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Endogenous neurosteroids regulate GABA(A) receptors through two discrete transmembrane sites

机译：内源性神经固醇通过两个离散的跨膜位点调节GABA（A）受体

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摘要

Inhibitory neurotransmission mediated by GABA(A) receptors can be modulated by the endogenous neurosteroids, allopregnanolone and tetrahydro-deoxycorticosterone(1). Neurosteroids are synthesized de novo in the brain during stress(2), pregnancy(3) and after ethanol consumption(4), and disrupted steroid regulation of GABAergic transmission is strongly implicated in several debilitating conditions such as panic disorder, major depression, schizophrenia, alcohol dependence and catamenial epilepsy(3,5-8). Determining how neurosteroids interact with the GABA(A) receptor is a prerequisite for understanding their physiological and pathophysiological roles in the brain. Here we identify two discrete binding sites in the receptor's transmembrane domains that mediate the potentiating and direct activation effects of neurosteroids. They potentiate GABA responses from a cavity formed by the alpha-subunit transmembrane domains, whereas direct receptor activation is initiated by interfacial residues between alpha and beta subunits and is enhanced by steroid binding to the potentiation site. Thus, significant receptor activation by neurosteroids relies on occupancy of both the activation and potentiation sites. These sites are highly conserved throughout the GABA(A) receptor family, and their identification provides a unique opportunity for the development of new therapeutic, neurosteroid-based ligands and transgenic disease models of neurosteroid dysfunction.
机译：GABA（A）受体介导的抑制性神经传递可以通过内源性神经甾体，阿洛培那那龙和四氢-脱氧皮质酮（1）来调节。神经类固醇是在压力（2），妊娠（3）和乙醇摄入（4）后从头合成的，在一些使人衰弱的疾病中，如恐慌症，重度抑郁症，精神分裂症，酒精依赖和月经性癫痫（3,5-8）。确定神经甾体如何与GABA（A）受体相互作用是了解其在大脑中的生理和病理生理作用的前提。在这里，我们在受体的跨膜结构域中确定了两个离散的结合位点，它们介导了神经甾体的增强和直接激活作用。它们增强了由α-亚基跨膜结构域形成的腔中的GABA反应，而直接受体激活是由α和β亚基之间的界面残基引发的，并通过类固醇与增强位点的结合而增强。因此，神经甾体的显着受体活化依赖于活化位点和增强位点两者的占用。这些位点在整个GABA（A）受体家族中都是高度保守的，它们的鉴定为开发新的基于神经类固醇的治疗性配体和神经类固醇功能障碍的转基因疾病模型提供了独特的机会。

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