2002 Global Researcher Conference Proceeding

April 26 - 28, 2002

Conference: 2002 Global Researcher Conference
Title: Pharmacological Chaperones Functionally Rescue Misfolded V2-Vasopressin Receptor Mutants that Cause Nephrogenic Diabetes Insipidus: Potential Clinical Implications
Author: Bouvier, Michel
Institution: Universite de Montreal
Bouvier Protein misfolding and mistargeting is at the root of several genetic human diseases. These diseases stem from mutations that interfere with normal protein folding, their transport to the appropriate site of action or both. A well-characterized example is nephrogenic diabetes insipidus (NDI) that results from mutations within the V2-vasopressin receptor (V2R). To date, over 150 different V2R mutations occurring in unrelated families have been reported. From those tested, approximately 70% result in trafficking-deficient V2Rs. It was hypothesized that inappropriate retention in the endoplasmic reticulum (ER) of some of these mutant receptors could be responsible for their aberrant trafficking. Based on the previous observations that chemical compounds such as glycerol, trimethylamine-N-oxide or dimetyl sulfoxide could function as chemical chaperones and rescue the proper folding, targeting and function of mildly misfolded proteins, we reasoned that ligands which selectively binds the V2R could potentially facilitate folding and ER export of some NDI mutants. Thus, the effects of cell-permeable vasopressin ligands were assessed on the expression and function of 17 distinct NDI V2R mutants. We found that cell-permeant antagonists dramatically increase cell surface expression and rescue the function of 9 of these mutants by promoting their proper folding, maturation and cell surface trafficking. This has obvious potential clinical implications for the use of pharmacological chaperone in the treatment of NDI. The pharmacological chaperoning action is not limited to mutant V2Rs. Indeed, cell-permeant opioid antagonists and agonists were found to markedly increase the maturation and the cell surface targeting of d opioid receptors. This indicates that pharmacological chaperoning may be a general concept that could be applied in various diseases resulting from protein misfolding.

There are over 150 different vasopressin (V2R) mutations that result in NDI. Around 70% of these mutations result in V2Rs that can't travel to the section of the cell where they must be to perform their function. Researchers hypothesize that some of these mutations are improperly shaped and therefore not allowed to leave the endoplasmic reticulum (ER), a section in the cell interior that acts as a quality control agent.

Bouvier, Bichet and Colleagues, knew that there were chemical compounds that attach to some improperly folded proteins and help them travel and function properly. They tested several of these chemical chaperones on 17 different V2R mutants and found that the chaperones dramatically increased the mutants' ability to travel to their work site and function. The researchers' finding provides an important direction for the treatment of NDI.