The desensitization pathway of GABA(A) receptors, one subunit at a time.
The desensitization pathway of GABA(A) receptors, one subunit at a time.
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GABA（A）受体的脱敏途径，一次一个亚基。
DOI：
10.1038/s41467-020-19218-6
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发表时间：
2020-10-23
影响因子：
16.6
通讯作者：
Corringer PJ
中科院分区：
文献类型：
--
作者：
Gielen M;Barilone N;Corringer PJ
GABAA 受体介导脊椎动物大脑中大多数抑制性突触传递。 GABA 结合和快速激活后，这些受体会经历较慢的脱敏，其构象途径在很大程度上仍然难以捉摸。为了探索脱敏机制，我们使用串联 α1β2γ2 GABAA 受体一次选择性地引入一个亚基的脱敏增益突变。生成了二十六个突变体组合的文库，并测量了它们的双指数宏观脱敏率。在不同亚基处引入突变显示出强烈的不对称模式，其中 γ2 亚基的关键贡献是，并且组合突变会产生显着的协同效应，表明存在非协同机制。动力学模型确实表明了亚基独立移动的途径，需要两个亚基脱敏来闭塞毛孔。因此，我们的工作暗示了脱敏过程中非常多样化和不稳定的构象景观，对生理学和药理学具有潜在的影响。 GABAA 受体介导大脑中大部分抑制性突触传递。在这里，作者使用串联 α1β2γ2 GABAA 受体一次引入一个亚基的脱敏增益突变，揭示了脱敏过程中 γ2 亚基的关键贡献非协同重排。
GABAA receptors mediate most inhibitory synaptic transmission in the brain of vertebrates. Following GABA binding and fast activation, these receptors undergo a slower desensitization, the conformational pathway of which remains largely elusive. To explore the mechanism of desensitization, we used concatemeric α1β2γ2 GABAA receptors to selectively introduce gain-of-desensitization mutations one subunit at a time. A library of twenty-six mutant combinations was generated and their bi-exponential macroscopic desensitization rates measured. Introducing mutations at the different subunits shows a strongly asymmetric pattern with a key contribution of the γ2 subunit, and combining mutations results in marked synergistic effects indicating a non-concerted mechanism. Kinetic modelling indeed suggests a pathway where subunits move independently, the desensitization of two subunits being required to occlude the pore. Our work thus hints towards a very diverse and labile conformational landscape during desensitization, with potential implications in physiology and pharmacology. GABAA receptors mediate most inhibitory synaptic transmission in the brain. Here authors used concatemeric α1β2γ2 GABAA receptors to introduce gain-of-desensitization mutations one subunit at a time, revealing non-concerted rearrangements with a key contribution of the γ2 subunit during desensitization.
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影响因子：
16.6
作者：
Gielen, Marc;Thomas, Philip;Smart, Trevor G.
通讯作者：
Smart, Trevor G.
人类 GABAA 受体的晶体结构。
影响因子：
64.8
作者：
Miller PS;Aricescu AR
通讯作者：
Aricescu AR
影响因子：
16.8
作者：
Miller PS;Scott S;Masiulis S;De Colibus L;Pardon E;Steyaert J;Aricescu AR
通讯作者：
Aricescu AR
影响因子：
3.7
作者：
Jaiteh, Mariama;Taly, Antoine;Henin, Jerome
通讯作者：
Henin, Jerome
影响因子：
16.2
作者：
KRISHEK, BJ;XIE, XM;SMART, TG
通讯作者：
SMART, TG