Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors
Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors
复制标题
DOI：
10.1016/j.bcp.2009.06.020
复制
发表时间：
2009-10-01
影响因子：
5.8
通讯作者：
Blundell, Charles D.
中科院分区：
文献类型：
--
作者：
Sattelle, David B.;Buckingham, Steven D.;Blundell, Charles D.
人α - 7烟碱乙酰胆碱受体（nAChR）亚基及其秀丽隐杆线虫同源物ACR-16在非洲爪蟾卵母细胞中表达后，可产生功能性重组同源受体。这两种nAChRs在共注射的伴侣蛋白ric3存在下都能稳定表达，并且在I型阳性变构调节剂伊维菌素（IVM）的作用上表现出显著差异。I型PAMs的特点是仅对乙酰胆碱（ACh）的反应幅度增加，而11型PAMs还表现出对乙酰胆碱反应的时间过程/脱敏性变化。I型PAM，伊维菌素，5-羟基吲哚（5-HI）， NS-1738和染料木素，以及11型PAM， pnu120596，都对人α - 7有活性，但对ACR-16没有PAM活性，它们减弱了ACh反应的幅度。我们使用已发表的阿维菌素B1a结构来生成IVM模型，然后将其停靠在α 7和ACR-16的候选跨膜变构结合位点上，试图深入了解观察到的IVM作用差异。新的药理学发现和正在开发的计算方法可能为设计针对主要神经系统疾病的新型PAM药物提供信息。(C) 2009爱思唯尔公司版权所有。
The human alpha 7 nicotinic acetylcholine receptor (nAChR) subunit and its Caenorhabditis elegans homolog, ACR-16, can generate functional recombinant homomeric receptors when expressed in Xenopus laevis oocytes. Both nAChRs express robustly in the presence of the co-injected chaperone, RIC-3, and show striking differences in the actions of a type I positive allosteric modulator (PAM), ivermectin (IVM). Type I PAMs are characterised by an increase in amplitude only of the response to acetylcholine (ACh), whereas type 11 PAMs exhibit, in addition, changes in time-course/desensitization of the ACh response. The type I PAMs, ivermectin, 5-hydroxyindole (5-HI), NS-1738 and genistein and the type 11 PAM, PNU-120596, are all active on human alpha 7 but are without PAM activity on ACR-16, where they attenuate the amplitude of the ACh response. We used the published structure of avermectin B1a to generate a model of IVM, which was then docked into the candidate transmembrane allosteric binding site on alpha 7 and ACR-16 in an attempt to gain insights into the observed differences in IVM actions. The new pharmacological findings and computational approaches being developed may inform the design of novel PAM drugs targeting major neurological disorders. (C) 2009 Elsevier Inc. All rights reserved.