Innovative Approach Reveals How Receptors Control G Protein State Equilibria

Abstract

G protein-coupled receptors (GPCRs) constitute the largest family of drug targets, acting through heterotrimeric G proteins. Agonist bound GPCRs promote GDP release from G proteins allowing their activation upon GTP binding. Here, we analyze this process with innovative tools that detect the main states of native Gi proteins: the GDP-bound, the open nucleotide-free and the active GTP-bound states. We show that receptor activation increases the amount of open-state Gi proteins, consistent with GDP release from inactive Gi proteins. We also observe that the active receptor can release GTP from the active Gi protein, to return to an inactive open state. Consistently, receptor activation also promotes the formation of the Gαβγ complex from the GTP-bound state in cells, in agreement with the formation of the receptor-G protein ternary complex. These data suggest that the amount of active GTP-bound form produced upon GPCR activation can be controlled by the receptor-induced GTP release. This control of G protein state equilibrium that depends on the receptor subtype may affect coupling efficacy. These data reveal receptor-dependent G-protein state equilibria and identify GTP release as an additional, context-dependent control point that can shape apparent coupling efficacy.

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BibTeX RIS

BibTeX

@article{bouyssou2026innovative,
  title = {{Innovative Approach Reveals How Receptors Control G Protein State Equilibria}},
  author = {Alexandre Bouyssou and Mélanie da Silva and Julien Soulé and Ludovic Fabre and Laurent Lamarque and Rémy Sounier and Thierry Durroux and Sébastien Granier and Thomas Roux and Elodie Dupuis and Eric Trinquet and Philippe Rondard and Jean‐philippe Pin},
  journal = {Advanced Science},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.77969},
  url = {https://hal.science/hal-05830409v1},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Innovative Approach Reveals How Receptors Control G Protein State Equilibria
AU  - Alexandre Bouyssou
AU  - Mélanie da Silva
AU  - Julien Soulé
AU  - Ludovic Fabre
AU  - Laurent Lamarque
AU  - Rémy Sounier
AU  - Thierry Durroux
AU  - Sébastien Granier
AU  - Thomas Roux
AU  - Elodie Dupuis
AU  - Eric Trinquet
AU  - Philippe Rondard
AU  - Jean‐philippe Pin
PY  - 2026
DA  - 2026/10/15
JO  - Advanced Science
DO  - 10.1002/advs.77969
UR  - https://hal.science/hal-05830409v1
AB  - G protein-coupled receptors (GPCRs) constitute the largest family of drug targets, acting through heterotrimeric G proteins. Agonist bound GPCRs promote GDP release from G proteins allowing their activation upon GTP binding. Here, we analyze this process with innovative tools that detect the main states of native Gi proteins: the GDP-bound, the open nucleotide-free and the active GTP-bound states. We show that receptor activation increases the amount of open-state Gi proteins, consistent with GDP release from inactive Gi proteins. We also observe that the active receptor can release GTP from the active Gi protein, to return to an inactive open state. Consistently, receptor activation also promotes the formation of the Gαβγ complex from the GTP-bound state in cells, in agreement with the formation of the receptor-G protein ternary complex. These data suggest that the amount of active GTP-bound form produced upon GPCR activation can be controlled by the receptor-induced GTP release. This control of G protein state equilibrium that depends on the receptor subtype may affect coupling efficacy. These data reveal receptor-dependent G-protein state equilibria and identify GTP release as an additional, context-dependent control point that can shape apparent coupling efficacy.
SN  - 2198-3844
ER  -

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