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Structural basis for GABAA receptor potentiation by neurosteroids
Nature Structural & Molecular Biology ( IF 16.8 ) Pub Date : , DOI: 10.1038/nsmb.3484 Paul S Miller 1 , Suzanne Scott 1, 2 , Simonas Masiulis 1, 2 , Luigi De Colibus 1 , Els Pardon 3, 4 , Jan Steyaert 3, 4 , A Radu Aricescu 1, 2
Nature Structural & Molecular Biology ( IF 16.8 ) Pub Date : , DOI: 10.1038/nsmb.3484 Paul S Miller 1 , Suzanne Scott 1, 2 , Simonas Masiulis 1, 2 , Luigi De Colibus 1 , Els Pardon 3, 4 , Jan Steyaert 3, 4 , A Radu Aricescu 1, 2
Affiliation
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.
中文翻译:
神经类固醇增强 GABAA 受体的结构基础
A型γ-氨基丁酸受体(GABA A Rs)是人脑中抑制性神经传递的主要介质。内源性神经类固醇与 GABA A R 相互作用以调节急性和慢性焦虑,并且是有效的镇静剂、镇痛剂、抗惊厥剂和麻醉剂。然而,它们的结合方式和受体增强机制仍然未知。在这里,我们报告了嵌合 GABA A R 构建体在 apo 和孕烯醇酮结合状态下的晶体结构。神经类固醇结合位点与离子通道孔内的螺旋机械耦合并调节脱敏门构象。我们证明等效位点负责生理异聚 GABA AR 增强并解释 3a 与 3b 神经类固醇差向异构体的对比调节特性。这些结果说明了外周脂质配体如何调节 GABA A Rs 的脱敏门,这是一个与五聚配体门控离子通道广泛相关的过程。
更新日期:2017-10-11
中文翻译:
神经类固醇增强 GABAA 受体的结构基础
A型γ-氨基丁酸受体(GABA A Rs)是人脑中抑制性神经传递的主要介质。内源性神经类固醇与 GABA A R 相互作用以调节急性和慢性焦虑,并且是有效的镇静剂、镇痛剂、抗惊厥剂和麻醉剂。然而,它们的结合方式和受体增强机制仍然未知。在这里,我们报告了嵌合 GABA A R 构建体在 apo 和孕烯醇酮结合状态下的晶体结构。神经类固醇结合位点与离子通道孔内的螺旋机械耦合并调节脱敏门构象。我们证明等效位点负责生理异聚 GABA AR 增强并解释 3a 与 3b 神经类固醇差向异构体的对比调节特性。这些结果说明了外周脂质配体如何调节 GABA A Rs 的脱敏门,这是一个与五聚配体门控离子通道广泛相关的过程。