V2R mutations in partial nephrogenic diabetes insipidus highlight protean agonism of V2R antagonists
V2R mutations in partial nephrogenic diabetes insipidus highlight protean agonism of V2R antagonists
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部分肾性尿崩症中的 V2R 突变凸显了 V2R 拮抗剂的多样化激动作用
DOI：
10.1074/jbc.m111.268797
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发表时间：
2012
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影响因子：
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et al.
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作者：
Takahashi K;Makita N;et al.
V2血管加压素受体（V2 R）的失活突变导致交联的先天性肾源性尿崩症（NDI），导致肾对抗利尿激素AVP的抵抗。在两个家庭显示部分NDI，其特征是一个明显的正常反应的诊断测试和增加的基础ADH水平表明AVP抗性，我们已经确定了两个V2 R突变，Ser-333 del和Y128 S。当在COS-7细胞中表达时，这两种突变V2 Rs在加压素刺激的cAMP积累和细胞内定位中显示出部分缺陷。抑制内化并不能挽救它们的定位。相反，非肽V2 R拮抗剂OPC 41061和OPC 31260部分拯救这些V2 R突变体的膜定位和基础功能，而它们抑制野生型V2 R的基础活性。这些结果表明Ser-333 del和Y128 S突变体V2 Rs的部分功能丧失是由膜运输缺陷引起的。这些发现进一步表明，V2 R拮抗剂可以作为蛋白酶激动剂，作为药理学伴侣失活V2 R突变体，也作为野生型受体的反向激动剂。我们推测，这种蛋白质激动作用可能是V2 R拮抗剂可能的双重有益作用的基础：改善心力衰竭或多囊肾病的低钠血症，并可能挽救NDI。
Inactivating mutations of the V2 vasopressin receptor (V2R) cause cross-linked congenital nephrogenic diabetes insipidus (NDI), resulting in renal resistance to the antidiuretic hormone AVP. In two families showing partial NDI, characterized by an apparently normal response to diagnostic tests and an increase in the basal ADH levels suggesting AVP resistance, we have identified two V2R mutations, Ser-333del and Y128S. Both mutant V2Rs, when expressed in COS-7 cells, show partial defects in vasopressin-stimulated cAMP accumulation and intracellular localization. The inhibition of internalization does not rescue their localization. In contrast, the non-peptide V2R antagonists OPC41061 and OPC31260 partially rescue the membrane localization and basal function of these V2R mutants, whereas they inhibit the basal activity of the wild-type V2R. These results indicate that a partial loss of function of Ser-333del and Y128S mutant V2Rs results from defective membrane trafficking. These findings further indicate that V2R antagonists can act as protean agonists, serving as pharmacological chaperones for inactivating V2R mutants and also as inverse agonists of wild-type receptors. We speculate that this protean agonism could underlie the possible dual beneficial effects of the V2R antagonist: improvement of hyponatremia with heart failure or polycystic kidney disease and potential rescue of NDI.