This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bernier, V. Articles by Bouvier, M. Search for Related Content PubMed PubMed Citation Articles by Bernier, V. Articles by Bouvier, M.

Functional Rescue of the Constitutively Internalized V2 Vasopressin Receptor Mutant R137H by the Pharmacological Chaperone Action of SR49059

Département de Biochimie and Groupe de Recherche sur le Système Nerveux Autonome (V.B., M.La., M.B.), Université de Montréal, Montréal, Québec, Canada H3C 3J7; and Unité de Recherche Clinique and Département de Médecine (V.B., M.Lo., M.-F.A., D.G.B.), Centre de Recherche et Service de Néphrologie, Hôpital du Sacré-Cur de Montréal, Montréal, Québec, Canada H4J 1C5

Address all correspondence and requests for reprints to: Michel Bouvier, Department of Biochemistry, Université de Montréal, C.P. 6128 Succursale Centre-Ville, Montréal, Québec, Canada H3C 3J7. E-mail: michel.bouvier{at}umontreal.ca.

In most cases, nephrogenic diabetes insipidus results from mutations in the V2 vasopressin receptor (V2R) gene that cause intracellular retention of improperly folded receptors. We previously reported that cell permeable V2R antagonists act as pharmacological chaperones that rescue folding, trafficking, and function of several V2R 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 V2R by preventing its endocytosis. Here we report that the ß-arrestin-mediated constitutive endocytosis of R137H V2R 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 V2R 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 V2Rs results from the pharmacological chaperone action of the antagonist.

This article has been cited by other articles:

				A. Sobolewski, N. Rudarakanchana, P. D. Upton, J. Yang, T. K. Crilley, R. C. Trembath, and N. W. Morrell Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: potential for rescue Hum. Mol. Genet., October 15, 2008; 17(20): 3180 - 3190. [Abstract] [Full Text] [PDF]

				F. F. Hamdan, M. D. Rochdi, B. Breton, D. Fessart, D. E. Michaud, P. G. Charest, S. A. Laporte, and M. Bouvier Unraveling G Protein-coupled Receptor Endocytosis Pathways Using Real-time Monitoring of Agonist-promoted Interaction between beta-Arrestins and AP-2 J. Biol. Chem., October 5, 2007; 282(40): 29089 - 29100. [Abstract] [Full Text] [PDF]

				P. M. Conn, A. Ulloa-Aguirre, J. Ito, and J. A. Janovick G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue in Vivo Pharmacol. Rev., September 1, 2007; 59(3): 225 - 250. [Abstract] [Full Text] [PDF]

				T. T. Leskela, P. M. H. Markkanen, E. M. Pietila, J. T. Tuusa, and U. E. Petaja-Repo Opioid Receptor Pharmacological Chaperones Act by Binding and Stabilizing Newly Synthesized Receptors in the Endoplasmic Reticulum J. Biol. Chem., August 10, 2007; 282(32): 23171 - 23183. [Abstract] [Full Text] [PDF]

				Z.-L. Lu, M. Coetsee, C. D. White, and R. P. Millar Structural Determinants for Ligand-Receptor Conformational Selection in a Peptide G Protein-coupled Receptor J. Biol. Chem., June 15, 2007; 282(24): 17921 - 17929. [Abstract] [Full Text] [PDF]

				J. H. Robben, M. Sze, N. V. A. M. Knoers, and P. M. T. Deen Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus Am J Physiol Renal Physiol, January 1, 2007; 292(1): F253 - F260. [Abstract] [Full Text] [PDF]

				J. H. Robben, N. V. A. M. Knoers, and P. M. T. Deen Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus. Am J Physiol Renal Physiol, August 1, 2006; 291(2): F257 - F270. [Abstract] [Full Text] [PDF]

				A. U. Gehret, A. Bajaj, F. Naider, and M. E. Dumont Oligomerization of the Yeast {alpha}-Factor Receptor: IMPLICATIONS FOR DOMINANT NEGATIVE EFFECTS OF MUTANT RECEPTORS J. Biol. Chem., July 28, 2006; 281(30): 20698 - 20714. [Abstract] [Full Text] [PDF]

				S. R. Hawtin Pharmacological Chaperone Activity of SR49059 to Functionally Recover Misfolded Mutations of the Vasopressin V1a Receptor J. Biol. Chem., May 26, 2006; 281(21): 14604 - 14614. [Abstract] [Full Text] [PDF]

				T. Milojevic, V. Reiterer, E. Stefan, V. M. Korkhov, M. M. Dorostkar, E. Ducza, E. Ogris, S. Boehm, M. Freissmuth, and C. Nanoff The Ubiquitin-Specific Protease Usp4 Regulates the Cell Surface Level of the A2a Receptor Mol. Pharmacol., April 1, 2006; 69(4): 1083 - 1094. [Abstract] [Full Text] [PDF]

				V. Bernier, J.-P. Morello, A. Zarruk, N. Debrand, A. Salahpour, M. Lonergan, M.-F. Arthus, A. Laperriere, R. Brouard, M. Bouvier, et al. Pharmacologic Chaperones as a Potential Treatment for X-Linked Nephrogenic Diabetes Insipidus J. Am. Soc. Nephrol., January 1, 2006; 17(1): 232 - 243. [Abstract] [Full Text] [PDF]

				T. M. Fujiwara and D. G. Bichet Molecular Biology of Hereditary Diabetes Insipidus J. Am. Soc. Nephrol., October 1, 2005; 16(10): 2836 - 2846. [Abstract] [Full Text] [PDF]