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

J Clin Invest. 2000 Apr;105(7):887-95. doi: 10.1172/JCI8688.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidiuretic Hormone Receptor Antagonists*
  • Arginine Vasopressin / analogs & derivatives*
  • Arginine Vasopressin / pharmacology
  • Azepines / pharmacology*
  • Benzamides / pharmacology*
  • COS Cells
  • Cell Line
  • Cell Membrane / metabolism
  • Diabetes Insipidus, Nephrogenic / genetics
  • Diabetes Insipidus, Nephrogenic / metabolism
  • Flow Cytometry
  • Humans
  • Intracellular Fluid / metabolism
  • Molecular Chaperones / pharmacology*
  • Morpholines / pharmacology*
  • Mutagenesis
  • Protein Folding*
  • Pyrroles
  • Receptors, Vasopressin / genetics
  • Spiro Compounds / pharmacology*


  • Antidiuretic Hormone Receptor Antagonists
  • Azepines
  • Benzamides
  • Molecular Chaperones
  • Morpholines
  • Pyrroles
  • Receptors, Vasopressin
  • Spiro Compounds
  • Arginine Vasopressin
  • lixivaptan
  • 1-((beta-mercapto-beta)beta cyclopentamethylenepropionic acid)-2-(O-ethyl-Tyr)-4-Val-9-des-Gly-arginine vasopressin
  • satavaptan