-H.; Lee, J. K.; Park, K.; Kim, J. S.; Oh, S. B.
  
  Journal of Dental Research (2003), 82 (10), 781-785CODEN: JDREAF; ISSN:0022-0345. (International Association for Dental Research)
  
  The structural similarity of eugenol with capsaicin suggests that these two agents may share mol. mechanisms to produce their effects. The authors investigated the effects of eugenol in comparison with those of capsaicin using whole-cell patch clamp and Fura-2-based calcium-imaging techniques in a heterologous expression system and with sensory neurons. In vanilloid receptor 1 (VR1)-expressing human embryonic kidney (HEK) 293 cells and trigeminal ganglion (TG) neurons, eugenol activated inward currents, whereas capsazepine, a competitive VR antagonist, and ruthenium red (RR), a functional VR antagonist, completely blocked eugenol-induced inward currents. Moreover, eugenol caused elevation of [Ca2+]i, and this was completely abolished by both capsazepine and ruthenium red in VR1-expressing HEK 293 cells and TG neurons. The authors' results provide strong evidence that eugenol produces its effects, at least in part, via VR1 expressed by the sensory nerve endings in the teeth.
  
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116. 116
  Behrendt, H. J., Germann, T., Gillen, C., Hatt, H., and Jostock, R. (2004) Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay Br. J. Pharmacol. 141, 737– 45
  
  116
  Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay
  
  Behrendt, H.-J.; Germann, T.; Gillen, C.; Hatt, H.; Jostock, R.
  
  British Journal of Pharmacology (2004), 141 (4), 737-745CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)
  
  TRPM8 (CMR1) is a Ca2+-permeable channel, which can be activated by low temps., menthol, eucalyptol and icilin. It belongs to the transient receptor potential (TRP) family, and therefore is related to vanilloid receptor type-1 (VR1, TRPV1). We tested whether substances which are structurally related to menthol, or which produce a cooling sensation, could activate TRPM8, and compared the responses of TRPM8 and VR1 to these ligands. The effects of 70 odorants and menthol-related substances on recombinant mouse TRPM8 (mTRPM8), expressed in HEK293 cells, were examd. using a FLIPR assay. In all, 10 substances (linalool, geraniol, hydroxycitronellal, WS-3, WS-23, FrescolatMGA, FrescolatML, PMD38, CoolactP and Cooling Agent 10) were found to be agonists. The EC50 values of the agonists defined their relative potencies: icilin (0.2 ± 0.1 μM) > FrescolatML (3.3 ± 1.5 μM) > WS-3 (3.7 ± 1.7 μM) (-)menthol (4.1 ± 1.3 μM) frescolatMAG (4.8 ± 1.1 μM) > cooling agent 10 (6 ± 2.2 μM) (+)menthol (14.4 ± 1.3 μM) > PMD38 (31 ± 1.1 μM) > WS-23 (44 ± 7.3 μM) > Coolact P (66 ± 20 μM) > geraniol (5.9 ± 1.6 mM) > linalool (6.7 ± 2.0 mM) > eucalyptol (7.7 ± 2.0 mM) > hydroxycitronellal (19.6 ± 2.2 mM). Known VR1 antagonists (BCTC, thio-BCTC and capsazepine) were also able to block the response of TRPM8 to menthol (IC50: 0.8 ± 1.0, 3.5 ± 1.1 and 18 ± 1.1 μM, resp.). The Ca2+ response of hVR1-transfected HEK293 cells to the endogenous VR1 agonist N-arachidonoyl-dopamine was potentiated by low pH. In contrast, menthol- and icilin-activated TRPM8 currents were suppressed by low pH. In conclusion, in the present study, we identified 10 new agonists and three antagonists of TRPM8. We found that, in contrast to VR1, TRPM8 is inhibited rather than potentiated by protons.
  
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117. 117
  McNamara, F. N., Randall, A., and Gunthorpe, M. J. (2005) Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1) Br. J. Pharmacol. 144, 781– 790
  
  117
  Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1)
  
  McNamara, Fergal N.; Randall, Andrew; Gunthorpe, Martin J.
  
  British Journal of Pharmacology (2005), 144 (6), 781-790CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)
  
  1. We have characterized the effects of piperine, a pungent alkaloid found in black pepper, on the human vanilloid receptor TRPV1 using whole-cell patch-clamp electrophysiol. 2. Piperine produced a clear agonist activity at the human TRPV1 receptor yielding rapidly activating whole-cell currents that were antagonized by the competitive TRPV1 antagonist capsazepine and the non-competitive TRPV1 blocker ruthenium red. 3. The current-voltage relationship of piperine-activated currents showed pronounced outward rectification (25±4-fold between -70 and +70 mV) and a reversal potential of 0.0±0.4 mV, which was indistinguishable from that of the prototypical TRPV1 agonist capsaicin. 4. Although piperine was a less potent agonist (EC50=37.9±1.9 μM) than capsaicin (EC50=0.29±0.05 μM), it demonstrated a much greater efficacy (approx. two-fold) at TRPV1. 5. This difference in efficacy did not appear to be related to the proton-mediated regulation of the receptor since a similar degree of potentiation was obsd. for responses evoked by piperine (230±20%, n=11) or capsaicin (284±32%, n=8) upon acidification to pH 6.5. 6. The effects of piperine upon receptor desensitization were also unable to explain this effect since piperine resulted in more pronounced macroscopic desensitization (t1/2=9.9±0.7 s) than capsaicin (t1/2>20 s) and also caused greater tachyphylaxis in response to repetitive agonist applications. 7. Overall, our data suggest that the effects of piperine at human TRPV1 are similar to those of capsaicin except for its propensity to induce greater receptor desensitization and, rather remarkably, exhibit a greater efficacy than capsaicin itself. These results may provide insight into the TRPV1-mediated effects of piperine on gastrointestinal function.
  
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118. 118
  Bhardwaj, R. K., Glaeser, H., Becquemont, L., Klotz, U., Gupta, S. K., and Fromm, M. F. (2002) Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4 J. Pharmacol. Exp. Ther. 302, 645– 650
  
  118
  Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4
  
  Bhardwaj, Rajinder K.; Glaeser, Hartmut; Becquemont, Laurent; Klotz, Ulrich; Gupta, Suresh K.; Fromm, Martin F.
  
