Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111; and.
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111; andDepartment of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6B, United Kingdom.
Proc Natl Acad Sci U S A. 2014 May 13;111(19):7132-7. doi: 10.1073/pnas.1403285111. Epub 2014 Apr 28.
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 γ-aminobutyric acid type A receptors (GABAARs). Although neurosteroids are accepted allosteric modulators of GABAARs, here we reveal they exert sustained effects on GABAergic inhibition by selectively enhancing the trafficking of GABAARs that mediate tonic inhibition. We demonstrate that neurosteroids potentiate the protein kinase C-dependent phosphorylation of S443 within α4 subunits, a component of GABAAR subtypes that mediate tonic inhibition in many brain regions. This process enhances insertion of α4 subunit-containing GABAAR 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 α4 subunit-containing GABAARs may underlie the profound effects these endogenous signaling molecules have on neuronal excitability and behavior.
神经甾体在大脑内合成，作为内源性的抗焦虑、抗惊厥、催眠和镇静剂，其主要通过增强γ-氨基丁酸 A 型受体 (GABAAR) 介导的相位和紧张性抑制性神经传递来发挥作用。尽管神经甾体被认为是 GABAAR 的变构调节剂，但我们在这里揭示它们通过选择性增强介导紧张性抑制的 GABAAR 的贩运来对 GABA 能抑制产生持续影响。我们证明神经甾体增强 S443 残基在 α4 亚基内的蛋白激酶 C 依赖性磷酸化，这是介导许多脑区紧张性抑制的 GABAAR 亚型的一个组成部分。这个过程增强了含有 α4 亚基的 GABAAR 亚型插入到膜中的能力，导致紧张性抑制的效力选择性和持续升高。因此，神经甾体调节含有 α4 亚基的 GABAAR 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产生深远影响的基础。
