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Probing the Existence of G Protein-Coupled Receptor Dimers by Positive and Negative Ligand-Dependent Cooperative Binding

Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203, Montpellier, France (L.A., M.-N.B., J.-P.P., B.M., C.B., T.D.); Institut National de la Santé et de la Recherche Médicale U 661, Montpellier, France (L.A., M.-N.B., J.-P.P., B.M., C.B., T.D.); Universités 1 and 2 Montpellier, Montpellier, France (L.A., M.-N.B., J.-P.P., B.M., C.B., T.D.); Laboratoire de Neuroendocrinologie du Développement, Département de Physiologie, Unité Propre de Recherche et de l'Enseignement Supérieur, Equipe d'Accueil 2701, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq, France (C.B.); and Department of Biochemistry and Cancer Biology, Medical University of Ohio, Toledo, Ohio (M.M.)

An increasing amount of ligand binding data on G protein-coupled receptors (GPCRs) is not compatible with the prediction of the simple mass action law. This may be related to the propensity of most GPCRs, if not all, to oligomerize. Indeed, one of the consequences of receptor oligomerization could be a possible cross-talk between the protomers, which in turn could lead to negative or positive cooperative ligand binding. We prove here that this can be demonstrated experimentally. Saturation, dissociation, and competition binding experiments were performed on vasopressin and oxytocin receptors expressed in Chinese hamster ovary or COS-7 cells. Linear, concave, and convex Scatchard plots were then obtained, depending on the ligand used. Moreover, some competition curves exhibited an increase of the radiotracer binding for low concentrations of competitors, suggesting a cooperative binding process. These data demonstrate that various vasopressin analogs display either positive or negative cooperative binding. Because positive cooperative binding cannot be explained without considering receptor as multivalent, these binding data support the concept of GPCR dimerization process. The results, which are in good accordance with the predictions of previous mathematical models, suggest that binding experiments can be used to probe the existence of receptor dimers.

Address correspondence to: Thierry Durroux, Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique UMR 5203, 141 rue de la Cardonille, 34094 Montpellier CEDEX 5, France. E-mail: tdurroux{at}igf.cnrs.fr

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