  Journal of Pharmacology and Experimental Therapeutics (2002), 302 (2), 645-650CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
  
  Dietary constituents (e.g., in grapefruit juice; NaCl) and phytochems. (e.g., St. John's wort) are important agents modifying drug metab. and transport and thereby contribute to interindividual variability in drug disposition. Most of these drug-food interactions are due to induction or inhibition of P-glycoprotein and/or CYP3A4. Preliminary data indicate that piperine, a major component of black pepper, inhibits drug-metabolizing enzymes in rodents and increases plasma concns. of several drugs, including P-glycoprotein substrates (phenytoin and rifampin) in humans. However, there are no direct data whether piperine is an inhibitor of human P-glycoprotein and/or CYP3A4. We therefore investigated the influence of piperine on P-glycoprotein-mediated, polarized transport of digoxin and cyclosporine in monolayers of Caco-2 cells. Moreover, by using human liver microsomes we detd. the effect of piperine on CYP3A4-mediated formation of the verapamil metabolites D-617 and norverapamil. Piperine inhibited digoxin and cyclosporine A transport in Caco-2 cells with IC50 values of 15.5 and 74.1 μM, resp. CYP3A4-catalyzed formation of D-617 and norverapamil was inhibited in a mixed fashion, with Ki values of 36±8 (liver 1)/49±6 (liver 2) and 44±10 (liver 1)/77±10 μM (liver 2), resp. In summary, we showed that piperine inhibits both the drug transporter P-glycoprotein and the major drug-metabolizing enzyme CYP3A4. Because both proteins are expressed in enterocytes and hepatocytes and contribute to a major extent to first-pass elimination of many drugs, our data indicate that dietary piperine could affect plasma concns. of P-glycoprotein and CYP3A4 substrates in humans, in particular if these drugs are administered orally.
  
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119. 119
  Bisogno, T., Hanus, L., De Petrocellis, L., Tchilibon, S., Ponde, D. E., Brandi, I., Moriello, A. S., Davis, J. B., Mechoulam, R., and Di Marzo, V. (2001) Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide Br. J. Pharmacol. 134, 845– 852
  
  119
  Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide
  
  Bisogno, Tiziana; Hanus, Lumir; De Petrocellis, Luciano; Tchilibon, Susanna; Ponde, Datta E.; Brandi, Ines; Moriello, Aniello Schiano; Davis, John B.; Mechoulam, Raphael; Di Marzo, Vincenzo
  
  British Journal of Pharmacology (2001), 134 (4), 845-852CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)
  
  (-)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible mol. targets of this compd. We investigated whether CBD and some of its derivs. interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). CBD and its enantiomer, (+)-CBD, together with seven analogs, obtained by exchanging the C-7 Me group of CBD with a hydroxy-Me or a carboxyl function and/or the C-5' pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concns. in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalyzed by the fatty acid amide hydrolase. Both CBD and (+)-CBD, but not the other analogs, stimulated VR1 with EC50=3.2-3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67-70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compds. were not additive. (+)-5'-DMH-CBD and (+)-7-hydroxy-5'-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (-)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM). CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (-)-7-hydroxy-CBD (IC50=34 μM), but not the other analogs (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis. Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors. These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacol. effects of CBD and its analogs. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (-)-5'-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent.
  
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120. 120
  Xu, H., Blair, N. T., and Clapham, D. E. (2005) Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism J. Neurosci. 25, 8924– 8937
  
  120
  Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism
  
  Xu, Haoxing; Blair, Nathaniel T.; Clapham, David E.
  
  Journal of Neuroscience (2005), 25 (39), 8924-8937CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
  
  Camphor is a naturally occurring compd. that is used as a major active ingredient of balms and liniments supplied as topical analgesics. Despite its long history of common medical use, the underlying mol. mechanism of camphor action is not understood. Capsaicin and menthol, two other topically applied agents widely used for similar purposes, are known to excite and desensitize sensory nerves by acting on two members of transient receptor potential (TRP) channel superfamily: heat-sensitive TRP vanilloid subtype 1 (TRPV1) and cold-sensitive TRP channel M8, resp. Camphor has recently been shown to activate TRPV3, and here we show that camphor also activates heterologously expressed TRPV1, requiring higher concns. than capsaicin. Activation was enhanced by phospholipase C-coupled receptor stimulation mimicking inflamed conditions. Similar camphor-activated TRPV1-like currents were obsd. in isolated rat DRG neurons and were strongly potentiated after activation of protein kinase C with phorbol-12-myristate-13-acetate. Camphor activation of rat TRPV1 was mediated by distinct channel regions from capsaicin, as indicated by camphor activation in the presence of the competitive inhibitor capsazepine and in a capsaicin-insensitive point mutant. Camphor did not activate the capsaicin-insensitive chicken TRPV1. TRPV1 desensitization is believed to contribute to the analgesic actions of capsaicin. We found that, although camphor activates TRPV1 less effectively, camphor application desensitized TRPV1 more rapidly and completely than capsaicin. Conversely, TRPV3 current sensitized after repeated camphor applications, which is inconsistent with the analgesic role of camphor. We also found that camphor inhibited several other related TRP channels, including ankyrin-repeat TRP 1 (TRPA1). The camphor-induced desensitization of TRPV1 and block of TRPA1 may underlie the analgesic effects of camphor.
  
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121. 121
  Pearce, L. V., Petukhov, P. A., Szabo, T., Kedei, N., Bizik, F., Kozikowski, A. P., and Blumberg, P. M. (2004) Evodiamine functions as an agonist for the vanilloid receptor TRPV1 Org. Biomol. Chem. 2, 2281– 2286
  
  121
  Evodiamine functions as an agonist for the vanilloid receptor TRPV1
  
  Pearce, Larry V.; Petukhov, Pavel A.; Szabo, Tamas; Kedei, Noemi; Bizik, Fero; Kozikowski, Alan P.; Blumberg, Peter M.
  
  Organic & Biomolecular Chemistry (2004), 2 (16), 2281-2286CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  
  Evodiamine, a quinozole alkaloid constituent of Evodia rutaecarpa, has been reported previously to induce several responses comparable to capsaicin in animal systems. Here, we characterize evodiamine as an agonist for rat TRPV1 expressed heterologously in CHO cells. Evodiamine bound to rat TRPV1 with a Ki of 5.95±0.87 μM, as measured by inhibition of [3H] RTX binding (capsaicin, Ki = 1.8±0.3 μM). Evodiamine was a full agonist for induction of 45Ca2+ uptake, with an EC50 of 856±43 nM (capsaicin, EC50 = 45±4 nM) and was competitively antagonized by capsazepine, as revealed by a Schild plot. The pattern of cellular response, as detd. by calcium imaging, was similar to that with capsaicin and yielded an EC50 of 1.03±0.21 μM. Mol. modeling suggested a consistent pattern of overlap between evodiamine and TRPV1 agonists. We conclude that evodiamine represents a novel class of agonists for rat TRPV1, albeit 3-19-fold less potent than capsaicin, and thus represents a new potential class of lead mols. for drug development.
  
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122. 122
  Morera, E., De Petrocellis, L., Morera, L., Moriello, A. S., Nalli, M., Di Marzo, V., and Ortar, G. (2012) Synthesis and biological evaluation of [6]-gingerol analogues as transient receptor potential channel TRPV1 and TRPA1 modulators Bioorg. Med. Chem. Lett. 22, 1674– 1677
  
  There is no corresponding record for this reference.
123. 123
  Xu, H., Delling, M., Jun, J. C., and Clapham, D. E. (2006) Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels Nat. Neurosci. 9, 628– 635
  
  123
  Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels
  
  Xu, Haoxing; Delling, Markus; Jun, Janice C.; Clapham, David E.
  
