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

Simon A Hawley1, David A Pan, Kirsty J Mustard

  • 1Division of Molecular Physiology University of Dundee, Dundee, Scotland, United Kingdom.

Cell Metabolism
|August 2, 2005
PubMed

Insights

AMP-activated protein kinase (AMPK) activity is regulated by CaMKKbeta, especially in LKB1-deficient cells. This calcium-dependent pathway suggests a novel neuroprotective mechanism.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Neuroscience

Background:

  • AMP-activated protein kinase (AMPK) is a key regulator of cellular and organismal energy homeostasis.
  • LKB1 and CaMKK are known upstream activators of AMPK in cell-free systems, but physiological relevance is established only for LKB1.
  • Investigating alternative AMPK activation pathways is crucial for understanding energy balance and cellular protection.

Purpose of the Study:

  • To investigate the role of CaMKKbeta in AMPK activation in LKB1-deficient cells.
  • To explore the physiological relevance of CaMKKbeta-mediated AMPK activation in neuronal tissue.
  • To elucidate a potential calcium-dependent neuroprotective pathway involving AMPK.

Main Methods:

  • Utilized LKB1-deficient cells and Ca2+ ionophores to assess basal and stimulated AMPK activity.
  • Employed the CaMKK inhibitor STO-609 and isoform-specific siRNAs to determine CaMKKbeta's role.
  • Used K(+)-induced depolarization in rat cerebrocortical slices to mimic physiological conditions and measure AMPK activation.

Main Results:

  • Significant basal AMPK activity and phosphorylation were observed in LKB1-deficient cells.
  • Ca2+ ionophores stimulated AMPK activity, a process dependent on CaMKKbeta.
  • CaMKKbeta demonstrated rapid activation of AMPK in cell-free assays compared to CaMKKalpha.
  • Neuronal depolarization increased intracellular Ca2+ and activated AMPK, an effect blocked by STO-609.

Conclusions:

  • CaMKKbeta plays a significant role in AMPK activation, particularly in the absence of LKB1.
  • A calcium-dependent pathway involving CaMKKbeta activates AMPK in neuronal cells.
  • This pathway represents a potential Ca(2+)-dependent neuroprotective mechanism.

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