TY - JOUR T1 - Functional Characterization of V2-Vasopressin 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 DO - 10.1124/mol.109.061804 SP - mol.109.061804 AU - Moulay D Rochdi AU - Gabriel A Vargas AU - Eric Carpentier AU - Genevieve Oligny-Longpre AU - Stanford Chen AU - Abraham Kovoor AU - Stephen E Gitelman AU - Stephen M Rosenthal AU - Mark von Zastrow AU - Michel Bouvier Y1 - 2010/01/01 UR - http://molpharm.aspetjournals.org/content/early/2010/02/12/mol.109.061804.abstract N2 - 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), two diseases with 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 MAPK activation as well as 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 R137 to C/L, but not H, leads to constitutive V2R-stimulated cAMP accumulation that most likely underlies NSIAD. The constitutively elevated endocytosis of R137C/L-V2R attenuates the signalling and most likely reduces the severity of NSIAD whereas the elevated endocytosis of R137H-V2R probably contributes to NDI. The constitutive signalling of R137C/L-V2R was not inhibited by treatment with the V2R inverse agonist 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 R137C/L-V2R NSIAD patients. However, vasopressin was found to promote β-arrestin/AP2-dependent internalization of R137H/C/L-V2R beyond their already elevated endocytosis levels, raising the possibility that vasopressin could have a therapeutic value for R137C/L NSIAD patients by reducing steady state surface receptor levels, thus lowering basal cAMP production.The American Society for Pharmacology and Experimental Therapeutics ER -