  Nature Neuroscience (2006), 9 (5), 628-635CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
  
  Carvacrol, eugenol and thymol are major components of plants such as oregano, savory, clove and thyme. When applied to the tongue, these flavors elicit a warm sensation. They are also known to be skin sensitizers and allergens. The transient receptor potential channel (TRPV3) is a warm-sensitive Ca2+-permeable cation channel highly expressed in the skin, tongue and nose. Here we show that TRPV3 is strongly activated and sensitized by carvacrol, thymol and eugenol. Tongue and skin epithelial cells respond to carvacrol and eugenol with an increase in intracellular Ca2+ levels. We also show that this TRPV3 activity is strongly potentiated by phospholipase C-linked, G protein-coupled receptor stimulation. In addn., carvacrol activates and rapidly desensitizes TRPA1, which may explain the pungency of oregano. Our results support a role for temp.-sensitive TRP channels in chemesthesis in oral and nasal epithelium and suggest that TRPV3 may be a mol. target of plant-derived skin sensitizers.
  
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124. 124
  Andre, E., Campi, B., Trevisani, M., Ferreira, J., Malheiros, A., Yunes, R. A., Calixto, J. B., and Geppetti, P. (2006) Pharmacological characterisation of the plant sesquiterpenes polygodial and drimanial as vanilloid receptor agonists Biochem. Pharmacol. 71, 1248– 1254
  
  There is no corresponding record for this reference.
125. 125
  Iwasaki, Y., Tanabe, M., Kayama, Y., Abe, M., Kashio, M., Koizumi, K., Okumura, Y., Morimitsu, Y., Tominaga, M., Ozawa, Y., and Watanabe, T. (2009) Miogadial and miogatrial with alpha,beta-unsaturated 1,4-dialdehyde moieties—novel and potent TRPA1 agonists Life Sci. 85, 60– 69
  
  There is no corresponding record for this reference.
126. 126
  Lübbert, M., Kyereme, J., Schöbel, N., Beltrán, L., Wetzel, C. H., and Hatt, H. (2013) Transient receptor potential channels encode volatile chemicals sensed by rat trigeminal ganglion neurons PLoS One 8, e77998
  
  There is no corresponding record for this reference.
127. 127
  Trevisan, G., Rossato, M. F., Walker, C. I., Klafke, J. Z., Rosa, F., Oliveira, S. M., Tonello, R., Guerra, G. P., Boligon, A. A., Zanon, R. B., Athayde, M. L., and Ferreira, J. (2012) Identification of the plant steroid alpha-spinasterol as a novel transient receptor potential vanilloid 1 antagonist with antinociceptive properties J. Pharmacol. Exp. Ther. 343, 258– 269
  
  127
  Identification of the plant steroid α-spinasterol as a novel transient receptor potential vanilloid 1 antagonist with antinociceptive properties
  
  Trevisan, Gabriela; Rossato, Mateus Fortes; Walker, Cristiani Isabel Bandero; Klafke, Jonatas Zeni; Rosa, Fernanda; Oliveira, Sara Marchesan; Tonello, Raquel; Guerra, Gustavo Petri; Boligon, Aline Augusti; Zanon, Ricardo Basso; Athayde, Margareth Linde; Ferreira, Juliano
  
  Journal of Pharmacology and Experimental Therapeutics (2012), 343 (2), 258-269CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)
  
  The transient receptor potential vanilloid 1 (TRPV1) receptor is relevant to the perception of noxious information and has been studied as a therapeutic target for the development of new analgesics. The goal of this study was to perform in vivo and in vitro screens to identify novel, efficacious, and safe TRPV1 antagonists isolated from leaves of the medicinal plant Vernonia tweedieana Baker. All of the fractions and the hydroalcoholic ext. produced antinociception in mice during the capsaicin test, but the dichloromethane fraction also had antioedematogenic effect. Among the compds. isolated from the dichloromethane fraction, only α-spinasterol reduced the nociception and edema induced by capsaicin injection. Moreover, α-spinasterol demonstrated good oral absorption and high penetration into the brain and spinal cord of mice. α-Spinasterol was able to displace [3H]resiniferatoxin binding and diminish calcium influx mediated by capsaicin. Oral administration of the dichloromethane fraction and α-spinasterol also produced antinociceptive effect in the noxious heat-induced nociception test; however, they did not change the mech. threshold of naive mice. The treatment with α-spinasterol did not produce antinociceptive effect in mice systemically pretreated with resiniferatoxin. In addn., α-spinasterol and the dichloromethane fraction reduced the edema, mech., and heat hyperalgesia elicited by complete Freund's adjuvant paw injection. The dichloromethane fraction and α-spinasterol did not affect body temp. or locomotor activity. In conclusion, α-spinasterol is a novel efficacious and safe antagonist of the TRPV1 receptor with antinociceptive effect.
  
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128. 128
  Birnbaumer, L., Yildirim, E., and Abramowitz, J. (2003) A comparison of the genes coding for canonical TRP channels and their M, V and P relatives Cell Calcium 33, 419– 432
  
  There is no corresponding record for this reference.
129. 129
  Peier, A. M., Reeve, A. J., Andersson, D. A., Moqrich, A., Earley, T. J., Hergarden, A. C., Story, G. M., Colley, S., Hogenesch, J. B., McIntyre, P., Bevan, S., and Patapoutian, A. (2002) A heat-sensitive TRP channel expressed in keratinocytes Science 296, 2046– 2049
  
  There is no corresponding record for this reference.
130. 130
  Moqrich, A., Hwang, S. W., Earley, T. J., Petrus, M. J., Murray, A. N., Spencer, K. S., Andahazy, M., Story, G. M., and Patapoutian, A. (2005) Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin Science 307, 1468– 1472
  
  130
  Impaired Thermosensation in Mice Lacking TRPV3, a Heat and Camphor Sensor in the Skin
  
  Moqrich, Aziz; Hwang, Sun Wook; Earley, Taryn J.; Petrus, Matt J.; Murray, Amber N.; Spencer, Kathryn S. R.; Andahazy, Mary; Story, Gina M.; Patapoutian, Ardem
  
  Science (Washington, DC, United States) (2005), 307 (5714), 1468-1472CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  
  Environmental temp. is thought to be directly sensed by neurons through their projections in the skin. A subset of the mammalian transient receptor potential (TRP) family of ion channels has been implicated in this process. These "thermoTRPs" are activated at distinct temp. thresholds and are typically expressed in sensory neurons. TRPV3 is activated by heat (>33°) and, unlike most thermoTRPs, is expressed in mouse keratinocytes. We found that TRPV3 null mice have strong deficits in responses to innocuous and noxious heat but not in other sensory modalities; hence, TRPV3 has a specific role in thermosensation. The natural compd. camphor, which modulates sensations of warmth in humans, proved to be a specific activator of TRPV3. Camphor activated cultured primary keratinocytes but not sensory neurons, and this activity was abolished in TRPV3 null mice. Therefore, heat-activated receptors in keratinocytes are important for mammalian thermosensation.
  
