期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 17, 页码 4501-4506出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1712725115
关键词
GPCR; G protein; heteromer; conformational dynamics; signaling
资金
- CNRS
- Universite Montpellier
- Agence Nationale de Recherches [ANR-13-BSV8-0006-01]
- Chemisyst Labex
- Labex EpiGenMed, an Investissements d'avenir Program [ANR-10-LABX-12-01]
- Demande d'Attribution de Ressources Informatiques [2016077530]
- Centre Informatique National de l'Enseignement Superieur [2016077530]
- HPC@LR
- Agence Nationale de la Recherche (ANR) [ANR-13-BSV8-0006] Funding Source: Agence Nationale de la Recherche (ANR)
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 alpha-subunit. Indeed, association to the purified GHSR: D2R heteromer triggers a different active conformation of G alpha i 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.
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