Vasopressin receptors and pharmacological chaperones: from functional rescue to promising therapeutic strategies.
Conformational diseases result from protein misfolding and/or aggregation and constitute a major public health problem. Congenital Nephrogenic Diabetes Insipidus is a typical conformational disease. In most of the cases, it is associated to inactivating mutations of the renal arginine-vasopressin V2 receptor gene leading to misfolding and intracellular retention of the receptor, causing the inability of patients to concentrate their urine in response to the antidiuretic hormone. Cell-permeable pharmacological chaperones have been successfully challenged to restore plasma membrane localization of the receptor mutants and to rescue their function. Interestingly, different classes of specific ligands such as antagonists (vaptans), agonists as well as biased agonists of the V2 receptor have proven their usefulness as efficient pharmacochaperones. These compounds represent a potential therapeutic treatment of this X-linked genetic pathology.
CNRS UMR 5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; INSERM U661, F-34000 Montpellier, France; Universités de Montpellier 1 and 2, F-34000 Montpellier, France. Electronic address: bernard.mouillac@igf.cnrs.fr.
Bernard
B
Mouillac
CNRS UMR 5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; INSERM U661, F-34000 Montpellier, France; Universités de Montpellier 1 and 2, F-34000 Montpellier, France.
Christiane
C
Mendre
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists / Q000494:pharmacology; D018500:Diabetes Insipidus, Nephrogenic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D009154:Mutation; D011487:Protein Conformation / Q000187:drug effects*; D017510:Protein Folding / Q000187:drug effects*; D017483:Receptors, Vasopressin / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D065092:Antidiuretic Hormone Receptor Antagonists; D017483:Receptors, Vasopressin
Antidiuretic hormone; Biased agonists; Therapeutic rescue; V2 vasopressin receptor; Vaptans; congenital Nephrogenic Diabetes Insipidus