Nat：差异性组装使 GABAA受体的结构和信号传导多样化 抑制

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Nature：差异性组装使 GABAA受体的结构和信号传导多样化

全身麻醉剂和苯二氮卓类药物。抑制。

领研网

2022/04/18

论文
论文标题：Differential assembly diversifies GABAA receptor structures and signalling
作者：Andrija Sente, Rooma Desai, Katerina Naydenova, Tomas Malinauskas, Youssef Jounaidi, Jonas Miehling, Xiaojuan Zhou, Simonas Masiulis, Steven W. Hardwick, Dimitri Y. Chirgadze, Keit

期刊：Nature
发表时间：2022/03/30
数字识别码：10.1038/s41586-022-04517-3
摘要：Type A γ-aminobutyric acid receptors (GABAARs) are pentameric ligand-gated chloride channels that mediate fast inhibitory signalling in neural circuits1,2 and can be modulated by essential medicines including general anaesthetics and benzodiazepines3. Human GABAAR subunits are encoded by 19 paralogous genes that can, in theory, give rise to 495,235 receptor types. However, the principles that govern the formation of pentamers, the permutational landscape of receptors that may emerge from a subunit set and the effect that this has on GABAergic signalling remain largely unknown. Here we use cryogenic electron microscopy to determine the structures of extrasynaptic GABAARs assembled from α4, β3 and δ subunits, and their counterparts incorporating γ2 instead of δ subunits. In each case, we identified two receptor subtypes with distinct stoichiometries and arrangements, all four differing from those previously observed for synaptic, α1-containing receptors4,5,6,7. This, in turn, affects receptor responses to physiological and synthetic modulators by creating or eliminating ligand-binding sites at subunit interfaces. We provide structural and functional evidence that selected GABAAR arrangements can act as coincidence detectors, simultaneously responding to two neurotransmitters: GABA and histamine. Using assembly simulations and single-cell RNA sequencing data8,9, we calculated the upper bounds for receptor diversity in recombinant systems and in vivo. We propose that differential assembly is a pervasive mechanism for regulating the physiology and pharmacology of GABAARs.

所属学科：
生物
（导读 阿金）GABAARs是五聚体配体门控的氯离子通道，介导神经回路中快速的抑制性信号传导，也可通过关键药物来调控。本研究解析出由α4, β3和δ亚基，及其结合γ2亚基而组装成的突触外GABAARs冷冻电镜结构，并识别出两类受体亚型，具有不同的化学计量和排列，从而通过创造或者消除亚基界面上的配体结合位点来影响受体对生理以及合成调控因子的应答。该结果揭示了调控GABAARs生理和药理学的机制。

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文章标签
氯离子通道
GABAAR
冷冻电镜结构

https://www.nature.com/articles/s41586-022-04517-3

https://www.linkresearcher.com/t ... c-b2a6-726016c4b434



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