美国加州大学圣迭戈分校Ryan E. Hibbs研究小组解析来自人脑的原生GABAA受体结构。2025年1月22日，《自然》杂志在线发表了这一最新研究成果。

研究人员从癫痫患者中分离了含α1亚单位的A型GABA（γ-氨基丁酸）受体（GABA_A受体）受体，并利用冷冻电镜技术定义了一组12种原生亚单位组合及其三维结构。研究人员解决了之前原生和重组方法之间的不一致，并揭示了以前未定义的亚单位界面的细节。在这些界面的子集中的类药物密度促使研究人员发现了抗癫痫药物在GABA_A受体上的意外活性，并将其中一种药物定位到苯二氮卓类药物结合位点。蛋白质组学和进一步的结构分析表明，这些受体与辅助亚单位神经连蛋白2（neuroligin 2）和GARLH4相互作用，这些亚单位定位并调节GABA_A受体在抑制性突触中的功能。这项工作为理解GABA_A受体信号传导及其在人体大脑中的靶向药理提供了结构基础。

据悉，GABA_A受体介导大脑中大多数快速抑制性信号传导，是治疗癫痫、焦虑、抑郁、失眠以及麻醉药物的靶点。这些受体由19种相关亚单位组成，形成五聚体配体门控离子通道。人脑中原生GABA_A受体的组成和结构是通过亚单位在组织中的定位、功能测量、重组表达的结构分析以及小鼠模型推断出来的。然而，原生人类GABA_A受体中亚单位的生理性共同组装方式仍然未知。

附：英文原文

Title: Resolving native GABAA receptor structures from the human brain

Author: Zhou, Jia, Noviello, Colleen M., Teng, Jinfeng, Moore, Haley, Lega, Bradley, Hibbs, Ryan E.

Issue&Volume: 2025-01-22

Abstract: Type A GABA (γ-aminobutyric acid) receptors (GABAA receptors) mediate most fast inhibitory signalling in the brain and are targets for drugs that treat epilepsy, anxiety, depression and insomnia and for anaesthetics1,2. These receptors comprise a complex array of 19 related subunits, which form pentameric ligand-gated ion channels. The composition and structure of native GABAA receptors in the human brain have been inferred from subunit localization in tissue1,3, functional measurements and structural analysis from recombinant expression4,5,6,7 and in mice8. However, the arrangements of subunits that co-assemble physiologically in native human GABAA receptors remain unknown. Here we isolated α1 subunit-containing GABAA receptors from human patients with epilepsy. Using cryo-electron microscopy, we defined a set of 12 native subunit assemblies and their 3D structures. We address inconsistencies between previous native and recombinant approaches, and reveal details of previously undefined subunit interfaces. Drug-like densities in a subset of these interfaces led us to uncover unexpected activity on the GABAA receptor of antiepileptic drugs and resulted in localization of one of these drugs to the benzodiazepine-binding site. Proteomics and further structural analysis suggest interactions with the auxiliary subunits neuroligin 2 and GARLH4, which localize and modulate GABAA receptors at inhibitory synapses. This work provides a structural foundation for understanding GABAA receptor signalling and targeted pharmacology in the human brain.

DOI: 10.1038/s41586-024-08454-1

Source: https://www.nature.com/articles/s41586-024-08454-1