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131. 131
  Xu, H., Ramsey, I. S., Kotecha, S. A., Moran, M. M., Chong, J. A., Lawson, D., Ge, P., Lilly, J., Silos-Santiago, I., Xie, Y., DiStefano, P. S., Curtis, R., and Clapham, D. E. (2002) TRPV3 is a calcium-permeable temperature-sensitive cation channel Nature 418, 181– 186
  
  131
  TRPV3 is a calcium-permeable temperature-sensitive cation channel
  
  Xu, Haoxing; Ramsey, I. Scott; Kotecha, Suhas A.; Moran, Magdalene M.; Chong, Jayhong A.; Lawson, Deborah; Ge, Pei; Lilly, Jeremiah; Silos-Santiago, Inmaculada; Xie, Yu; DiStefano, Peter S.; Curtis, Rory; Clapham, David E.
  
  Nature (London, United Kingdom) (2002), 418 (6894), 181-186CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  
  Transient receptor potential (TRP) proteins are cation-selective channels that function in processes as diverse as sensation and vasoregulation. Mammalian TRP channels that are gated by heat and capsaicin (>43°C; TRPV1 (ref. 1)), noxious heat (>52°C; TRPV2 (ref. 2)), and cooling (< 22°C; TRPM8 (refs 3, 4)) have been cloned; however, little is known about the mol. determinants of temp. sensing in the range between ∼22°C and 40°C. Here we have identified a member of the vanilloid channel family, human TRPV3 (hTRPV3) that is expressed in skin, tongue, dorsal root ganglion, trigeminal ganglion, spinal cord and brain. Increasing temp. from 22°C to 40°C in mammalian cells transfected with hTRPV3 elevated intracellular calcium by activating a nonselective cationic conductance. As in published recordings from sensory neurons, the current was steeply dependent on temp., sensitized with repeated heating, and displayed a marked hysteresis on heating and cooling. On the basis of these properties, we propose that hTRPV3 is thermosensitive in the physiol. range of temps. between TRPM8 and TRPV1.
  
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132. 132
  Smith, G. D., Gunthorpe, M. J., Kelsell, R. E., Hayes, P. D., Reilly, P., Facer, P., Wright, J. E., Jerman, J. C., Walhin, J. P., Ooi, L., Egerton, J., Charles, K. J., Smart, D., Randall, A. D., Anand, P., and Davis, J. B. (2002) TRPV3 is a temperature-sensitive vanilloid receptor-like protein Nature 418, 186– 190
  
  There is no corresponding record for this reference.
133. 133
  Gopinath, P., Wan, E., Holdcroft, A., Facer, P., Davis, J. B., Smith, G. D., Bountra, C., and Anand, P. (2005) Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain BMC Women’s Health 5, 2
  
  There is no corresponding record for this reference.
134. 134
  Facer, P., Casula, M. A., Smith, G. D., Benham, C. D., Chessell, I. P., Bountra, C., Sinisi, M., Birch, R., and Anand, P. (2007) Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy BMC Neurol. 7, 11
  
  134
  Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy
  
  Facer Paul; Casula Maria A; Smith Graham D; Benham Christopher D; Chessell Iain P; Bountra Chas; Sinisi Marco; Birch Rolfe; Anand Praveen
  
  BMC neurology (2007), 7 (), 11 ISSN:.
  
  BACKGROUND: Transient receptor potential (TRP) receptors expressed by primary sensory neurons mediate thermosensitivity, and may play a role in sensory pathophysiology. We previously reported that human dorsal root ganglion (DRG) sensory neurons co-expressed TRPV1 and TRPV3, and that these were increased in injured human DRG. Related receptors TRPV4, activated by warmth and eicosanoids, and TRPM8, activated by cool and menthol, have been characterised in pre-clinical models. However, the role of TRPs in common clinical sensory neuropathies needs to be established. METHODS: We have studied TRPV1, TRPV3, TRPV4, and TRPM8 in nerves (n = 14) and skin from patients with nerve injury, avulsed dorsal root ganglia (DRG) (n = 11), injured spinal nerve roots (n = 9), diabetic neuropathy skin (n = 8), non-diabetic neuropathic nerve biopsies (n = 6), their respective control tissues, and human post mortem spinal cord, using immunohistological methods. RESULTS: TRPV1 and TRPV3 were significantly increased in injured brachial plexus nerves, and TRPV1 in hypersensitive skin after nerve repair, whilst TRPV4 was unchanged. TRPM8 was detected in a few medium diameter DRG neurons, and was unchanged in DRG after avulsion injury, but was reduced in axons and myelin in injured nerves. In diabetic neuropathy skin, TRPV1 expressing sub- and intra-epidermal fibres were decreased, as was expression in surviving fibres. TRPV1 was also decreased in non-diabetic neuropathic nerves. Immunoreactivity for TRPV3 was detected in basal keratinocytes, with a significant decrease of TRPV3 in diabetic skin. TRPV1-immunoreactive nerves were present in injured dorsal spinal roots and dorsal horn of control spinal cord, but not in ventral roots, while TRPV3 and TRPV4 were detected in spinal cord motor neurons. CONCLUSION: The accumulation of TRPV1 and TRPV3 in peripheral nerves after injury, in spared axons, matches our previously reported changes in avulsed DRG. Reduction of TRPV1 levels in nerve fibres in diabetic neuropathy skin may result from the known decrease of nerve growth factor (NGF) levels. The role of TRPs in keratinocytes is unknown, but a relationship to changes in NGF levels, which is produced by keratinocytes, deserves investigation. TRPV1 represents a more selective therapeutic target than other TRPs for pain and hypersensitivity, particularly in post-traumatic neuropathy.
  
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135. 135
  Huang, S. M., Lee, H., Chung, M. K., Park, U., Yu, Y. Y., Bradshaw, H. B., Coulombe, P. A., Walker, J. M., and Caterina, M. J. (2008) Overexpressed transient receptor potential vanilloid 3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2 J. Neurosci. 28, 13727– 13737
  
  135
  Overexpressed transient receptor potential vanilloid 3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2
  
  Huang, Susan M.; Lee, Hyosang; Chung, Man-Kyo; Park, Una; Yu, Yin Yin; Bradshaw, Heather B.; Coulombe, Pierre A.; Walker, J. Michael; Caterina, Michael J.
  
