Institut de Recherche en Immunologie et Cancérologie, Département de Biochimie, Université de Montréal, Montréal, Québec, Canada.
Mol Pharmacol. 2010 May;77(5):836-45. doi: 10.1124/mol.109.061804. Epub 2010 Feb 16.
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 beta-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 beta-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.
精氨酸 137 取代血管加压素 2 型受体 (V2R) 为组氨酸 (R137H-V2R) 可导致肾性尿崩症 (NDI)，而相同残基取代为半胱氨酸或亮氨酸 (R137C/L-V2R) 可导致肾性尿崩症综合征 (NSIAD)。这两种疾病具有相反的临床结果。然而，三种突变受体都表现出组成型β-arrestin 募集和内吞作用、对血管加压素刺激的 cAMP 产生和丝裂原激活蛋白激酶激活的抗性以及细胞表面靶向的受损，这引发了对这些现象对疾病的贡献及其潜在治疗方法的质疑。阻断内吞作用加剧了 R137C/L-V2R 促进的基础 cAMP 水平升高，但对 R137H-V2R 引起的 cAMP 产生没有影响，这表明 R137 取代为 Cys/Leu，但不是 His，导致组成型 V2R 刺激的 cAMP 积累，这很可能是 NSIAD 的基础。R137C/L-V2R 的组成型内吞作用增强减弱了信号转导，很可能减轻了 NSIAD 的严重程度，而 R137H-V2R 的内吞作用升高可能导致 NDI。R137C/L-V2R 的组成型信号转导不受 V2R 反向激动剂 satavaptan (SR121463) 的治疗抑制。相反，由于其药理学伴侣特性，SR121463 增加了 R137C/L-V2R 的成熟和细胞表面靶向，导致基础 cAMP 产生进一步增加，因此不适合作为 R137C/L-V2R 诱导的 NSIAD 患者的潜在治疗方法。然而，发现血管加压素可促进 R137H/C/L-V2R 的β-arrestin/AP-2 依赖性内化，超过其已经升高的内吞作用水平，这增加了血管加压素通过降低稳态表面受体水平从而降低基础 cAMP 产生，对 R137C/L-V2R 诱导的 NSIAD 患者具有治疗价值的可能性。
