Nat：突触外αβ GABAA受体的抑制和激活 堵孔外阻氯离子传

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突触外αβ GABAA受体的抑制和激活机制  

堵住孔核的细胞外末端以阻断氯离子的传导  堵孔外阻氯离子传   兴抑控

领研网

2022/02/28

论文
论文标题：Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors
作者：Kasaragod, Vikram Babu, Mortensen, Martin, Hardwick, Steven W., Wahid, Ayla A., Dorovykh, Valentina, Chirgadze, Dimitri Y., Smart, Trevor G., Miller, Paul S.

期刊：Nature
发表时间：2022/02/09
数字识别码：10.1038/s41586-022-04402-z
摘要：Type A GABA (γ-aminobutyric acid) receptors represent a diverse population in the mammalian brain, forming pentamers from combinations of α-, β-, γ-, δ-, ε-, ρ-, θ- and π-subunits1. αβ, α4βδ, α6βδ and α5βγ receptors favour extrasynaptic localization, and mediate an essential persistent (tonic) inhibitory conductance in many regions of the mammalian brain1,2. Mutations of these receptors in humans are linked to epilepsy and insomnia3,4. Altered extrasynaptic receptor function is implicated in insomnia, stroke and Angelman and Fragile X syndromes1,5, and drugs targeting these receptors are used to treat postpartum depression6. Tonic GABAergic responses are moderated to avoid excessive suppression of neuronal communication, and can exhibit high sensitivity to Zn2+ blockade, in contrast to synapse-preferring α1βγ, α2βγ and α3βγ receptor responses5,7,8,9,10,11,12. Here, to resolve these distinctive features, we determined structures of the predominantly extrasynaptic αβ GABAA receptor class. An inhibited state bound by both the lethal paralysing agent α-cobratoxin13 and Zn2+ was used in comparisons with GABA–Zn2+ and GABA-bound structures. Zn2+ nullifies the GABA response by non-competitively plugging the extracellular end of the pore to block chloride conductance. In the absence of Zn2+, the GABA signalling response initially follows the canonical route until it reaches the pore. In contrast to synaptic GABAA receptors, expansion of the midway pore activation gate is limited and it remains closed, reflecting the intrinsic low efficacy that characterizes the extrasynaptic receptor. Overall, this study explains distinct traits adopted by αβ receptors that adapt them to a role in tonic signalling.

所属学科：
结构生物学
（导读 阿金）A型GABA（γ-氨基丁酸）受体代表哺乳动物大脑中的一个多样化群体，由α-、β-、γ-、δ-、ε-、ρ-、θ-和π-亚基组合形成五聚体。本研究解析突触外αβ GABAA受体类型的结构，研究人员使用麻醉剂α-cobratoxin和Zn2+结合的抑制状态，比较了GABA–Zn2+和GABA结合状态结构。Zn2+ 通过非竞争性堵住孔核的细胞外末端以阻断氯离子的传导，使GABA应答失效。该结果解释了αβ受体在强直信号传导的独特性状。

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文章标签
A型GABA（γ-氨基丁酸）受体
哺乳动物
五聚体
突触外αβ GABAA受体
强直信



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