title: Ghrelin receptor conformational dynamics regulate the transition from a preassembled to an active receptor:Gq complex.
abstract: How G protein-coupled receptor conformational dynamics control G protein coupling to trigger signaling is a key but still open question. We addressed this question with a model system composed of the purified ghrelin receptor assembled into lipid discs. Combining receptor labeling through genetic incorporation of unnatural amino acids, lanthanide resonance energy transfer, and normal mode analyses, we directly demonstrate the occurrence of two distinct receptor:Gq assemblies with different geometries whose relative populations parallel the activation state of the receptor. The first of these assemblies is a preassembled complex with the receptor in its basal conformation. This complex is specific of Gq and is not observed with Gi. The second one is an active assembly in which the receptor in its active conformation triggers G protein activation. The active complex is present even in the absence of agonist, in a direct relationship with the high constitutive activity of the ghrelin receptor. These data provide direct evidence of a mechanism for ghrelin receptor-mediated Gq signaling in which transition of the receptor from an inactive to an active conformation is accompanied by a rearrangement of a preassembled receptor:G protein complex, ultimately leading to G protein activation and signaling.
authors.affiliation: CNRS UMR 5247 and Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, Université Montpellier 1 et 2, 34093 Montpellier Cedex 05, France;
authors.forename: Marjorie
authors.initials: M
authors.lastname: Damian
authors.affiliation: CNRS UMR 5247 and Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, Université Montpellier 1 et 2, 34093 Montpellier Cedex 05, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Mary
authors.affiliation: CNRS UMR 5247 and Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, Université Montpellier 1 et 2, 34093 Montpellier Cedex 05, France;
authors.forename: Mathieu
authors.initials: M
authors.lastname: Maingot
authors.affiliation: CNRS UMR 5247 and Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, Université Montpellier 1 et 2, 34093 Montpellier Cedex 05, France;
authors.forename: Céline
authors.initials: C
authors.lastname: M'Kadmi
authors.affiliation: CNRS UMR 5247 and Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, Université Montpellier 1 et 2, 34093 Montpellier Cedex 05, France;
authors.forename: Didier
authors.initials: D
authors.lastname: Gagne
authors.affiliation: CNRS UMR 5247 and Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, Université Montpellier 1 et 2, 34093 Montpellier Cedex 05, France;
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Leyris
authors.affiliation: CNRS UMR 5247 and Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, Université Montpellier 1 et 2, 34093 Montpellier Cedex 05, France;
authors.forename: Séverine
authors.initials: S
authors.lastname: Denoyelle
authors.affiliation: CNRS UMR 5203, INSERM U661, and Institut de Génomique Fonctionnelle, Université Montpellier 1 et 2, 34094 Montpellier Cedex 05, France;
authors.forename: Gérald
authors.initials: G
authors.lastname: Gaibelet
authors.affiliation: CNRS UMR 5247 and Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, Université Montpellier 1 et 2, 34093 Montpellier Cedex 05, France;
authors.forename: Laurent
authors.initials: L
authors.lastname: Gavara
authors.affiliation: CNRS UMR 8113 and Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan, F-94235 Cachan, France;
authors.forename: Mauricio
authors.initials: M
authors.lastname: Garcia de Souza Costa
authors.affiliation: CNRS UMR 8113 and Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan, F-94235 Cachan, France;
authors.forename: David
authors.initials: D
authors.lastname: Perahia
authors.affiliation: Cisbio Bioassays, 30200 Codolet, France; and.
authors.forename: Eric
authors.initials: E
authors.lastname: Trinquet
authors.affiliation: CNRS UMR 5203, INSERM U661, and Institut de Génomique Fonctionnelle, Université Montpellier 1 et 2, 34094 Montpellier Cedex 05, France;
authors.forename: Bernard
authors.initials: B
authors.lastname: Mouillac
authors.affiliation: UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, 31432 Toulouse Cedex 4, France.
authors.forename: Ségolène
authors.initials: S
authors.lastname: Galandrin
authors.affiliation: UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, 31432 Toulouse Cedex 4, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Galès
authors.affiliation: CNRS UMR 5247 and Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, Université Montpellier 1 et 2, 34093 Montpellier Cedex 05, France;
authors.forename: Jean-Alain
authors.initials: JA
authors.lastname: Fehrentz
authors.affiliation: CNRS UMR 5247 and Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, Université Montpellier 1 et 2, 34093 Montpellier Cedex 05, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Floquet
authors.affiliation: CNRS UMR 5247 and Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, Université Montpellier 1 et 2, 34093 Montpellier Cedex 05, France;
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
authors.affiliation: CNRS UMR 5247 and Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, Université Montpellier 1 et 2, 34093 Montpellier Cedex 05, France;
authors.forename: Jacky
authors.initials: J
authors.lastname: Marie
authors.affiliation: CNRS UMR 5247 and Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, Université Montpellier 1 et 2, 34093 Montpellier Cedex 05, France; jean-louis.baneres@univ-montp1.fr.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Banères
mesh_terms: D004735:Energy Transfer; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000737:chemistry*; D011487:Protein Conformation; D054440:Receptors, Ghrelin / Q000737:chemistry*
chemical_list: D054440:Receptors, Ghrelin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: G protein; GPCR; conformation dynamics; preassembly; signaling