Zhou_2025_Nature__

Type A GABA (gamma-aminobutyric acid) receptors (GABA(A) receptors) mediate most fast inhibitory signalling in the brain and are targets for drugs that treat epilepsy, anxiety, depression and insomnia and for anaesthetics(1,2). These receptors comprise a complex array of 19 related subunits, which form pentameric ligand-gated ion channels. The composition and structure of native GABA(A) receptors in the human brain have been inferred from subunit localization in tissue(1,3), functional measurements and structural analysis from recombinant expression(4-7) and in mice(8). However, the arrangements of subunits that co-assemble physiologically in native human GABA(A) receptors remain unknown. Here we isolated alpha1 subunit-containing GABA(A) 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(A) 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(A) receptors at inhibitory synapses. This work provides a structural foundation for understanding GABA(A) receptor signalling and targeted pharmacology in the human brain.