1. Asymmetric functioning of dimeric metabotropic glutamate receptors disclosed by positive allosteric modulators
- Author
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Goudet, Cyril, Kniazeff, Julie, Hlavackova, Veronika, Malhaire, Fanny, Maurel, Damien, Acher, Francine, Blahos, Jaroslav, Prézeau, Laurent, Pin, Jean-Philippe, Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Czech Academy of Sciences [Prague] (CAS), CIS BIOINTERNATIONAL, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), This work was supported in part by grants from the CNRS, the Action Concertée Incitative 'Molécules et Cibles Thérapeutiques' of the French ministry of research and technology, the fondation Paul Hamel, the comité Parkinson from the Fondation de France, Addex pharmaceuticals and the European Community (Grant LSHB-CT-200-503337) (to J.-P. P.) and by the Grant Agency of Czech Republic (GACR 301/03/1183 and 301/03/H095), Grant Agency Academy of Science of Czech Republic (KJB5039402), and AVOZ 50390512 (to J. B.). CG is supported by a fellowship from the Fondation pour la Recherche Médicale. JK is supported by a bourse de Docteur Ingénieur from the CNRS. DM is supported by both CisBio International and the French government (CIFRE fellowship)., and Goudet, Cyril
- Subjects
MESH: GTP-Binding Proteins ,MESH: Fluorescence Resonance Energy Transfer ,MESH: Binding, Competitive ,MESH: Receptors, G-Protein-Coupled ,MESH: Actins ,MESH: Protein Conformation ,MESH: Plasmids ,MESH: Recombinant Fusion Proteins ,MESH: Protein Binding ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,MESH: Allosteric Site ,MESH: Receptors, GABA-B ,MESH: Receptors, Metabotropic Glutamate ,MESH: Point Mutation ,MESH: Humans ,MESH: Time Factors ,MESH: Models, Biological ,MESH: Enzyme-Linked Immunosorbent Assay ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,MESH: Inositol Phosphates ,MESH: Cell Line ,[SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences ,MESH: Mutagenesis, Site-Directed ,MESH: Dimerization ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,MESH: Cell Membrane - Abstract
International audience; The recent discovery of positive allosteric modulators (PAMs) for G-protein-coupled receptors open new possibilities to control a number of physiological and pathological processes. Understanding the mechanism of action of such compounds will provide new information on the activation process of these important receptors. Within the last 10 years, a number of studies indicate that G-protein-coupled receptors can form dimers, but the functional significance of this phenomenon remains elusive. Here we used the metabotropic glutamate receptors as a model, because these receptors, for which PAMs have been identified, are constitutive dimers. We used the quality control system of the GABA(B) receptor to generate metabotropic glutamate receptor dimers in which a single subunit binds a PAM. We show that one PAM/dimer is sufficient to enhance receptor activity. Such a potentiation can still be observed if the subunit unable to bind the PAM is also made unable to activate G-proteins. However, the PAM acts as a non-competitive antagonist when it binds in the subunit that cannot activate G-proteins. These data are consistent with a single heptahelical domain reaching the active state per dimer during receptor activation.
- Published
- 2005
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