期刊
NEURON
卷 53, 期 2, 页码 233-247出版社
CELL PRESS
DOI: 10.1016/j.neuron.2006.12.015
关键词
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资金
- Medical Research Council [MC_U120027537, G0601529] Funding Source: Medline
- NINDS NIH HHS [R01 NS047478-02, R01 NS051195, R01 NS047478, NS 048045, R01 NS051195-01A1, R21NS42100, R21 NS080064, NS 046478, R01 NS048045, NS051195, R01 NS048045-02, R01 NS048045-01A2, R01 NS081986, R01 NS047478-01A2, R01 NS046478] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
- Medical Research Council [MC_U120027537, G0601529] Funding Source: researchfish
- MRC [MC_U120027537, G0601529] Funding Source: UKRI
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.
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