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


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.

SUBMITTER: Jang W 

PROVIDER: S-EPMC7720138 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Jang Wonjo W   Adams C Elizabeth CE   Liu Heng H   Zhang Cheng C   Levy Finn Olav FO   Andressen Kjetil Wessel KW   Lambert Nevin A NA  

Proceedings of the National Academy of Sciences of the United States of America 20201116 48


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<sub>7</sub> serotonin receptors with G<sub>s</sub  ...[more]

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