  Journal of Neuroscience (2008), 28 (51), 13727-13737CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
  
  The ability to sense changes in the environment is essential for survival because it permits responses such as withdrawal from noxious stimuli and regulation of body temp. Keratinocytes, which occupy much of the skin epidermis, are situated at the interface between the external environment and the body's internal milieu, and have long been appreciated for their barrier function against external insults. The recent discovery of temp.-sensitive transient receptor potential vanilloid (TRPV) ion channels in keratinocytes has raised the possibility that these cells also actively participate in acute temp. and pain sensation. To address this notion, the authors generated and characterized transgenic mice that overexpress TRPV3 in epidermal keratinocytes under the control of the keratin 14 promoter. Compared with wild-type controls, keratinocytes overexpressing TRPV3 exhibited larger currents as well as augmented prostaglandin E2 (PGE2) release in response to two TRPV3 agonists, 2-aminoethoxydiphenyl borate (2APB) and heat. Thermal selection behavior and heat-evoked withdrawal behavior of naive mice overexpressing TRPV3 were not consistently altered. Upon selective pharmacol. inhibition of TRPV1 with JNJ-7203212, however, the keratinocyte-specific TRPV3 transgenic mice showed increased escape responses to noxious heat relative to their wild-type littermates. Coadministration of the cyclooxygenase inhibitor, ibuprofen, with the TRPV1 antagonist decreased inflammatory thermal hyperalgesia in transgenic but not wild-type animals. The authors' results reveal a previously undescribed mechanism for keratinocyte participation in thermal pain transduction through keratinocyte TRPV3 ion channels and the intercellular messenger PGE2.
  
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136. 136
  Hammarstrom, S., Hamberg, M., Samuelsson, B., Duell, E. A., Stawiski, M., and Voorhees, J. J. (1975) Increased concentrations of nonesterified arachidonic acid, 12L-hydroxy-5,8,10,14-eicosatetraenoic acid, prostaglandin E2, and prostaglandin F2alpha in epidermis of psoriasis Proc. Natl. Acad. Sci. U.S.A. 72, 5130– 5134
  
  There is no corresponding record for this reference.
137. 137
  Brash, A. R. (2001) Arachidonic acid as a bioactive molecule J. Clin. Invest. 107, 1339– 1345
  
  137
  Arachidonic acid as a bioactive molecule
  
  Brash, Alan R.
  
  Journal of Clinical Investigation (2001), 107 (11), 1339-1345CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)
  
  A review, with 46 refs., of the biol. activity of arachidonic acid. Before dealing with bioactivity, the authors consider the soly. properties of the mol., which are crucial to understanding the availability within the cell of endogenous and exogenous arachidonic acid. This is followed by a discussion of two controversial issues, arachidonic acid transport into cells and the accessibility of added arachidonic acid to endogenous cellular compartments, and finally selected biol. actions of this lipid. The enzymes of arachidonic acid release have been well covered in specialized reviews and are introduced here only in passing.
  
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138. 138
  Mandadi, S., Sokabe, T., Shibasaki, K., Katanosaka, K., Mizuno, A., Moqrich, A., Patapoutian, A., Fukumi-Tominaga, T., Mizumura, K., and Tominaga, M. (2009) TRPV3 in keratinocytes transmits temperature information to sensory neurons via ATP Pfluegers Arch. 458, 1093– 2002
  
  138
  TRPV3 in keratinocytes transmits temperature information to sensory neurons via ATP
  
  Mandadi, Sravan; Sokabe, Takaaki; Shibasaki, Koji; Katanosaka, Kimiaki; Mizuno, Atsuko; Moqrich, Aziz; Patapoutian, Ardem; Fukumi-Tominaga, Tomoko; Mizumura, Kazue; Tominaga, Makoto
  
  Pfluegers Archiv (2009), 458 (6), 1093-1102CODEN: PFLABK; ISSN:0031-6768. (Springer GmbH)
  
  Transient receptor potential V3 (TRPV3) and TRPV4 are heat-activated cation channels expressed in keratinocytes. It has been proposed that heat-activation of TRPV3 and/or TRPV4 in the skin may release diffusible mols. which would then activate termini of neighboring dorsal root ganglion (DRG) neurons. Here we show that ATP is such a candidate mol. released from keratinocytes upon heating in the co-culture systems. Using TRPV1-deficient DRG neurons, we found that increase in cytosolic Ca2+-concn. in DRG neurons upon heating was obsd. only when neurons were co-cultured with keratinocytes, and this increase was blocked by P2 purinoreceptor antagonists, PPADS and suramin. In a co-culture of keratinocytes with HEK293 cells (transfected with P2X2 cDNA to serve as a bio-sensor), we obsd. that heat-activated keratinocytes secretes ATP, and that ATP release is compromised in keratinocytes from TRPV3-deficient mice. This study provides evidence that ATP is a messenger mol. for mainly TRPV3-mediated thermotransduction in skin.
  
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139. 139
  Xiao, R., Tang, J., Wang, C., Colton, C. K., Tian, J., and Zhu, M. X. (2008) Calcium plays a central role in the sensitization of TRPV3 channel to repetitive stimulations J. Biol. Chem. 283, 6162– 6174
  
  There is no corresponding record for this reference.
140. 140
  Imura, K. (2007) Influence of TRPV3 mutation on hair growth cycle in mice Biochem. Biophys. Res. Commun. 363, 479– 483
  
  There is no corresponding record for this reference.
141. 141
  Asakawa, M., Yoshioka, T., Matsutani, T., Hikita, I., Suzuki, M., Oshima, I., Tsukahara, K., Arimura, A., Horikawa, T., Hirasawa, T., and Sakata, T. (2006) Association of a mutation in TRPV3 with defective hair growth in rodents J. Invest. Dermatol. 126, 2664– 2672
  
  There is no corresponding record for this reference.
142. 142
  Macpherson, L. J., Hwang, S. W., Miyamoto, T., Dubin, A. E., Patapoutian, A., and Story, G. M. (2006) More than cool: promiscuous relationships of menthol and other sensory compounds Mol. Cell Neurosci. 32, 335– 343
  
  142
  More than cool: Promiscuous relationships of menthol and other sensory compounds
  
  Macpherson, Lindsey J.; Hwang, Sun Wook; Miyamoto, Takashi; Dubin, Adrienne E.; Patapoutian, Ardem; Story, Gina M.
  
  Molecular and Cellular Neuroscience (2006), 32 (4), 335-343CODEN: MOCNED; ISSN:1044-7431. (Elsevier)
  
  Several temp.-activated transient receptor potential (thermoTRP) ion channels are the mol. receptors of natural compds. that evoke thermal and pain sensations. Menthol, popularly known for its cooling effect, activates TRPM8 - a cold-activated thermoTRP ion channel. However, human physiol. studies demonstrate a paradoxical role of menthol in modulation of warm sensation, and here, we show that menthol also activates heat-activated TRPV3. We further show that menthol inhibits TRPA1, potentially explaining the use of menthol as an analgesic. Similar to menthol, both camphor and cinnamaldehyde (initially reported to be specific activators of TRPV3 and TRPA1, resp.) also modulate other thermoTRPs. Therefore, we find that many "sensory compds." presumed to be specific have a promiscuous relationship with thermoTRPs.
  
