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The ligand-bound state of a G protein-coupled receptor stabilizes the interaction of functional cholesterol molecules.
Lemel, Laura; Niescierowicz, Katarzyna; García-Fernández, M Dolores; Darré, Leonardo; Durroux, Thierry; Busnelli, Marta; Pezet, Mylène; Rébeillé, Fabrice; Jouhet, Juliette; Mouillac, Bernard; Domene, Carmen; Chini, Bice; Cherezov, Vadim; Moreau, Christophe J.
Afiliación
  • Lemel L; Univ. Grenoble Alpes, CNRS, CEA, IBS, Grenoble, France.
  • Niescierowicz K; Univ. Grenoble Alpes, CNRS, CEA, IBS, Grenoble, France.
  • García-Fernández MD; Univ. Grenoble Alpes, CNRS, CEA, IBS, Grenoble, France.
  • Darré L; Functional Genomics Laboratory and Biomolecular Simulations Laboratory, Institut Pasteur de Montevideo, Montevideo, Uruguay.
  • Durroux T; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.
  • Busnelli M; CNR, Institute of Neuroscience, U28 and NeuroMI Center for Neuroscience, University of Milano-Bicocca, Vedano al Lambro (MB), Italy.
  • Pezet M; Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR 5309, Grenoble Alpes University, Grenoble, France.
  • Rébeillé F; Laboratoire de Physiologie Cellulaire Végétale, Univ. Grenoble Alpes, CNRS, CEA, INRAE, Grenoble, France.
  • Jouhet J; Laboratoire de Physiologie Cellulaire Végétale, Univ. Grenoble Alpes, CNRS, CEA, INRAE, Grenoble, France.
  • Mouillac B; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.
  • Domene C; Department of Chemistry, University of Bath, Bath, United Kingdom; Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom.
  • Chini B; CNR, Institute of Neuroscience, U28 and NeuroMI Center for Neuroscience, University of Milano-Bicocca, Vedano al Lambro (MB), Italy.
  • Cherezov V; Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
  • Moreau CJ; Univ. Grenoble Alpes, CNRS, CEA, IBS, Grenoble, France. Electronic address: christophe.moreau@ibs.fr.
J Lipid Res ; 62: 100059, 2021.
Article en En | MEDLINE | ID: mdl-33647276
Cholesterol is a major component of mammalian plasma membranes that not only affects the physical properties of the lipid bilayer but also is the function of many membrane proteins including G protein-coupled receptors. The oxytocin receptor (OXTR) is involved in parturition and lactation of mammals and in their emotional and social behaviors. Cholesterol acts on OXTR as an allosteric modulator inducing a high-affinity state for orthosteric ligands through a molecular mechanism that has yet to be determined. Using the ion channel-coupled receptor technology, we developed a functional assay of cholesterol modulation of G protein-coupled receptors that is independent of intracellular signaling pathways and operational in living cells. Using this assay, we discovered a stable binding of cholesterol molecules to the receptor when it adopts an orthosteric ligand-bound state. This stable interaction preserves the cholesterol-dependent activity of the receptor in cholesterol-depleted membranes. This mechanism was confirmed using time-resolved FRET experiments on WT OXTR expressed in CHO cells. Consequently, a positive cross-regulation sequentially occurs in OXTR between cholesterol and orthosteric ligands.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Acoplados a Proteínas G Idioma: En Revista: J Lipid Res Año: 2021 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Acoplados a Proteínas G Idioma: En Revista: J Lipid Res Año: 2021 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos