期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：48
页码：30755-30762
DOI：10.1073/pnas.2010801117
出版社：The National Academy of Sciences of the United States of America
摘要：Agonist binding promotes activation of G protein-coupled receptors (GPCRs) and association of active receptors with G protein heterotrimers. The resulting active-state ternary complex is the basis for conventional stimulus-response coupling. Although GPCRs can also associate with G proteins before agonist binding, the impact of such preassociated complexes on agonist-induced signaling is poorly understood. Here we show that preassociation of 5-HT 7 serotonin receptors with G s heterotrimers is necessary for agonist-induced signaling. 5-HT 7 receptors in their inactive state associate with G s , as these complexes are stabilized by inverse agonists and receptor mutations that favor the inactive state. Inactive-state 5-HT 7 –G s complexes dissociate in response to agonists, allowing the formation of conventional agonist–5-HT 7 –G s ternary complexes and subsequent G s activation. Inactive-state 5-HT 7 –G s complexes are required for the full dynamic range of agonist-induced signaling, as 5-HT 7 receptors spontaneously activate G s variants that cannot form inactive-state complexes. Therefore, agonist-induced signaling in this system involves two distinct receptor-G protein complexes, a conventional ternary complex that activates G proteins and an inverse-coupled binary complex that maintains the inactive state when agonist is not present.
关键词：GPCR ; G protein ; ternary complex ; precoupling ; serotonin
