Editors' ChoiceNeuroscience

A Protective Partnership

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Science's STKE  23 Jan 2007:
Vol. 2007, Issue 370, pp. tw31
DOI: 10.1126/stke.3702007tw31

Kuramoto et al. identified the catalytic α1 subunit of adenosine monophosphate (AMP)-activated protein kinase (AMPK, which, in neurons, is activated in response to hypoxia, ischemia, or enhanced metabolic activity) in a yeast two-hybrid screen of rat brain cDNA for proteins that bind the γ-aminobutyric acid type B (GABAB) receptor, which is a G protein-coupled receptor. In vitro binding, coimmunoprecipitation, and immunofluorescence analysis of the subcellular distribution in cultured hippocampal neurons of AMPK and GABAB receptors confirmed an interaction between GABAB receptors and the AMPK α1 and 2 isoforms. GABAB receptors exist as R1 and R2 heterodimers; AMPK bound the cytoplasmic tail of the R1 subunit and phosphorylated Ser917 of R1 and Ser783 of R2. Using HEK-293 cells that heterologously expressed Kir3.1 and 3.2 K+ channels and GABAB receptors as a system in which to assess rundown of GABAB receptor-dependent activation of K+ current, the authors found that AMP decreased rundown elicited by intracellular perfusion with adenosine triphosphate (ATP) and guanosine triphosphate (GTP). Furthermore, the protective effect of AMP or of pharmacological activation of AMPK on GABA-activated K+ current depended on phosphorylation of R2 Ser783. Moreover, pharmacological activation of AMPK stimulated Ser783 phosphorylation and reduced GABAB receptor-activated K+ current rundown in cultured hippocampal neurons. Ischemic brain injury (following transient occlusion of the middle cerebral artery) led to an increase in Ser783 phosphorylation in rat hippocampus. Pharmacological inhibition of glycolysis and oxidative phosphorylation activated AMPK and stimulated Ser783 phosphorylation in cultured hippocampal neurons; intriguingly, neurons overexpressing Ser783Ala R2 mutants survived this treatment less well than those overexpressing wild-type R2. Thus, the authors conclude that AMPK activation has a neuroprotective effect that depends on phosphorylation of the GABAB receptor. Hardie and Frenguelli discuss this research in a thoughtful Preview.

N. Kuramoto, M. E. Wilkins, B. P. Fairfax, R. Revilla-Sanchez, M. Terunuma, K. Tamaki, M. Iemata, N. Warren, A. Couve, A. Calver, Z. Horvath, K. Freeman, D. Carling, L. Huang, C. Gonzales, E. Cooper, T. G. Smart, M. N. Pangalos, S. J. Moss, Phospho-dependent functional modulation of GABAB receptors by the metabolic sensor AMP-dependent protein kinase. Neuron 53, 233-247 (2007). [PubMed]

D. G. Hardie, B. G. Frenguelli, A neural protection racket: AMPK and the GABAB receptor. Neuron 53, 159-162 (2007). [PubMed]

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