Pharmacological Chaperones Rescue Cell-Surface Expression and Function of Misfolded V2 Vasopressin Receptor Mutants

Title: Pharmacological Chaperones Rescue Cell-Surface Expression and Function of Misfolded V2 Vasopressin Receptor Mutants
Authors: Morello, Jean-Pierre; Salahpour, Ali; Laperriere, Andre; Bernier, Virginie; Arthus, Marie-Francoise; Lonergan, Michele; Petaja-Repo, Ulla; Angers, Stephane; Morin, Denis; Bichet, Daniel G.; Bouvier, Michel
Publisher: Journal of Clinical Investigation
Date Published: April 01, 2000
Reference Number: 494
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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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

X-linked nephrogenic diabetes insipidus (NDI) is an inherited disease caused by mutations of the vasopressin-2 receptor (V2R) gene. Normally, healthy V2Rs bind with the hormone, arginine vasopressin (AVP). This initiates a molecular sequence which results in the concentration of urine. To date, 155 different mutations of the V2R gene resulting in NDI have been documented.

Different V2R mutations result in different structural and functional defects. However, many of those structural defects result in the same functional defect: the mutant V2R is retained within the endoplasmic reticulum (ER) inside the kidney collecting duct cell and is unable to travel to the cell membrane. Because the V2R must be at the cell membrane in order to bind with AVP, mutant V2Rs retained in the ER are unable to perform their function.

Research confirmed that may of the mutant V2Rs were retained in the ER because they had not matured and therefore had not attained the normal V2R shape. Researchers speculated that many of these retained V2Rs could be capable of binding with AVP and initiating the urine concentrating process if they could only free themselves from the ER and get to the cell membrane.

Morello, et al., hypothesized that select V2R antagonists (substances that bind to V2R without eliciting a biological response) could penetrate the collecting duct cells and could help certain mutant V2Rs stabilize, develop their proper shape and thus escape the ER. They treated 15 different mutant V2Rs in laboratory cell cultures with the V2R antagonist SR 121463A. They found that 8 of the 15 mutant V2Rs were functionally restored by the antagonist. That is, the antagonist enabled the 8 mutant V2Rs to escape the ER, reach the cell membrane, bind with AVP and initiate the molecular sequence that leads to urine concentration.

The researchers also reported that even after the antagonist was removed from the cell culture, the mutant V2Rs remained able to perform their function for at least 24 hours. They suggest the antagonist was able to bind to the immature mutant V2Rs and somehow increase its chances of maturing into a normal V2R shape and thus be released by the ER. Morello, et al.'s data show that another V2R antagonist, VPA-985, was able to elicit the same response from the same 8 mutant V2Rs that responded to SR121463A. This points to a possible new therapeutic approach for treatment of NDI caused by mutant V2Rs that are capable of performing their function were it not for being retained in the ER due to their immature shape.