Neuronal Inhibition in Epilepsy: Native Human GABA-A Receptors and Pharmacological Chaperones Restoring Expression of Disease Associated Variants
Year: 2026
Type: editorial
Abstract: Resolving Native GABA A Receptor Structures From the Human Brain Zhou J, Noviello CM, Teng J, Moore H, Lega B, Hibbs RE. Nature . 2025;638(8050):562–568. DOI: 10.1038/s41586-024-08454-1 Type A GABA (γ-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 α1 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. Pharmacological Chaperones Restore Proteostasis of Epilepsy-Associated GABA A Receptor Variants Wang YJ, Seibert H, Ahn LY, Schaffer AE, Mu TW. Pharmacol Res. 2024 208, 107356 DOI: 10.1016/j.phrs.2024.107356 Recent advances in genetic diagnosis identified variants in genes encoding GABA A receptors as causative for genetic epilepsy. Here, we selected eight disease-associated variants in the α1 subunit of GABA A receptors causing mild to severe clinical phenotypes and showed that they are loss of function, mainly by reducing the folding and surface trafficking of the α1 protein. Furthermore, we sought client protein-specific pharmacological chaperones to restore the function of pathogenic receptors. Applications of positive allosteric modulators, including Hispidulin and TP003, increase the functional surface expression of the α1 variants. Mechanism of action study demonstrated that they enhance the folding, assembly, and trafficking and reduce the degradation of GABA A variants without activating the unfolded protein response in HEK293T cells and human iPSC-derived neurons. Since these compounds cross the blood-brain barrier, such a pharmacological chaperoning strategy holds great promise to treat genetic epilepsy in a GABA A receptor-specific manner.
Authors: Nela Durisic, Karin Borges
Institution: The University of Queensland
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7118235659