University of Oulu

Morello, J.-P., Salahpour, A., Laperrière, A., Bernier, V., Arthus, M.-F., Lonergan, M., … Bouvier, M. (2000). Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. Journal of Clinical Investigation, 105(7), 887–895.

Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants

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Author: Morello, Jean-Pierre1,2,3; Salahpour, Ali1; Laperrière, André1;
Organizations: 1Département de Biochimie and Le Groupe de Recherche sur le Système Nerveux Autonome, Université de Montréal, Montréal, Quebec H3C 3J7, Canada
2Unité de Recherche Clinique, Centre de Recherche et Service de Néphrologie, Hôpital du Sacré-Coeur de Montréal, Montréal, Quebec H4J 1C5, Canada
3Département de Médecine, Université de Montréal, Montréal, Quebec H3C 3J7, Canada
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 5.2 MB)
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Language: English
Published: American Society for Clinical Investigation, 2000
Publish Date: 2019-12-19


Over 150 mutations within the coding sequence of the V2 vasopressin receptor (V2R) gene are known to cause nephrogenic diabetes insipidus (NDI). A large number of these mutant receptors fail to fold properly and therefore are not routed to the cell surface. Here we show that selective, nonpeptidic V2R antagonists dramatically increase cell-surface expression and rescue the function of 8 mutant NDI-V2Rs by promoting their proper folding and maturation. A cell-impermeant V2R antagonist could not mimic these effects and was unable to block the rescue mediated by a permeant agent, indicating that the nonpeptidic antagonists act intracellularly, presumably by binding to and stabilizing partially folded mutants. In addition to opening new therapeutic avenues for NDI patients, these data demonstrate that by binding to newly synthesized mutant receptors, small ligands can act as pharmacological chaperones, promoting the proper folding and maturation of receptors and their targeting to the cell surface.

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Series: Journal of clinical investigation
ISSN: 0021-9738
ISSN-E: 1558-8238
ISSN-L: 0021-9738
Volume: 105
Issue: 7
Pages: 887 - 895
DOI: 10.1172/JCI8688
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This work was supported by grants from the Kidney Foundation of Canada and the Medical Research Council of Canada (MRC) to M. Bouvier and D.G. Bichet. D.G. Bichet thanks la Fondation J. Rodolphe-La Haye for generous support. J.P. Morello held a studentship from the Heart and Stroke Foundation of Canada. A. Salahpour and S. Angers hold studentships from the MRC. M. Bouvier holds an MRC Scientist Award.
Copyright information: Copyright © 2019 American Society for Clinical Investigation. Published in this repository with the kind permission of the publisher.