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GABA(B) receptors are heterodimeric G protein-coupled receptors composed of R1 and R2 subunits that mediate slow synaptic inhibition in the brain by activating inwardly rectifying K(+) channels (GIRKs) and inhibiting Ca(2+) channels. We demonstrate here that GABA(B) receptors are intimately associated with 5'AMP-dependent protein kinase (AMPK). AMPK acts as a metabolic sensor that is potently activated by increases in 5'AMP concentration that are caused by enhanced metabolic activity, anoxia, or ischemia. AMPK binds the R1 subunit and directly phosphorylates S783 in the R2 subunit to enhance GABA(B) receptor activation of GIRKs. Phosphorylation of S783 is evident in many brain regions, and is increased dramatically after ischemic injury. Finally, we also reveal that S783 plays a critical role in enhancing neuronal survival after ischemia. Together our results provide evidence of a neuroprotective mechanism, which, under conditions of metabolic stress or after ischemia, increases GABA(B) receptor function to reduce excitotoxicity and thereby promotes neuronal survival.

Original publication

DOI

10.1016/j.neuron.2006.12.015

Type

Journal

Neuron

Publication Date

01/2007

Volume

53

Pages

233 - 247

Addresses

Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA.

Keywords

Brain, Hippocampus, Neurons, Cells, Cultured, Animals, Humans, Rats, Brain Ischemia, Cyclic AMP-Dependent Protein Kinases, Potassium Channels, Inwardly Rectifying, Receptors, GABA-B, Protein Isoforms, Adenosine Monophosphate, Immune Sera, Cell Survival, Phosphorylation, Osmolar Concentration, Hypoxia