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A new mutation associated with nephrogenic diabetes insipidus was isolated: a 6-AA deletion between G107 and C112. A new mutation associated with nephrogenic diabetes insipidus was isolated: a 6-AA deletion between G107 and C112. A novel type of contiguous gene deletion of AVPR2 has been identified in unrelated Japanese kindreds with nephrogenic diabetes insipidus. Genetic analysis confirmed a mutation in AVPR2. HV2R has a serine/threonine motif that is required for retention in the cytoplasm. Mutations causing NDI include R106C, F287L, and R337X. Results show that the hydrophobic amino acid residues in the membrane-proximal C tail of the G protein-coupled vasopressin V2 receptor are necessary for transport-competent receptor folding. The data suggested that lysine 231 and glutamate 268 might interact with each other and might play a role in promoting GDP/GTP exchange in V2 vasopressin receptors. The human AVPR2 locus encodes the vasopressin receptor, type 2, also known as the V2 receptor, located in cytogenetic band Xq28. The gene's three exons and two introns are contained within 2.1 kilobases. The L1CAM gene lies some 29 kb centromeric to AVPR2, and the C1 gene immediately teleomeric. Both are apparently transcribed in opposite orientation to AVPR2 (see NID g1302657). The AVPR2 protein product belongs to the seven-transmembrane-domain G protein-coupled receptor (GPCR) superfamily, and it couples to Gs thus stimulating adenylate cyclase. The subfamily that includes the V2 receptor, the V1a and V1b vasopressin receptors, the oxytocin receptor, and isotocin and mesotocin receptors in non-mammals, is well conserved, though several members signal via other G proteins. All bind similar cyclic nonapeptide hormones. The V2 receptor is expressed in the kidney tubule, predominantly in the distal convoluted tubule and collecting ducts, where its primary property is to respond to the pituitary hormone arginine vasopressin (AVP) by stimulating mechanisms that concentrate the urine and maintain water homeostasis in the organism. When the function of this gene is lost, the disease Nephrogenic Diabetes Insipidus (NDI) results. The V2 receptor is also expressed outside the kidney although its tissue localization is uncertain. When these 'extrarenal receptors' are stimulated by infusion of a V2 selective agonist (dDAVP), a variety of clotting factors are released into the bloodstream. The physiologic importance of this property is not known - its absence does not appear to be detrimental in NDI patients. AVPR2 expression has also been described in fetal lung tissue and lung cancer associated with alternative splicing. V2 vasopressin receptor degradation is regulated by agonist-promoted ubiquitination. V2 vasopressin receptor has a role in inhibiting signaling through its interaction with receptor dimer and G protein. A C-terminal region of the V2R important for calmodulin interaction is also important in modulation of V2R elevation of intracellular Ca2. A single amino acid difference in the first extracellular loop determines the efficiency of cell surface expression. Analysis of pharmacochaperone cell surface delivery with a three-dimensional homology model of the antagonist-bound hV2R. Examination of interaction with beta-arrestin and trafficking patterns by heterodimerization with V1 vasopressin receptor. Palmitoylation enhances the recruitment of beta-arrestin to the activated V2 vasopressin receptor thus facilitating processes requiring the scaffolding action of beta-arrestin. Proteolytic cleavage of the V2 receptor requires a defined conformation and might play a role in signal termination at elevated hormone concentrations.
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