Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase.
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.
Hawley
Simon A
SA
Division of Molecular Physiology University of Dundee, Dundee, Scotland, United Kingdom.
Pan
David A
DA
Mustard
Kirsty J
KJ
Ross
Louise
L
Bain
Jenny
J
Edelman
Arthur M
AM
Frenguelli
Bruno G
BG
Hardie
D Grahame
DG
D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053644:Naphthalimides; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013379:Substrate Specificity
D001562:Benzimidazoles; D007546:Isoquinolines; D009097:Multienzyme Complexes; D053644:Naphthalimides; D034741:RNA, Small Interfering; C458525:STO 609; D000001:Calcimycin; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; C517698:CAMKK2 protein, human; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; C517700:Camkk2 protein, mouse; C517702:Camkk2 protein, rat; D055372:AMP-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D000103:Acetyl-CoA Carboxylase