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Submitted on February 25, 2004
Accepted on May 19, 2004
Département de Biochimie and Groupe de Recherche sur le Système Nerveux Autonome, Université de Montréal, Montréal, Québec, Canada, H3C 3J7; Unité de Recherche Clinique, Centre de Recherche et Service de Néphrologie, Hôpital du Sacré-C
ur de Montréal, Montréal, and Département de Médecine, Université de Montréal, Québec, Canada, H4J 1C5
* To whom correspondence should be addressed. E-mail: michel.bouvier{at}umontreal.ca.
In most cases, nephrogenic diabetes insipidus results from mutations in the V2 vasopressin receptor gene that cause intracellular retention of improperly folded receptors. We previously reported that cell permeable V2 vasopressin receptor antagonists act as pharmacological chaperones that rescue folding, trafficking and function of several V2 vasopressin receptor mutants. More recently, the vasopressin antagonist, SR49059, was found to be therapeutically active in nephrogenic diabetes insipidus patients. Three of the patients with positive responses harbored the mutation R137H, previously reported to lead to constitutive endocytosis. This raises the possibility that instead of acting as a pharmacological chaperone by favoring proper maturation of the receptors, SR49059 could mediate its action on R137H V2 vasopressin receptor by preventing its endocytosis. Here we report that the 
arrestin-mediated constitutive endocytosis of R137H V2 vasopressin receptor is not affected by SR49059, indicating that the functional rescue observed does not result from a stabilization of the receptor at the cell surface. Moreover, metabolic labeling revealed that R137H V2 vasopressin receptor is also poorly processed to the mature form. SR49059 treatment significantly improved its maturation and cell surface targeting, indicating that the functional rescue of R137H V2 vasopressin receptors results from the pharmacological chaperone action of the antagonist.
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