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143. 143
  Moussaieff, A., Rimmerman, N., Bregman, T., Straiker, A., Felder, C. C., Shoham, S., Kashman, Y., Huang, S. M., Lee, H., Shohami, E., Mackie, K., Caterina, M. J., Walker, J. M., Fride, E., and Mechoulam, R. (2008) Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain FASEB J. 22, 3024– 3034
  
  There is no corresponding record for this reference.
144. 144
  De Petrocellis, L., Orlando, P., Moriello, A. S., Aviello, G., Stott, C., Izzo, A. A., and Di Marzo, V. (2012) Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation Acta Physiol. 204, 255– 266
  
  144
  Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation
  
  De Petrocellis, L.; Orlando, P.; Moriello, A. Schiano; Aviello, G.; Stott, C.; Izzo, A. A.; Di Marzo, V.
  
  Acta Physiologica (2012), 204 (2), 255-266CODEN: APCHC4; ISSN:1748-1708. (Wiley-Blackwell)
  
  Aim: Plant cannabinoids, like Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), activate/desensitize thermosensitive transient receptor potential (TRP) channels of vanilloid type-1 or -2 (TRPV1 or TRPV2). We investigated whether cannabinoids also activate/desensitize two other "thermo-TRP's", the TRP channels of vanilloid type-3 or -4 (TRPV3 or TRPV4), and if the TRPV-inactive cannabichromene (CBC) modifies the expression of TRPV1-4 channels in the gastrointestinal tract. Methods: TRP activity was assessed by evaluating elevation of [Ca2+]i in rat recombinant TRPV3- and TRPV4-expressing HEK-293 cells. TRP channel mRNA expression was measured by quant. RT-PCR in the jejunum and ileum of mice treated with vehicle or the pro-inflammatory agent croton oil. Results: (i) CBD and tetrahydrocannabivarin (THCV) stimulated TRPV3-mediated [Ca2+]i with high efficacy (50-70% of the effect of ionomycin) and potency (EC50∼3.7 μM), whereas cannabigerovarin (CBGV) and cannabigerolic acid (CBGA) were significantly more efficacious at desensitizing this channel to the action of carvacrol than at activating it; (ii) cannabidivarin and THCV stimulated TRPV4-mediated [Ca2+]i with moderate-high efficacy (30-60% of the effect of ionomycin) and potency (EC50 0.9-6.4 μM), whereas CBGA, CBGV, cannabinol and cannabigerol were significantly more efficacious at desensitizing this channel to the action of 4-α-phorbol 12,13-didecanoate (4α-PDD) than at activating it; (iii) CBC reduced TRPV1β, TRPV3 and TRPV4 mRNA in the jejunum, and TRPV3 and TRPV4 mRNA in the ileum of croton oil-treated mice. Conclusions: Cannabinoids can affect both the activity and the expression of TRPV1-4 channels, with various potential therapeutic applications, including in the gastrointestinal tract.
  
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145. 145
  Strotmann, R., Harteneck, C., Nunnenmacher, K., Schultz, G., and Plant, T. D. (2000) OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity Nat. Cell Biol. 2, 695– 702
  
  145
  OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity
  
  Strotmann, Rainer; Harteneck, Christian; Nunnenmacher, Karin; Schultz, Gunter; Plant, Tim D.
  
  Nature Cell Biology (2000), 2 (10), 695-702CODEN: NCBIFN; ISSN:1465-7392. (Nature Publishing Group)
  
  Ca2+-permeable channels that are involved in the responses of mammalian cells to changes in extracellular osmolarity have not been characterized at the mol. level. Here we identify a new TRP (transient receptor potential)-like channel protein, OTRPC4, that is expressed at high levels in the kidney, liver and heart. OTRPC4 forms Ca2+-permeable, nonselective cation channels that exhibit spontaneous activity in isotonic media and are rapidly activated by decreases in, and are inhibited by increases in, extracellular osmolarity. Changes in osmolarity of as little as 10% result in significant changes in intracellular Ca2+ concn. We propose that OTRPC4 is a candidate for a mol. sensor that confers osmosensitivity on mammalian cells.
  
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146. 146
  Watanabe, H., Davis, J. B., Smart, D., Jerman, J. C., Smith, G. D., Hayes, P., Vriens, J., Cairns, W., Wissenbach, U., Prenen, J., Flockerzi, V., Droogmans, G., Benham, C. D., and Nilius, B. (2002) Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives J. Biol. Chem. 277, 13569– 13577
  
  There is no corresponding record for this reference.
147. 147
  Suzuki, M., Mizuno, A., Kodaira, K., and Imai, M. (2003) Impaired pressure sensation in mice lacking TRPV4 J. Biol. Chem. 278, 22664– 22668
  
  There is no corresponding record for this reference.
148. 148
  Nilius, B., Droogmans, G., and Wondergem, R. (2003) Transient receptor potential channels in endothelium: solving the calcium entry puzzle? Endothelium 10, 5– 15
  
  148
  Transient Receptor Potential Channels in Endothelium: Solving the Calcium Entry Puzzle?
  
  Nilius, Bernd; Droogmans, Guy; Wondergem, Robert
  
  Endothelium (2003), 10 (1), 5-15CODEN: ENDTE9; ISSN:1062-3329. (Taylor & Francis Ltd.)
  
  A review. Many endothelial cell (EC) functions depend on influx of extracellular Ca2+, which is triggered by a variety of mech. and chem. signals. Here, we discuss possible pathways for this Ca2+ entry. The superfamily of cation channels derived from the "transient receptor potential" (TRP) channels is introduced. Several members of this family are expressed in ECs, and they provide pathways for Ca2+ entry. All TRP subfamilies may contribute to the Ca2+ entry channels or to the regulation of Ca2+ entry in EC. Members of Ca2+ entry channels in endothelium probably belong to the canonical TRP subfamily, TRPC. All TRPC1-6 have been discussed as Ca2+ entry channels that might be store-operated and/or receptor-operated. More importantly, knockout models of TRPC4 have proven that this channel is functionally involved in the regulation of endothelial-dependent vasorelaxation and in the control of EC barrier function. TRPC1 might be an important candidate for involvement of endothelial growth factors. TRPC3 is unequivocally important for a sustained EC Ca2+ entry. ECs express different patterns of TRPCs, which may increase the variability of TRPC channel function by formation of different multiheteromers. Among the two other TRP subfamilies, TRPMV and TRPM, at least TRPV4 and TRPM4 are EC channels. TRPV4 is a Ca2+ entry channel that is activated by an increase in cell vol., which might be involved in mechano-sensing, by an increase in temp., and perhaps by ligand-activation. TRPM4 is a nonselective cation channel, which is not Ca2+ permeable. It is probably modulated by NO and might be essential for regulating the inward driving force for Ca2+ entry. Possible modes of TRP channel regulation are described, involving (a) activation via the phospholipase (PL)Cβ and PLCγ pathways; (b) activation by lipids (diacylglycerol [DAG], arachidonic acid); (c) Ca2+ depletion of Ca2+ stores in the endoplasmic reticulum; (d) shear stress; and (e) radicals.
  
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149. 149
  Kohler, R., Heyken, W. T., Heinau, P., Schubert, R., Si, H., Kacik, M., Busch, C., Grgic, I., Maier, T., and Hoyer, J. (2006) Evidence for a functional role of endothelial transient receptor potential V4 in shear stress-induced vasodilatation Arterioscler., Thromb., Vasc. Biol. 26, 1495– 15502
  
  149
  Evidence for a functional role of endothelial transient receptor potential V4 in shear stress-induced vasodilatation
  
  Kohler Ralf; Heyken Willm-Thomas; Heinau Philipp; Schubert Rudolf; Si Han; Kacik Michael; Busch Christoph; Grgic Ivica; Maier Tanja; Hoyer Joachim
  
  Arteriosclerosis, thrombosis, and vascular biology (2006), 26 (7), 1495-502 ISSN:.
  
  OBJECTIVE: Ca2+-influx through transient receptor potential (TRP) channels was proposed to be important in endothelial function, although the precise role of specific TRP channels is unknown. Here, we investigated the role of the putatively mechanosensitive TRPV4 channel in the mechanisms of endothelium-dependent vasodilatation. METHODS AND RESULTS: Expression and function of TRPV4 was investigated in rat carotid artery endothelial cells (RCAECs) by using in situ patch-clamp techniques, single-cell RT-PCR, Ca2+ measurements, and pressure myography in carotid artery (CA) and Arteria gracilis. In RCAECs in situ, TRPV4 currents were activated by the selective TRPV4 opener 4alpha-phorbol-12,13-didecanoate (4alphaPDD), arachidonic acid, moderate warmth, and mechanically by hypotonic cell swelling. Single-cell RT-PCR in endothelial cells demonstrated mRNA expression of TRPV4. In FURA-2 Ca2+ measurements, 4alphaPDD increased [Ca2+]i by &140 nmol/L above basal levels. In pressure myograph experiments in CAs and A gracilis, 4alphaPDD caused robust endothelium-dependent and strictly endothelium-dependent vasodilatations by &80% (K(D) 0.3 microL), which were suppressed by the TRPV4 blocker ruthenium red (RuR). Shear stress-induced vasodilatation was similarly blocked by RuR and also by the phospholipase A2 inhibitor arachidonyl trifluoromethyl ketone (AACOCF3). 4alphaPDD produced endothelium-derived hyperpolarizing factor (EDHF)-type responses in A gracilis but not in rat carotid artery. Shear stress did not produce EDHF-type vasodilatation in either vessel type. CONCLUSIONS: Ca2+ entry through endothelial TRPV4 channels triggers NO- and EDHF-dependent vasodilatation. Moreover, TRPV4 appears to be mechanistically important in endothelial mechanosensing of shear stress.
  
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150. 150
  Watanabe, H., Vriens, J., Suh, S. H., Benham, C. D., Droogmans, G., and Nilius, B. (2002) Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells J. Biol. Chem. 277, 47044– 47051
  
  There is no corresponding record for this reference.
151. 151
  Watanabe, H., Vriens, J., Prenen, J., Droogmans, G., Voets, T., and Nilius, B. (2003) Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels Nature 424, 434– 438
  
  There is no corresponding record for this reference.
152. 152
  Loukin, S. H., Su, Z., and Kung, C. (2009) Hypotonic shocks activate rat TRPV4 in yeast in the absence of polyunsaturated fatty acids FEBS Lett. 583, 754– 758
  
  There is no corresponding record for this reference.
153. 153
  Cao, D. S., Yu, S. Q., and Premkumar, L. S. (2009) Modulation of transient receptor potential Vanilloid 4-mediated membrane currents and synaptic transmission by protein kinase C Mol. Pain 5, 5
  
  153
  Modulation of transient receptor potential Vanilloid 4-mediated membrane currents and synaptic transmission by protein kinase C
  
  Cao De-Shou; Yu Shuang-Quan; Premkumar Louis S
  
  Molecular pain (2009), 5 (), 5 ISSN:.
  
  BACKGROUND: Transient receptor potential Vanilloid (TRPV) receptors are involved in nociception and are expressed predominantly in sensory neurons. TRPV1, a non-selective cation channel has been extensively studied and is responsible for inflammatory thermal hypersensitivity. In this study, the expression and function of TRPV4 have been characterized and compared with those of TRPV1. RESULTS: Immunohistochemical studies revealed that both TRPV1 and TRPV4 were co-expressed in dorsal root ganglion (DRG) neuronal cell bodies and in the central terminals of laminae I and II of the spinal dorsal horn (DH). In Ca2+ fluorescence imaging and whole-cell patch-clamp experiments, TRPV1- and TRPV4-mediated responses were observed in a population of the same DRG neurons. Sensitization of TRPV1 has been shown to be involved in inflammatory pain conditions. Incubation with phorbol 12, 13-dibutyrate (PDBu), a PKC activator, resulted in a significant potentiation of TRPV4 currents in DRG neurons. In TRPV4 expressing HEK 293T cells, PDBu increased 4alpha-phorbol 12, 13-didecanoate (4alpha-PDD)-induced single-channel activity in cell-attached patches, which was abrogated by bisindolylmaleimide (BIM), a selective PKC inhibitor. TRPV4 is also expressed at the central terminals of sensory neurons. Activation of TRPV4 by 4alpha-PDD increased the frequency of miniature excitatory post synaptic currents (mEPSCs) in DRG-DH neuronal co-cultures. 4alpha-PDD-induced increase in the frequency of mEPSCs was further enhanced by PDBu. The expression of TRP channels has been shown in other areas of the CNS; application of 4alpha-PDD significantly increased the mEPSC frequency in cultured hippocampal neurons, which was further potentiated by PDBu, whereas, TRPV1 agonist capsaicin did not modulate synaptic transmission. CONCLUSION: These results indicate that TRPV4 and TRPV1 are co-expressed in certain DRG neurons and TRPV4 can be sensitized by PKC not only in DRG neuronal cell bodies, but also in the central sensory and non-sensory nerve terminals. Co-expression of TRPV1 and TRPV4 ion channels, their modulation of synaptic transmission and their sensitization by PKC may synergistically play a role in nociception.
  
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154. 154
  Matthews, B. D., Thodeti, C. K., Tytell, J. D., Mammoto, A., Overby, D. R., and Ingber, D. E. (2010) Ultra-rapid activation of TRPV4 ion channels by mechanical forces applied to cell surface beta1 integrins Integr. Biol. 2, 435– 442
  
  154
  Ultra-rapid activation of TRPV4 ion channels by mechanical forces applied to cell surface β1 integrins
  
  Matthews, Benjamin D.; Thodeti, Charles K.; Tytell, Jessica D.; Mammoto, Akiko; Overby, Darryl R.; Ingber, Donald E.
  
