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Biochemical Basis of Partial Nephrogenic Diabetes Insipidus Phenotypes

Department of Anesthesiology (H.S., G.I., M.B.) University of California Los Angeles School of Medicine Los Angeles, California 90095
Department of Medicine (D.G.B.) Université de Montréal Centre de Recherche et Unité de Recherches Cliniques Hôpital du Sacré-Coeur de Montréal Montréal, Québec, H4J 1C5 Canada
Center for Endocrinology, Metabolism, and Nutrition (G.L.R.) Northwestern University Medical School Chicago, Illinois 60611-3008

Biochemical properties of mutant type 2 vasopressin receptors (V2Rs) causing a partial phenotype of nephrogenic diabetes insipidus were investigated in transiently transfected HEK 293 cells. Cell surface expression of the V2R was not altered by substituting Asp⁸⁵ in the second transmembrane region by Asn as determined by saturation binding assays. Although the affinity of the mutant V2R for arginine vasopressin (AVP) was reduced only 6-fold, the response of adenylyl cyclase activity to AVP revealed a 50-fold right shift in EC₅₀ and a decreased maximum response for the mutant V2R. These data indicated that replacement of Asp⁸⁵ by Asn affected coupling of the receptor to G_s, a conclusion substantiated by a 20-fold decrease in the calculated coupling efficiency of this receptor. The Gly²⁰¹Asp mutation in the second extracellular loop, also found associated with an NDI partial phenotype, decreased cell surface expression of the V2R with minor reduction in ligand-binding affinity and coupling efficiency to G_s. A pronounced difference was observed for this mutant V2R between the stimulation of adenylyl cyclase activity promoted by AVP and the V2 vasopressin receptor agonist deamino[Cys¹,D-Arg⁸]-vasopressin, suggesting an involvement of Gly²⁰¹ in the selectivity of the receptor for different ligands. These data demonstrated that while decreased ligand-binding affinity and decreased coupling to G_s are responsible for the attenuation of response to ligand in the Asp⁸⁵Asn mutant V2R, cell surface expression of the V2R is the major factor reducing cellular responses to ligand for the Gly²⁰¹Asp mutant V2R.

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