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

J P Morello1, A Salahpour, A Laperrière

  • 1Département de Biochimie and Le Groupe de Recherche sur le Système Nerveux Autonome, Université de Montréal, Montréal, Quebec H3C 3J7, Canada.

The Journal of Clinical Investigation
|April 5, 2000
PubMed

Insights

Selective V2R antagonists act as pharmacological chaperones, improving cell-surface expression and function of mutant vasopressin receptors (V2R) in nephrogenic diabetes insipidus (NDI). This offers new therapeutic potential for NDI patients.

Area of Science:

  • Molecular Pharmacology
  • Genetics
  • Endocrinology

Background:

  • Over 150 mutations in the V2 vasopressin receptor (V2R) gene cause nephrogenic diabetes insipidus (NDI).
  • Many V2R mutants exhibit misfolding, preventing cell-surface expression and leading to NDI.
  • Current NDI treatments are limited, highlighting the need for novel therapeutic strategies.

Purpose of the Study:

  • To investigate the potential of small molecule V2R antagonists as pharmacological chaperones.
  • To determine if these antagonists can rescue the function of misfolded V2R mutants associated with NDI.
  • To elucidate the intracellular mechanism of action for V2R antagonist-mediated rescue.

Main Methods:

  • Utilized cell-based assays to assess V2R expression and function.
  • Tested a panel of selective, nonpeptidic V2R antagonists on cell lines expressing 8 different NDI-V2R mutants.
  • Compared the effects of cell-permeant and cell-impermeant V2R antagonists.

Main Results:

  • Selective, nonpeptidic V2R antagonists significantly increased cell-surface expression of 8 NDI-V2R mutants.
  • These antagonists restored V2R function in the tested mutants.
  • Intracellular action was confirmed, as cell-permeant antagonists rescued function while cell-impermeant ones did not.

Conclusions:

  • Nonpeptidic V2R antagonists act as pharmacological chaperones, promoting proper folding and cell-surface targeting of mutant V2R.
  • This mechanism offers a promising therapeutic strategy for NDI patients with specific V2R mutations.
  • The findings open new avenues for treating genetic disorders caused by protein misfolding.

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