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差异组装使GABAA受体结构和信号传导多样化
2022-04-04 12:20
来源：小柯机器人

英国剑桥大学A. Radu Aricescu等研究人员合作发现，差异组装使A型γ-氨基丁酸受体（GABAAR）受体结构和信号转导多样化。2022年3月30日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员使用冷冻电镜来确定了由α4、β3和δ亚单位组装的突触外GABAAR结构，以及它们纳入γ2而不是δ亚单位的对应物。在每一种情况下，研究人员都确定了两种具有不同化学计量和排列方式的受体亚型，所有四种都与以前观察到的突触、含α1的受体不同。这反过来又影响了受体对生理和合成调节剂的反应，因为它在亚单位界面上创造或消除了配体结合位点。研究人员提供的结构和功能证据表明，选定的GABAAR排列可以作为共存检测器，同时对两种神经递质作出反应：GABA和组胺。利用组装模拟和单细胞RNA测序数据，研究人员计算了重组系统和体内受体多样性的上限。研究人员提出，不同的组装是调节GABAAR生理和药理学的普遍机制。
 
据介绍，GABAAR是五聚体配体门控氯离子通道，在神经回路中介导快速抑制性信号，并可被基本药物（包括全身麻醉剂和苯二氮卓类药物）所调节。人类GABAAR亚基由19个同源基因编码，理论上可以产生495,235种受体类型。然而，管理五聚体形成的原则、可能从一个亚单位集合中出现的受体的排列组合以及这对GABA能信号的影响在很大程度上仍然是未知的。
 
附：英文原文
 
Title: Differential assembly diversifies GABAA receptor structures and signalling

Author: Sente, Andrija, Desai, Rooma, Naydenova, Katerina, Malinauskas, Tomas, Jounaidi, Youssef, Miehling, Jonas, Zhou, Xiaojuan, Masiulis, Simonas, Hardwick, Steven W., Chirgadze, Dimitri Y., Miller, Keith W., Aricescu, A. Radu

Issue&Volume: 2022-03-30

Abstract: 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.

DOI: 10.1038/s41586-022-04517-3

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

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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