Conformational diseases are often caused by modest mutations in proteins that are unnecessarily recognized by the endoplasmic reticulum (ER) quality control system as misfolded. A well-characterized example is nephrogenic diabetese 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% lead to trafficking-deficient V2Rs. Given that many of these mutations occurred outside of the predicted hormone binding or G protein-interaction sites, we predicted that rescuing cell surface expression of these receptor mutants could restore function. Based on the known stabilizing effects of ligand binding on receptor structure, we tested the ability of various V2R ligands to rescue the cell surface expression and function of 17 ER-retained NDI V2R mutants. We found that cell-permeant antagonists dramatically increase cell surface expression and rescue the function of 11 of these mutants by promoting their proper folding, maturation and cell surface trafficking. These compounds termed pharmacological chaperones, were found to act inside the cells most likely by binding to, and stabilizing folding intermediates of the mutant receptor thus favoring their proper folding and ER export. Their action in the ER is supported by the observation that sustained treatment with these compounds modulates the interactions of the receptor with ER-resident molecular chaperones such as calnexin and inhibits their ubiquitination and subsequent proteasome-mediated degradation. In a small scale clinical trial, the effect of one pharmacological chaperone, SR49059, was assessed in 5 patients harboring 3 different mutations. In all cases, treatment for 48 hours significantly decreased the urinary output and led to a corresponding elevation of urine osmolality without affecting plasma sodium concentrations. These data provide a proof of principle that pharmacological chaperones could represent valuable therapeutic agents in the treatment of NDI. Mutations in other G protein-coupled receptors have also been found to be involved in various human genetic diseases. For example mutations in the melanocortin type 4 recepto (MC4R) have been associated with congenital morbid obesity. Characterization of 14 of these mutations revealed that most lead to intracelluar retention and that treatments permitting escape from the quality control restore cell surface expression and function of many of these receptors systemt indicating that the development of pharmacological chaperones for the MC4R could represent a valid approach for the treatment of gongenital morbid obesity. In addition to their action on mutant receptors, pharmacological chaperones were found to markedly increase the maturation and the cell surface targeting of wild-type receptors. This indicates that pharmacological chaperoning maybe a general concept that could be applied to both normal and mutant proteins to modulate cell responsiveness to specific hormones thus offering a wide range of potential therapeutic applications.