Abstract
The AMP-activated protein kinase (AMPK) is a critical regulator of energy balance at both the cellular and whole-body levels. Two upstream kinases have been reported to activate AMPK in cell-free assays, i.e., the tumor suppressor LKB1 and calmodulin-dependent protein kinase kinase. However, evidence that this is physiologically relevant currently only exists for LKB1. We now report that there is a significant basal activity and phosphorylation of AMPK in LKB1-deficient cells that can be stimulated by Ca2+ ionophores, and studies using the CaMKK inhibitor STO-609 and isoform-specific siRNAs show that CaMKKbeta is required for this effect. CaMKKbeta also activates AMPK much more rapidly than CaMKKalpha in cell-free assays. K(+)-induced depolarization in rat cerebrocortical slices, which increases intracellular Ca2+ without disturbing cellular adenine nucleotide levels, activates AMPK, and this is blocked by STO-609. Our results suggest a potential Ca(2+)-dependent neuroprotective pathway involving phosphorylation and activation of AMPK by CaMKKbeta.
Publication types
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, P.H.S.
MeSH terms
- AMP-Activated Protein Kinases
- Acetyl-CoA Carboxylase / metabolism
- Adenosine Diphosphate / metabolism
- Adenosine Triphosphate / metabolism
- Animals
- Benzimidazoles / pharmacology
- Brain / drug effects
- Brain / metabolism
- Calcimycin / pharmacology
- Calcium-Calmodulin-Dependent Protein Kinase Kinase
- Enzyme Activation / drug effects
- Fibroblasts
- HeLa Cells
- Humans
- In Vitro Techniques
- Isoquinolines / pharmacology
- Mice
- Multienzyme Complexes / antagonists & inhibitors
- Multienzyme Complexes / metabolism*
- Naphthalimides
- Phosphoprotein Phosphatases / metabolism
- Phosphorylation
- Protein Serine-Threonine Kinases / antagonists & inhibitors
- Protein Serine-Threonine Kinases / deficiency
- Protein Serine-Threonine Kinases / genetics
- Protein Serine-Threonine Kinases / metabolism*
- RNA, Small Interfering / genetics
- RNA, Small Interfering / metabolism
- Rats
- Substrate Specificity
Substances
- Benzimidazoles
- Isoquinolines
- Multienzyme Complexes
- Naphthalimides
- RNA, Small Interfering
- STO 609
- Calcimycin
- Adenosine Diphosphate
- Adenosine Triphosphate
- Protein Serine-Threonine Kinases
- Stk11 protein, mouse
- CAMKK2 protein, human
- Calcium-Calmodulin-Dependent Protein Kinase Kinase
- Camkk2 protein, mouse
- Camkk2 protein, rat
- AMP-Activated Protein Kinases
- Phosphoprotein Phosphatases
- Acetyl-CoA Carboxylase