title: V2 vasopressin receptor (V2R) mutations in partial nephrogenic diabetes insipidus highlight protean agonism of V2R antagonists.
abstract: Inactivating mutations of the V2 vasopressin receptor (V2R) cause cross-linked congenital nephrogenic diabetes insipidus (NDI), resulting in renal resistance to the antidiuretic hormone AVP. In two families showing partial NDI, characterized by an apparently normal response to diagnostic tests and an increase in the basal ADH levels suggesting AVP resistance, we have identified two V2R mutations, Ser-333del and Y128S. Both mutant V2Rs, when expressed in COS-7 cells, show partial defects in vasopressin-stimulated cAMP accumulation and intracellular localization. The inhibition of internalization does not rescue their localization. In contrast, the non-peptide V2R antagonists OPC41061 and OPC31260 partially rescue the membrane localization and basal function of these V2R mutants, whereas they inhibit the basal activity of the wild-type V2R. These results indicate that a partial loss of function of Ser-333del and Y128S mutant V2Rs results from defective membrane trafficking. These findings further indicate that V2R antagonists can act as protean agonists, serving as pharmacological chaperones for inactivating V2R mutants and also as inverse agonists of wild-type receptors. We speculate that this protean agonism could underlie the possible dual beneficial effects of the V2R antagonist: improvement of hyponatremia with heart failure or polycystic kidney disease and potential rescue of NDI.
authors.affiliation: Department of Pediatrics, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takahashi
authors.forename: Noriko
authors.initials: N
authors.lastname: Makita
authors.forename: Katsunori
authors.initials: K
authors.lastname: Manaka
authors.forename: Masataka
authors.initials: M
authors.lastname: Hisano
authors.forename: Yuko
authors.initials: Y
authors.lastname: Akioka
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Miura
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Takubo
authors.forename: Atsuko
authors.initials: A
authors.lastname: Iida
authors.forename: Norishi
authors.initials: N
authors.lastname: Ueda
authors.forename: Makiko
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Takashi
authors.initials: T
authors.lastname: Igarashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Sekine
authors.forename: Taroh
authors.initials: T
authors.lastname: Iiri
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000494:pharmacology*; D019556:COS Cells; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D018500:Diabetes Insipidus, Nephrogenic / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009481:Neurophysins / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000235:genetics / Q000378:metabolism*; D000077602:Tolvaptan; D014667:Vasopressins / Q000235:genetics / Q000378:metabolism
chemical_list: C438657:AVP protein, human; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D009481:Neurophysins; D011498:Protein Precursors; D017483:Receptors, Vasopressin; D014667:Vasopressins; C076251:mozavaptan; D000077602:Tolvaptan