Abstract
In spite of the recognition that striatal D(2) receptors are critical determinants in a variety of psychomotor disorders, the cellular mechanisms by which these receptors shape neuronal activity have remained a mystery. The studies presented here reveal that D(2) receptor stimulation in enkephalin-expressing medium spiny neurons suppresses transmembrane Ca(2+) currents through L-type Ca(2+) channels, resulting in diminished excitability. This modulation is mediated by G(beta)(gamma) activation of phospholipase C, mobilization of intracellular Ca(2+) stores, and activation of the calcium-dependent phosphatase calcineurin. In addition to providing a unifying mechanism to explain the apparently divergent effects of D(2) receptors in striatal medium spiny neurons, this novel signaling linkage provides a foundation for understanding how this pivotal receptor shapes striatal excitability and gene expression.
Publication types
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, P.H.S.
MeSH terms
- Action Potentials / drug effects
- Adenylyl Cyclase Inhibitors
- Animals
- Barium / pharmacology
- Calcineurin / metabolism*
- Calcineurin Inhibitors
- Calcium / metabolism
- Calcium Channel Agonists / pharmacology
- Calcium Channel Blockers / pharmacology
- Calcium Channels, L-Type / metabolism*
- Corpus Striatum / cytology
- Corpus Striatum / metabolism
- Dopamine / metabolism
- Dopamine Agonists / pharmacology
- Dopamine Antagonists / pharmacology
- Dopamine D2 Receptor Antagonists
- Dose-Response Relationship, Drug
- Enzyme Inhibitors / pharmacology
- In Vitro Techniques
- Inositol 1,4,5-Trisphosphate / metabolism*
- Ion Transport / drug effects
- Isoenzymes / antagonists & inhibitors
- Isoenzymes / metabolism*
- Isoenzymes / pharmacology
- Neurons / cytology
- Neurons / drug effects
- Neurons / metabolism*
- Patch-Clamp Techniques
- Phospholipase C beta
- Rats
- Receptors, Dopamine D2 / agonists
- Receptors, Dopamine D2 / metabolism*
- Signal Transduction / physiology
- Sulpiride / pharmacology
- Type C Phospholipases / antagonists & inhibitors
- Type C Phospholipases / metabolism*
- Type C Phospholipases / pharmacology
Substances
- Adenylyl Cyclase Inhibitors
- Calcineurin Inhibitors
- Calcium Channel Agonists
- Calcium Channel Blockers
- Calcium Channels, L-Type
- Dopamine Agonists
- Dopamine Antagonists
- Dopamine D2 Receptor Antagonists
- Enzyme Inhibitors
- Isoenzymes
- Receptors, Dopamine D2
- Barium
- Sulpiride
- Inositol 1,4,5-Trisphosphate
- Calcineurin
- Type C Phospholipases
- Phospholipase C beta
- Calcium
- Dopamine