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Phospho-dependent functional modulation of GABA(B) receptors by the metabolic sensor AMP-dependent protein kinase

Kuramoto, N; Wilkins, ME; Fairfax, BP; Revilla-Sanchez, R; Terunuma, M; Tamaki, K; Iemata, M; ... Moss, SJ; + view all (2007) Phospho-dependent functional modulation of GABA(B) receptors by the metabolic sensor AMP-dependent protein kinase. NEURON , 53 (2) 233 - 247. 10.1016/j.neuron.2006.12.015.

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Abstract

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 Ca2+, channels. We demonstrate here that GABAB 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 GABAB 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 GABAB receptor function to reduce excitotoxicity and thereby promotes neuronal survival.

Type: Article
Title: Phospho-dependent functional modulation of GABA(B) receptors by the metabolic sensor AMP-dependent protein kinase
DOI: 10.1016/j.neuron.2006.12.015
Keywords: CEREBRAL-ARTERY OCCLUSION, INTRALUMINAL SUTURE, UPSTREAM KINASE, PHOSPHORYLATION, TRAFFICKING, ISCHEMIA, CASCADE, RAT, EXCITOTOXICITY, ASSOCIATION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/130180
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