An inactive receptor-G protein complex maintains the dynamic range of agonist-induced signaling

Wonjo Jang, C. Elizabeth Adams, Heng Liu, Cheng Zhang, Finn Olav Levy, Kjetil Wessel Andressen, Nevin A. Lambert

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)30755-30762
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number48
DOIs
StatePublished - Dec 1 2020

Keywords

  • GPCR | G protein | ternary complex | precoupling | serotonin

ASJC Scopus subject areas

  • General

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