Selective Ligand Behaviors Provide New Insights into Agonist Activation of Nicotinic Acetylcholine Receptors

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• 作者：Christopher B. Marotta ; Iva Rreza ; Henry A. Lester ; Dennis A. Dougherty
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：May 16, 2014
• 年：2014
• 卷：9
• 期：5
• 页码：1153-1159
• 全文大小：385K
• 年卷期：v.9,no.5(May 16, 2014)
• ISSN：1554-8937

文摘

Nicotinic acetylcholine receptors are a diverse set of ion channels that are essential to everyday brain function. Contemporary research studies selective activation of individual subtypes of receptors, with the hope of increasing our understanding of behavioral responses and neurodegenerative diseases. Here, we aim to expand current binding models to help explain the specificity seen among three activators of 伪4尾2 receptors: sazetidine-A, cytisine, and NS9283. Through mutational analysis, we can interchange the activation profiles of the stoichiometry-selective compounds sazetidine-A and cytisine. In addition, mutations render NS9283鈥攃urrently identified as a positive allosteric modulator鈥攊nto an agonist. These results lead to two conclusions: (1) occupation at each primary face of an 伪 subunit is needed to activate the channel and (2) the complementary face of the adjacent subunit dictates the binding ability of the agonist.