Department of Endocrinology and Nephrology, The University of Tokyo, Tokyo, Japan.
Department of Endocrinology and Nephrology, The University of Tokyo, Tokyo, Japan.
Vitam Horm. 2020;113:79-99. doi: 10.1016/bs.vh.2019.08.012. Epub 2019 Sep 13.
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.
V2 血管加压素受体 (V2R) 是 G 蛋白偶联受体 (GPCR) 家族的成员，该家族中已发现许多致病突变，因此引起了广泛关注。V2R 的功能丧失性突变会导致肾性尿崩症 (NDI)，而获得性功能的突变会导致肾性尿崩症伴抗利尿激素不适当分泌 (NSIAD)。V2R 功能丧失的理论机制可分为蛋白表达、定位（内质网保留）或功能障碍。然而，功能分析表明这些机制可能很复杂。引人注目的是，相同位置的 V2R 突变会导致相反的表型，例如，R137H 和 R137L/C 分别导致 NDI 和 NSIAD。这些发现支持这样一种观点，即 GPCR 的组成性激活可能常常与它们的不稳定性和变性有关。因此，对致病 V2R 突变的功能分析不仅可能揭示用于 NDI 的药理学伴侣和用于 NSIAD 的反向激动剂的潜在新治疗策略，还可能提供对 GPCR 生理功能的更深入了解，并强调新的范例，即偏性激动和多变激动。
