Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors
Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors
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DOI：
10.1073/pnas.1403285111
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发表时间：
2014-05-13
影响因子：
11.1
通讯作者：
Moss, Stephen J.
中科院分区：
文献类型：
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作者：
Abramian, Armen M.;Comenencia-Ortiz, Eydith;Moss, Stephen J.
神经类固醇在脑内合成，并作为内源性抗焦虑剂，抗惊厥剂，催眠剂和镇静剂，主要通过其增强由-介导的阶段性和紧张性抑制性神经传递的能力来介导的作用。氨基丁酸A型受体（GABA（A）Rs）。虽然神经甾体是公认的GABA（A）受体的变构调节剂，但在此我们揭示了它们通过选择性地增强介导紧张性抑制的GABA（A）受体的运输而对GABA能抑制产生持续的影响。我们证明，神经甾体增强α 4亚基内S443的蛋白激酶C依赖性磷酸化，α 4亚基是GABA（A）R亚型的一个组成部分，在许多脑区介导紧张性抑制。该过程增强了含有α 4亚单位的GABA（A）R亚型插入膜中，导致强直性抑制功效的选择性和持续性升高。因此，神经甾体调节含有α 4亚基的GABA（A）Rs的磷酸化和膜插入的能力可能是这些内源性信号分子对神经元兴奋性和行为的深远影响的基础。
Neurosteroids are synthesized within the brain and act as endogenous anxiolytic, anticonvulsant, hypnotic, and sedative agents, actions that are principally mediated via their ability to potentiate phasic and tonic inhibitory neurotransmission mediated by.-aminobutyric acid type A receptors (GABA(A)Rs). Although neurosteroids are accepted allosteric modulators of GABA(A)Rs, here we reveal they exert sustained effects on GABAergic inhibition by selectively enhancing the trafficking of GABA(A)Rs that mediate tonic inhibition. We demonstrate that neurosteroids potentiate the protein kinase C-dependent phosphorylation of S443 within alpha 4 subunits, a component of GABA(A)R subtypes that mediate tonic inhibition in many brain regions. This process enhances insertion of alpha 4 sub-unit-containing GABA(A)R subtypes into the membrane, resulting in a selective and sustained elevation in the efficacy of tonic inhibition. Therefore, the ability of neurosteroids to modulate the phosphorylation and membrane insertion of alpha 4 subunit-containing GABA(A)Rs may underlie the profound effects these endogenous signaling molecules have on neuronal excitability and behavior.