Zhou Jia, Noviello Colleen M, Teng Jinfeng, Moore Haley, Lega Bradley, Hibbs Ryan E
Department of Neurobiology, University of California San Diego, La Jolla, CA, USA.
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX, USA.
Nature. 2025 Feb;638(8050):562-568. doi: 10.1038/s41586-024-08454-1. Epub 2025 Jan 22.
Type A GABA (γ-aminobutyric acid) receptors (GABA receptors) mediate most fast inhibitory signalling in the brain and are targets for drugs that treat epilepsy, anxiety, depression and insomnia and for anaesthetics. These receptors comprise a complex array of 19 related subunits, which form pentameric ligand-gated ion channels. The composition and structure of native GABA receptors in the human brain have been inferred from subunit localization in tissue, functional measurements and structural analysis from recombinant expression and in mice. However, the arrangements of subunits that co-assemble physiologically in native human GABA receptors remain unknown. Here we isolated α1 subunit-containing GABA 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 GABA 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 GABA receptors at inhibitory synapses. This work provides a structural foundation for understanding GABA receptor signalling and targeted pharmacology in the human brain.
A型γ-氨基丁酸（GABA）受体（GABA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、抑郁和失眠的药物以及麻醉剂的作用靶点。这些受体由19个相关亚基组成的复杂阵列构成，形成五聚体配体门控离子通道。人脑中天然GABA受体的组成和结构已通过组织中亚基定位、功能测量以及重组表达和小鼠中的结构分析推断得出。然而，在天然人GABA受体中生理共组装的亚基排列仍然未知。在这里，我们从癫痫患者中分离出含α1亚基的GABA受体。使用冷冻电子显微镜，我们确定了一组12种天然亚基组装及其三维结构。我们解决了先前天然和重组方法之间的不一致之处，并揭示了先前未定义的亚基界面的细节。这些界面子集中的类药物密度使我们发现了抗癫痫药物对GABA受体的意外活性，并导致其中一种药物定位到苯二氮䓬结合位点。蛋白质组学和进一步的结构分析表明与辅助亚基神经连接蛋白2和GARLH4相互作用，它们在抑制性突触处定位并调节GABA受体。这项工作为理解人脑中GABA受体信号传导和靶向药理学提供了结构基础。
