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
- 16 February 2010
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 77 (5), 836-845
- https://doi.org/10.1124/mol.109.061804
Abstract
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.Keywords
This publication has 33 references indexed in Scilit:
- Agonist-Independent Interactions between β-Arrestins and Mutant Vasopressin Type II Receptors Associated with Nephrogenic Syndrome of Inappropriate AntidiuresisMolecular Endocrinology, 2009
- β-Arrestins: Multifunctional Cellular MediatorsPhysiology, 2008
- Unraveling G Protein-coupled Receptor Endocytosis Pathways Using Real-time Monitoring of Agonist-promoted Interaction between β-Arrestins and AP-2Published by Elsevier BV ,2007
- Nephrogenic Syndrome of Inappropriate AntidiuresisNew England Journal of Medicine, 2005
- Oxytocin- and vasopressin-induced growth of human small-cell lung cancer is mediated by the mitogen-activated protein kinase pathwayEndocrine-Related Cancer, 2004
- Palmitoylation of the V2 Vasopressin Receptor Carboxyl Tail Enhances β-Arrestin Recruitment Leading to Efficient Receptor Endocytosis and ERK1/2 ActivationPublished by Elsevier BV ,2003
- Gαq-coupled Receptor Internalization Specifically Induced by Gαq SignalingJournal of Biological Chemistry, 2003
- A Transplantable Sorting Signal That Is Sufficient to Mediate Rapid Recycling of G Protein-coupled ReceptorsPublished by Elsevier BV ,2001
- Nephrogenic Diabetes InsipidusAnnual Review of Physiology, 2001
- A G protein-gated K channel is activated via beta 2-adrenergic receptors and G beta gamma subunits in Xenopus oocytes.The Journal of general physiology, 1995