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

Proc Natl Acad Sci U S A. 2020 Dec 1;117(48):30755-30762. doi: 10.1073/pnas.2010801117. Epub 2020 Nov 16.


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.

Keywords: G protein; GPCR; precoupling; serotonin; ternary complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / metabolism*
  • Kinetics
  • Ligands
  • Models, Biological
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism*
  • Protein Binding
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Serotonin / chemistry
  • Receptors, Serotonin / metabolism
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Signal Transduction* / drug effects


  • Ligands
  • Multiprotein Complexes
  • Receptors, G-Protein-Coupled
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • serotonin 7 receptor
  • GTP-Binding Proteins