title: The constitutively active V2 receptor mutants conferring NSIAD are weakly sensitive to agonist and antagonist regulation.
abstract: Patients having the nephrogenic syndrome of inappropriate antidiuresis present either the R137C or R137L V2 mutated receptor. While the clinical features have been characterized, the molecular mechanisms of functioning of these two mutants remain elusive. In the present study, we compare the pharmacological properties of R137C and R137L mutants with the wild-type and the V2 D136A receptor, the latter being reported as a highly constitutively active receptor. We have performed binding studies, second messenger measurements and BRET experiments in order to evaluate the affinities of the ligands, their agonist and antagonist properties and the ability of the receptors to recruit beta-arrestins, respectively. The R137C and R137L receptors exhibit small constitutive activities regarding the G(s) protein activation. In addition, these two mutants induce a constitutive beta-arrestin recruitment. Of interest, they also exhibit weak sensitivities to agonist and to inverse agonist in term of G(s) protein coupling and beta-arrestin recruitment. The small constitutive activities of the mutants and the weak regulation of their functioning by agonist suggest a poor ability of the antidiuretic function to be adapted to the external stimuli, giving to the environmental factors an importance which can explain some of the phenotypic variability in patients having NSIAD.
authors.affiliation: CNRS, UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Tenenbaum
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Ayoub
authors.forename: Sanja
authors.initials: S
authors.lastname: Perkovska
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Adra-Delenne
authors.forename: Christiane
authors.initials: C
authors.lastname: Mendre
authors.forename: Bruno
authors.initials: B
authors.lastname: Ranchin
authors.forename: Giamperro
authors.initials: G
authors.lastname: Bricca
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Geelen
authors.forename: Bernard
authors.initials: B
authors.lastname: Mouillac
authors.forename: Thierry
authors.initials: T
authors.lastname: Durroux
authors.forename: Denis
authors.initials: D
authors.lastname: Morin
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D019390:Arrestins / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007177:Inappropriate ADH Syndrome / Q000378:metabolism*; D050505:Mutant Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors*; D011485:Protein Binding / Q000187:drug effects; D017483:Receptors, Vasopressin / Q000819:agonists*; D014667:Vasopressins / Q000494:pharmacology; D000071557:beta-Arrestins
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D019390:Arrestins; D050505:Mutant Proteins; D017483:Receptors, Vasopressin; D000071557:beta-Arrestins; D014667:Vasopressins