TY - JOUR
T1 - The constitutively active V2 receptor mutants conferring NSIAD are weakly sensitive to agonist and antagonist regulation
AU - Tenenbaum, Julie
AU - Ayoub, Mohammed A.
AU - Perkovska, Sanja
AU - Adra-Delenne, Anne Laure
AU - Mendre, Christiane
AU - Ranchin, Bruno
AU - Bricca, Giamperro
AU - Geelen, Ghislaine
AU - Mouillac, Bernard
AU - Durroux, Thierry
AU - Morin, Denis
PY - 2009
Y1 - 2009
N2 - 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 b-arrestins, respectively. The R137C and R137L receptors exhibit small constitutive activities regarding the Gs protein activation. In addition, these two mutants induce a constitutive b-arrestin recruitment. Of interest, they also exhibit weak sensitivities to agonist and to inverse agonist in term of Gs protein coupling and β-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.
AB - 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 b-arrestins, respectively. The R137C and R137L receptors exhibit small constitutive activities regarding the Gs protein activation. In addition, these two mutants induce a constitutive b-arrestin recruitment. Of interest, they also exhibit weak sensitivities to agonist and to inverse agonist in term of Gs protein coupling and β-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.
UR - http://www.scopus.com/inward/record.url?scp=77949508275&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0008383
DO - 10.1371/journal.pone.0008383
M3 - Article
C2 - 20027297
AN - SCOPUS:77949508275
SN - 1932-6203
VL - 4
JO - PLoS ONE
JF - PLoS ONE
IS - 12
M1 - e8383
ER -