Zinc-mediated inhibition of GABAA receptors:: discrete binding sites underlie subtype specificity
Zinc-mediated inhibition of GABAA receptors:: discrete binding sites underlie subtype specificity
复制标题
DOI：
10.1038/nn1030
复制
发表时间：
2003-04-01
影响因子：
25
通讯作者：
Smart, TG
中科院分区：
文献类型：
--
作者：
Hosie, AM;Dunne, EL;Smart, TG
锌离子集中在中枢神经系统并调节GABA（A）受体，GABA（A）受体是抑制性突触神经传递的关键介质。锌离子通过变构机制抑制GABA（A）受体功能，该变构机制严重依赖于受体亚基组成：α亚基组合显示出最高的敏感性，而α γ亚型最不敏感。在这里，我们提出了一个机制和结构的基础上，这种抑制和其依赖于受体亚基组成。我们使用分子建模，以确定三个离散的网站，介导Zn2+抑制。一个位于离子通道内，另外两个位于α和β亚基之间界面处的受体的外部氨基（N）末端表面上。我们发现，含有γ 2亚基的GABA（A）受体的特征性低Zn 2+敏感性是由于受体亚基共组装后三个位点中的两个被破坏所致。
Zinc ions are concentrated in the central nervous system and regulate GABA(A) receptors, which are pivotal mediators of inhibitory synaptic neurotransmission. Zinc ions inhibit GABA(A) receptor function by an allosteric mechanism that is critically dependent on the receptor subunit composition: alphabeta subunit combinations show the highest sensitivity, and alphabetagamma isoforms are the least sensitive. Here we propose a mechanistic and structural basis for this inhibition and its dependence on the receptor subunit composition. We used molecular modeling to identify three discrete sites that mediate Zn2+ inhibition. One is located within the ion channel, and the other two are on the external amino (N)-terminal face of the receptor at the interfaces between alpha and beta subunits. We found that the characteristically low Zn2+ sensitivity of GABA(A) receptors containing the gamma2 subunit results from disruption to two of the three sites after receptor subunit co-assembly.