  Integrative Biology (2010), 2 (9), 435-442CODEN: IBNIFL; ISSN:1757-9694. (Royal Society of Chemistry)
  
  Integrins are ubiquitous transmembrane mechanoreceptors that elicit changes in intracellular biochem. in response to mech. force application, but these alterations generally proceed over seconds to minutes. Stress-sensitive ion channels represent another class of mechanoreceptors that are activated much more rapidly (within msec), and recent findings suggest that calcium influx through Transient Receptor Potential Vanilloid-4 (TRPV4) channels expressed in the plasma membrane of bovine capillary endothelial cells is required for mech. strain-induced changes in focal adhesion assembly, cell orientation and directional migration. However, whether mech. stretching a cell's extracellular matrix (ECM) adhesions might directly activate cell surface ion channels remains unknown. Here we show that forces applied to β1 integrins result in ultra-rapid (within 4 ms) activation of calcium influx through TRPV4 channels. The TRPV4 channels were specifically activated by mech. strain in the cytoskeletal backbone of the focal adhesion, and not by deformation of the lipid bilayer or submembranous cortical cytoskeleton alone. This early-immediate calcium signaling response required the distal region of the β1 integrin cytoplasmic tail that contains a binding site for the integrin-assocd. transmembrane CD98 protein, and external force application to CD98 within focal adhesions activated the same ultra-rapid calcium signaling response. Local direct strain-dependent activation of TRPV4 channels mediated by force transfer from integrins and CD98 may therefore enable compartmentalization of calcium signaling within focal adhesions that is crit. for mech. control of many cell behaviors that underlie cell and tissue development.
  
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155. 155
  Alessandri-Haber, N., Dina, O. A., Joseph, E. K., Reichling, D. B., and Levine, J. D. (2008) Interaction of transient receptor potential vanilloid 4, integrin, and SRC tyrosine kinase in mechanical hyperalgesia J. Neurosci. 28, 1046– 1057
  
  155
  Interaction of transient receptor potential vanilloid 4, integrin, and Src tyrosine kinase in mechanical hyperalgesia
  
  Alessandri-Haber, Nicole; Dina, Olayinka A.; Joseph, Elizabeth K.; Reichling, David B.; Levine, Jon D.
  
  Journal of Neuroscience (2008), 28 (5), 1046-1057CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
  
  Although the transient receptor potential vanilloid 4 (TRPV4) has been implicated in the process of osmomech. transduction, it appears to make little contribution to the normal somatosensory detection of mech. stimuli. However, evidence suggests that it may play an important role in mech. hyperalgesia. In the present study, we examd. the common requirement for TRPV4 in mech. hyperalgesia assocd. with diverse pain models and investigated whether the very close assocn. obsd. between TRPV4 and mech. hyperalgesia, regardless of etiol., reflects a close functional connection of TRPV4 with other mols. implicated in mech. transduction. In models of painful peripheral neuropathy assocd. with vincristine chemotherapy, alcoholism, diabetes, and human immunodeficiency virus/acquired immune deficiency syndrome therapy, mech. hyperalgesia was markedly reduced by spinal intra-thecal administration of oligodeoxynucleotides antisense to TRPV4. Similarly, mech. hyperalgesia induced by paclitaxel, vincristine, or diabetes was strongly reduced in TRPV4 knock-out mice. We also show that α2β1 integrin and Src tyrosine kinase, which have been implicated in mech. transduction, are important for the development of mech. hyperalgesia, and that their contribution requires TRPV4. Furthermore, we establish a direct interaction between TRPV4, α2 integrin, and the Src tyrosine kinase Lyn in sensory neurons. We suggest that TRPV4 plays a role in mechanotransduction, as a component of a mol. complex that functions only in the setting of inflammation or nerve injury.
  
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156. 156
  Chen, X., Alessandri-Haber, N., and Levine, J. D. (2007) Marked attenuation of inflammatory mediator-induced C-fiber sensitization for mechanical and hypotonic stimuli in TRPV4–/– mice Mol. Pain 3, 31
  
  156
  Marked attenuation of inflammatory mediator-induced C-fiber sensitization for mechanical and hypotonic stimuli in TRPV4-/- mice
  
  Chen Xiaojie; Alessandri-Haber Nicole; Levine Jon D
  
  Molecular pain (2007), 3 (), 31 ISSN:.
  
  Inflammatory mediators can directly sensitize primary afferent nociceptors to mechanical and osmotic stimuli. Sensitized nociceptors have a lowered threshold of activation and increased spontaneous activity, which result in symptoms of hyperalgesia and pain, respectively. The transient receptor potential vanilloid 4 (TRPV4) ligand-gated ion channel has been implicated in the hyperalgesia for mechanical and osmotic stimuli associated with inflammatory states. To investigate whether TRPV4 directly contributes to the mechanisms of inflammatory mediator sensitization of C-fiber nociceptors, we compared the effect of the injection of simplified inflammatory soup (prostaglandin E2 and serotonin) into the mechanical receptive fields of C-fibers in TRPV4+/+ and TRPV4-/- mice in vivo. Following the injection of the soup, the percentage of C-fibers responding to a hypotonic stimulus and the magnitude of the response was significantly greater in TRPV4+/+ mice compared to TRPV4-/- mice. Moreover, in response to simplified inflammatory soup only C-fibers from TRPV4+/+ mice exhibited increased spontaneous activity and decreased mechanical threshold. These marked impairments in the response of C-fibers in TRPV4-/- mice demonstrate the importance of TRPV4 in nociceptor sensitization; we suggest that TRPV4, as TRPV1, underlies the nociceptive effects of multiple inflammatory mediators on primary afferent.
  
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157. 157
  Alessandri-Haber, N., Yeh, J. J., Boyd, A. E., Parada, C. A., Chen, X., Reichling, D. B., and Levine, J. D. (2003) Hypotonicity induces TRPV4-mediated nociception in rat Neuron 39, 497– 511
  
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158. 158
  Alessandri-Haber, N., Joseph, E., Dina, O. A., Liedtke, W., and Levine, J. D. (2005) TRPV4 mediates pain-related behavior induced by mild hypertonic stimuli in the presence of inflammatory mediator Pain 118, 70– 79
  
  There is no corresponding record for this reference.
159. 159
  Smith, P. L., Maloney, K. N., Pothen, R. G., Clardy, J., and Clapham, D. E. (2006) Bisandrographolide from Andrographis paniculata activates TRPV4 channels J. Biol. Chem. 281, 29897– 29904
  
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Transient Receptor Potential Channels as Targets for Phytochemicals

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Abstract

SPECIAL ISSUE

Phytochemicals That Activate Transient Receptor Potential Ankyrin (TRPA)

Figure 1

Figure 2

Phytochemicals That Activate Transient Receptor Potential Canonical (TRPC)

Phytochemicals That Activate Transient Receptor Potential Melastatin (TRPM)

TRPM5

TRPM8

Figure 3

Phytochemicals That Activate Transient Receptor Potential Polycystin (TRPP)

Phytochemicals That Activate Transient Receptor Potential Vanilloid (TRPV)

TRVP1

Figure 4

TRPV3

TRPV4

Concluding Remarks

Author Information

Acknowledgment

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Cited By

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

References

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