首页> 外文OA文献 >Functional Characterization of Vasopressin Type 2 Receptor Substitutions (R137H/C/L) Leading to Nephrogenic Diabetes Insipidus and Nephrogenic Syndrome of Inappropriate Antidiuresis: Implications for TreatmentsS⃞
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Functional Characterization of Vasopressin Type 2 Receptor Substitutions (R137H/C/L) Leading to Nephrogenic Diabetes Insipidus and Nephrogenic Syndrome of Inappropriate Antidiuresis: Implications for TreatmentsS⃞

机译:加压素2型受体取代的功能表征 (R137H / C / L)导致肾原性尿崩症和肾病综合征 抗利尿不当:对治疗的意义

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摘要

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.
机译:用2型加压素(V2R)的精氨酸137取代组氨酸(R137H-V2R)会导致肾病性尿崩症(NDI),而将相同残基替换为半胱氨酸或亮氨酸(R137C / L-V2R)会引起肾病抗利尿不当综合征(NSIAD)。这两种疾病的临床结果相反。尽管如此,这三种突变受体仍显示出组成性β-arrestin的募集和内吞作用,对加压素刺激的cAMP产生的抗性和有丝分裂原激活的蛋白激酶激活的抵抗力以及细胞表面靶向性的降低,这引发了关于这些现象对疾病的贡献的疑问。及其潜在的治疗方法。阻断内吞作用加剧了R137C / L-V2R促进的基础cAMP水平升高,但未加剧R137H-V2R诱导的cAMP产生,表明将Arg137替换为Cys / Leu(而非His)可导致本构V2R刺激的cAMP积累可能是NSIAD的基础。 R137C / L-V2R的内吞性组成性升高会减弱信号传导,最有可能降低NSIAD的严重性,而R137H-V2R的内吞性升高可能会导致NDI。 R137C / L-V2R的组成型信号转导不受V2R反向激动剂赛达伐普坦(SR121463)的处理抑制。相比之下,由于其药理学上的分子伴侣特性,SR121463增加了R137C / L-V2R的成熟度和细胞表面靶向性,导致基础cAMP产量进一步增加,从而使它失去了作为R137C / L-V2R-患者的潜在治疗手段的资格。诱导的NSIAD。然而,发现加压素可促进R137H / C / L-V2R的β-arrestin/ AP-2依赖性内在作用超过其已经升高的内吞作用水平,从而增加了加压素对R137C / L-V2R患者具有治疗价值的可能性降低稳态表面受体水平,从而降低基础cAMP产生,从而诱导NSIAD。

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