RT Journal Article
SR Electronic
T1 Functional Characterization of Vasopressin Type 2 Receptor Substitutions (R137H/C/L) Leading to Nephrogenic Diabetes Insipidus and Nephrogenic Syndrome of Inappropriate Antidiuresis: Implications for Treatments
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 836
OP 845
DO 10.1124/mol.109.061804
VO 77
IS 5
A1 Moulay D. Rochdi
A1 Gabriel A. Vargas
A1 Eric Carpentier
A1 Geneviève Oligny-Longpré
A1 Stanford Chen
A1 Abraham Kovoor
A1 Stephen E. Gitelman
A1 Stephen M. Rosenthal
A1 Mark von Zastrow
A1 Michel Bouvier
YR 2010
UL http://molpharm.aspetjournals.org/content/77/5/836.abstract
AB Substitution of arginine-137 of the vasopressin type 2 receptor (V2R) for histidine (R137H-V2R) leads to nephrogenic diabetes insipidus (NDI), whereas substitution of the same residue to cysteine or leucine (R137C/L-V2R) causes the nephrogenic syndrome of inappropriate antidiuresis (NSIAD). These two diseases have opposite clinical outcomes. Still, the three mutant receptors were shown to share constitutive β-arrestin recruitment and endocytosis, resistance to vasopressin-stimulated cAMP production and mitogen-activated protein kinase activation, and compromised cell surface targeting, raising questions about the contribution of these phenomenons to the diseases and their potential treatments. Blocking endocytosis exacerbated the elevated basal cAMP levels promoted by R137C/L-V2R but not the cAMP production elicited by R137H-V2R, demonstrating that substitution of Arg137 to Cys/Leu, but not His, leads to constitutive V2R-stimulated cAMP accumulation that most likely underlies NSIAD. The constitutively elevated endocytosis of R137C/L-V2R attenuates the signaling and most likely reduces the severity of NSIAD, whereas the elevated endocytosis of R137H-V2R probably contributes to NDI. The constitutive signaling of R137C/L-V2R was not inhibited by treatment with the V2R inverse agonist satavaptan (SR121463). In contrast, owing to its pharmacological chaperone property, SR121463 increased the R137C/L-V2R maturation and cell surface targeting, leading to a further increase in basal cAMP production, thus disqualifying it as a potential treatment for patients with R137C/L-V2R-induced NSIAD. However, vasopressin was found to promote β-arrestin/AP-2-dependent internalization of R137H/C/L-V2R beyond their already elevated endocytosis levels, raising the possibility that vasopressin could have a therapeutic value for patients with R137C/L-V2R-induced NSIAD by reducing steady-state surface receptor levels, thus lowering basal cAMP production.Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics