Influence of GABAA Receptor α Subunit Isoforms on the Benzodiazepine Binding Site
Influence of GABAA Receptor α Subunit Isoforms on the Benzodiazepine Binding Site
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DOI：
10.1371/journal.pone.0042101
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发表时间：
2012-07-27
期刊：
影响因子：
3.7
通讯作者：
Sigel, Erwin
中科院分区：
文献类型：
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作者：
Luescher, Benjamin P.;Baur, Roland;Sigel, Erwin
经典的苯二氮卓类药物，如地西泮，与α（x）β（2）γ（2）GABA（A）受体相互作用，x = 1，2，3，5，并调节其功能。不同受体亚型的调节可能导致选择性行为效应，如镇静和抗焦虑。了解不同受体亚型中结合口袋结构的差异对于产生亚型特异性配体是有意义的。我们在此研究了共价反应的地西泮类似物3-NCS与α（1）S204 C β（2）γ（2）、α（1）S205 C β（2）γ（2）和α（1）T206 C β（2）γ（2）以及与含有α（2）β（2）γ（2）、α（3）β（2）γ（2）α（5）β（1/2）γ（2）和α（6）β（2）γ（2）。使用放射性配体结合和在功能水平上使用电生理技术的相互作用进行了研究。这两种策略产生了重叠的结果。我们的数据允许关于α（1）S204 C β（2）γ（2）、α（1）S205 C β（2）γ（2）和α（1）T206 C β（2）γ（2）的相对并置以及α（2）、α（3）、α（5）和α（6）中与地西泮酮基相邻的C原子的同源位置的结论。与地西泮中携带Cl的C原子的类似数据一起，它们表明苯二氮卓类的结合位点的结构在每种GABAA受体亚型α（1）β（2）γ（2）、α（2）β（2）γ（2）、α（3）β（2）γ（2）、α（5）β（1/2）γ（2）和α（6）β（2）γ（2）中不同。
Classical benzodiazepines, such as diazepam, interact with alpha(x)beta(2)gamma(2) GABA(A) receptors, x = 1, 2, 3, 5 and modulate their function. Modulation of different receptor isoforms probably results in selective behavioural effects as sedation and anxiolysis. Knowledge of differences in the structure of the binding pocket in different receptor isoforms is of interest for the generation of isoform-specific ligands. We studied here the interaction of the covalently reacting diazepam analogue 3-NCS with alpha(1)S204C beta(2)gamma(2), alpha(1)S205C beta(2)gamma(2) and alpha(1)T206C beta(2)gamma(2) and with receptors containing the homologous mutations in alpha(2)beta(2)gamma(2), alpha(3)beta(2)gamma(2), alpha(5)beta(1/2)gamma(2) and alpha(6)beta(2)gamma(2). The interaction was studied using radioactive ligand binding and at the functional level using electrophysiological techniques. Both strategies gave overlapping results. Our data allow conclusions about the relative apposition of alpha(1)S204C beta(2)gamma(2), alpha(1)S205C beta(2)gamma(2) and alpha(1)T206C beta(2)gamma(2) and homologous positions in alpha(2), alpha(3), alpha(5) and alpha(6) with C-atom adjacent to the keto-group in diazepam. Together with similar data on the C-atom carrying Cl in diazepam, they indicate that the architecture of the binding site for benzodiazepines differs in each GABAA receptor isoform alpha(1)beta(2)gamma(2), alpha(2)beta(2)gamma(2), alpha(3)beta(2)gamma(2), alpha(5)beta(1/2)gamma(2) and alpha(6)beta(2)gamma(2).