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

TY - JOUR

T1 - Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase

AU - Hawley, Simon A.

AU - Pan, David A.

AU - Mustard, Kirsty J.

AU - Ross, Louise

AU - Bain, Jenny

AU - Edelman, Arthur M.

AU - Frenguelli, Bruno G.

AU - Hardie, D. Grahame

N1 - dc.publisher: Elsevier http://www.cell.com/cell-metabolism/

PY - 2005/7

Y1 - 2005/7

N2 - 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 CaMKKß is required for this effect. CaMKKß also activates AMPK much more rapidly than CaMKKa 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 Ca2+-dependent neuroprotective pathway involving phosphorylation and activation of AMPK by CaMKKß.

AB - 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 CaMKKß is required for this effect. CaMKKß also activates AMPK much more rapidly than CaMKKa 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 Ca2+-dependent neuroprotective pathway involving phosphorylation and activation of AMPK by CaMKKß.

U2 - 10.1016/j.cmet.2005.05.009

DO - 10.1016/j.cmet.2005.05.009

M3 - Article

SN - 1550-4131

VL - 2

SP - 9

EP - 19

JO - Cell Metabolism

JF - Cell Metabolism

IS - 1

ER -