Structural basis for GABAA receptor potentiation by neurosteroids

Type-A γ-aminobutyric acid receptors (GABAARs) are the principal mediators of inhibitory neurotransmission in the human brain. Endogenous neurosteroids interact with GABAARs to regulate acute and chronic anxiety and are potent sedative, analgesic, anticonvulsant and anaesthetic agents. Their mode of binding, and mechanism of receptor potentiation remain, however, unknown. Here we report crystal structures of a chimeric GABAAR construct, in apo and pregnanolone-bound states. The neurosteroid-binding site is mechanically coupled to the helices lining the ion channel pore, and modulates the desensitization gate conformation. We demonstrate that the equivalent site is responsible for physiological, heteromeric, GABAAR potentiation and explain the contrasting modulatory properties of 3α versus 3β neurosteroid epimers. These results illustrate how peripheral lipid ligands can regulate the desensitization gate of GABAARs, a process of broad relevance to pentameric ligand-gated ion channels.