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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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AMP-Activated Protein Kinases
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Acetyl-CoA Carboxylase / metabolism
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Adenosine Diphosphate / metabolism
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Adenosine Triphosphate / metabolism
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Animals
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Benzimidazoles / pharmacology
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Brain / drug effects
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Brain / metabolism
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Calcimycin / pharmacology
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Calcium-Calmodulin-Dependent Protein Kinase Kinase
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Enzyme Activation / drug effects
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Fibroblasts
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HeLa Cells
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Humans
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In Vitro Techniques
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Isoquinolines / pharmacology
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Mice
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Multienzyme Complexes / antagonists & inhibitors
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Multienzyme Complexes / metabolism*
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Naphthalimides
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Phosphoprotein Phosphatases / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Rats
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Substrate Specificity
Substances
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Benzimidazoles
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Isoquinolines
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Multienzyme Complexes
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Naphthalimides
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RNA, Small Interfering
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STO 609
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Calcimycin
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Adenosine Diphosphate
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Adenosine Triphosphate
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Protein Serine-Threonine Kinases
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Stk11 protein, mouse
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CAMKK2 protein, human
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Calcium-Calmodulin-Dependent Protein Kinase Kinase
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Camkk2 protein, mouse
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Camkk2 protein, rat
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AMP-Activated Protein Kinases
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Phosphoprotein Phosphatases
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Acetyl-CoA Carboxylase