Phospho-dependent functional modulation of GABAB receptors by the metabolic sensor AMP-dependent protein kinase
Phospho-dependent functional modulation of GABAB receptors by the metabolic sensor AMP-dependent protein kinase
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DOI：
10.1016/j.neuron.2006.12.015
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发表时间：
2007-01-18
期刊：
影响因子：
16.2
通讯作者：
Moss, Stephen J.
中科院分区：
文献类型：
--
作者：
Kuramoto, Nobuyuki;Wilkins, Megan E.;Moss, Stephen J.
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，通过激活内向整流钾通道(GIRKs)和抑制钙通道来介导脑内缓慢的突触抑制。我们在这里证明了GABAB受体与5‘AMP依赖的蛋白激酶(AMPK)密切相关。AMPK作为一种代谢感受器，可通过代谢活性增强、缺氧或缺血引起的5‘AMP浓度的增加而有效地激活。AMPK结合R1亚基，直接磷酸化R2亚基中的S783，增强GIRKs的GABAB受体活性。S783的磷酸化在许多脑区都很明显，并且在缺血损伤后显著增加。最后，我们还揭示了S783在提高缺血后神经元存活方面发挥着关键作用。总之，我们的结果提供了神经保护机制的证据，在代谢应激条件下或缺血后，增强GABAB受体功能以减少兴奋毒性，从而促进神经元存活。
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.