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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-HT7 serotonin receptors with Gs heterotrimers is necessary for agonist-induced signaling. 5-HT7 receptors in their inactive state associate with Gs, as these complexes are stabilized by inverse agonists and receptor mutations that favor the inactive state. Inactive-state 5-HT7-Gs complexes dissociate in response to agonists, allowing the formation of conventional agonist-5-HT7-Gs ternary complexes and subsequent Gs activation. Inactive-state 5-HT7-Gs complexes are required for the full dynamic range of agonist-induced signaling, as 5-HT7 receptors spontaneously activate Gs 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. Copyright © 2020 the Author(s). Published by PNAS.

Citation

Wonjo Jang, C Elizabeth Adams, Heng Liu, Cheng Zhang, Finn Olav Levy, Kjetil Wessel Andressen, Nevin A Lambert. An inactive receptor-G protein complex maintains the dynamic range of agonist-induced signaling. Proceedings of the National Academy of Sciences of the United States of America. 2020 Dec 01;117(48):30755-30762

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PMID: 33199589

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