神经活性类固醇
γ-氨基丁酸受体
长时程增强
孕酮
化学
变构调节
药理学
离子通道
受体
神经传递
脱敏(药物)
配体门控离子通道
生物物理学
神经科学
生物化学
生物
作者
Paul S. Miller,Suzanne Scott,Simonas Masiulis,Luigi De Colibus,Els Pardon,Jan Steyaert,A. Radu Aricescu
摘要
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 anesthetic agents. Their mode of binding and mechanism of receptor potentiation, however, remain 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 3a versus 3b 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.
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