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Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):4501-4506. doi: 10.1073/pnas.1712725115. Epub 2018 Apr 9.

GHSR-D2R heteromerization modulates dopamine signaling through an effect on G protein conformation.

Author information

1
Institut des Biomolécules Max Mousseron, CNRS, Ecole Nationale Superieure de Chimie de Montepellier, Université Montpellier, 34093 Montpellier, France.
2
I2MC, INSERM U1048, Université de Toulouse, F-31432 Toulouse, France.
3
Integral Membrane Proteins Research and Services (IMPReSs), UMR 7242 CNRS, Ecole Superieure de Biotechnologie de Strasbourg, Université de Strasbourg, F-67412 Illkirch, France.
4
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6600.
5
Pole d'expertise Biotechnologie, Chimie, Biologie, Institut de Recherches Servier, F-78290 Croissy-sur-Seine, France.
6
Institut des Biomolécules Max Mousseron, CNRS, Ecole Nationale Superieure de Chimie de Montepellier, Université Montpellier, 34093 Montpellier, France; jean-louis.baneres@umontpellier.fr.

Abstract

The growth hormone secretagogue receptor (GHSR) and dopamine receptor (D2R) have been shown to oligomerize in hypothalamic neurons with a significant effect on dopamine signaling, but the molecular processes underlying this effect are still obscure. We used here the purified GHSR and D2R to establish that these two receptors assemble in a lipid environment as a tetrameric complex composed of two each of the receptors. This complex further recruits G proteins to give rise to an assembly with only two G protein trimers bound to a receptor tetramer. We further demonstrate that receptor heteromerization directly impacts on dopamine-mediated Gi protein activation by modulating the conformation of its α-subunit. Indeed, association to the purified GHSR:D2R heteromer triggers a different active conformation of Gαi that is linked to a higher rate of GTP binding and a faster dissociation from the heteromeric receptor. This is an additional mechanism to expand the repertoire of GPCR signaling modulation that could have implications for the control of dopamine signaling in normal and physiopathological conditions.

KEYWORDS:

G protein; GPCR; conformational dynamics; heteromer; signaling

PMID:
29632174
PMCID:
PMC5924877
DOI:
10.1073/pnas.1712725115
[Indexed for MEDLINE]
Free PMC Article

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