V2 vasopressin receptor mutations.

Noriko Makita, Katsunori Manaka, Junichiro Sato, Taroh Iiri

Vitamins and hormones 2020

filter terms:

V2 vasopressin receptor (V2R) is a member of the G protein-coupled receptor (GPCR) family in which many disease-causing mutations have been identified and thus generated much interest. Loss-of-function V2R mutations cause nephrogenic diabetes insipidus (NDI) whereas gain-of-function mutations cause nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The mechanisms underlying a V2R loss-of-function can be theoretically classified as either protein expression, localization (ER retention) or functional disorders. Functional analyses have revealed however that these mechanisms are likely to be complex. Strikingly, V2R mutations at the same site can result in opposite phenotypes, e.g., R137H and R137L/C cause NDI and NSIAD, respectively. These findings support the notion that the constitutive activation of GPCRs might be often associated with their instability and denaturation. Thus, functional analysis of disease-causing V2R mutations may not only reveal potential new treatment strategies using pharmacochaperones for NDI and inverse agonists for NSIAD, but also provide a greater understanding of the physiological functions of GPCRs and highlight the new paradigms, i.e., biased agonism and protean agonism. © 2020 Elsevier Inc. All rights reserved.