Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase

Cell Metab. 2005 Jul;2(1):9-19. doi: 10.1016/j.cmet.2005.05.009.

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
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • CAMKK2 protein, human
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase
  • Camkk2 protein, mouse
  • Camkk2 protein, rat
  • AMP-Activated Protein Kinases
  • Phosphoprotein Phosphatases
  • Acetyl-CoA Carboxylase