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首页> 外文期刊>Neuron >Phospho-dependent functional modulation of GABA(B) receptors by the metabolic sensor AMP-dependent protein kinase.
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Phospho-dependent functional modulation of GABA(B) receptors by the metabolic sensor AMP-dependent protein kinase.

机译：代谢传感器AMP依赖性蛋白激酶对GABA（B）受体的磷依赖性功能调节。

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摘要

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.
机译：GABA（B）受体是由R1和R2亚基组成的异二聚体G蛋白偶联受体，通过激活向内整流K（+）通道（GIRKs）和抑制Ca（2+）通道来介导大脑中缓慢的突触抑制。我们在这里证明，GABA（B）受体与5'AMP依赖蛋白激酶（AMPK）密切相关。 AMPK充当代谢传感器，可通过增强的代谢活性，缺氧或局部缺血引起的5'AMP浓度增加有效激活。 AMPK结合R1亚基并直接磷酸化R2亚基中的S783，以增强GIRKs的GABA（B）受体激活。 S783的磷酸化在许多大脑区域都很明显，并且在缺血性损伤后急剧增加。最后，我们还揭示了S783在增强缺血后神经元存活中起关键作用。我们的研究结果共同提供了一种神经保护机制的证据，该机制在代谢应激条件下或缺血后可增加GABA（B）受体功能，从而降低兴奋性毒性，从而促进神经元存活。

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