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Key Amino Acids Located within the Transmembrane Domains 5 and 7 Account for the Pharmacological Specificity of the Human V1b Vasopressin Receptor

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 469 (S.D., A.P., T.D., G.G.), 34094 Montpellier, Cedex 05 France; Unité Mixte de Recherche (UMR), Centre National de la Recherche Scientifique (CNRS) 7081 (M.H., D.R.), F-67401 Illkirch, France; Sanofi-Synthélabo Recherche (J.W.), 31100 Toulouse, France; and Sanofi-Synthélabo Recherche (C.S.-L.G.), 34000 Montpellier, France

Address all correspondence and requests for reprints to: Guillon Gilles, Institut National de la Santé et de la Recherche Médicale Unité 469, 141 rue de la Cardonille, 34094 Montpellier, Cedex 05, France. E-mail: gilles.guillon{at}ccipe.cnrs.fr.

In mammals, the vasopressin V_1b receptor (V_1b-R) is known to regulate ACTH secretion and, more recently, stress and anxiety. The characterization of the molecular determinant responsible for its pharmacological selectivity was made possible by the recent discovery of the first V_1b antagonist, SSR149415. Based upon the structure of the crystallized bovine rhodopsin, we established a three-dimensional molecular model of interaction between the human V_1b-R (hV_1b-R) and SSR149415. Four amino acids located in distinct transmembrane helices (fourth, fifth, and seventh) were found potentially responsible for the hV_1b-R selectivity. To validate these assumptions, we selectively replaced the leucine 181, methionine 220, alanine 334, and serine 338 residues of hV_1a-R by their corresponding amino acids present in the hV_1b-R (phenylalanine 164, threonine 203, methionine 324, and asparagine 328, respectively). Four mutants, which all exhibited nanomolar affinities for vasopressin and good coupling to phospholipase C pathway, were generated. hV_1a receptors mutated at position 220 and 334 exhibited striking increase in affinity for SSR149415 both in binding and phospholipase C assays at variance with the hV_1a-R modified at position 181 or 338. In conclusion, this study provides the first structural features concerning the hV_1b-R and highlights the role of few specific residues in its pharmacological selectivity.

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