Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus
Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus
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DOI：
10.1152/ajprenal.00247.2006
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发表时间：
2007-01-01
影响因子：
4.2
通讯作者：
Deen, P. M. T.
中科院分区：
文献类型：
--
作者：
Robben, J. H.;Sze, M.;Deen, P. M. T.
药物伴侣对MDCK细胞中抗利尿激素V2受体突变体的功能拯救：与肾源性尿崩症的治疗相关。[J] .中国生物医学工程学报，2016,31(2):559 - 563。首次发表于2006年8月22日；doi: 10.1152 / ajprenal.00247.2006。-细胞内功能性抗利尿素V2受体（V2R）的滞留是先天性肾源性尿崩症（NDI）的主要原因，非肽拮抗剂对V2R突变体的拯救可能恢复其基底外膜（BM）定位和功能。然而，在临床可行的拮抗剂浓度下，G蛋白偶联受体（GPCR）突变体有效功能拯救的标准尚不清楚。我们发现四种非肽拮抗剂SR49059、OPC31260、OPC41061和SR121463B诱导了9种不同V2R突变体中的8种成熟，并恢复了BM的表达，在生理相关的极化细胞中稳定表达。成熟程度和挽救的BM表达与拮抗剂浓度和对V2R的亲和力相关。拮抗剂被AVP取代以及随后的cAMP生成与拮抗剂对V2R的亲和力呈负相关，但部分受拮抗剂特异性方面的影响。尽管V2R突变体的成熟和细胞表面表达的增加有限，但低亲和力的SR49059在高浓度下最容易诱导功能恢复，因为它容易被抗利尿激素取代。然而，在临床可行的拮抗剂浓度下，只有高亲和力拮抗剂OPC31260和OPC41061诱导功能恢复，因为在这些浓度下，BM的表达程度变得有限。总之，在临床可行的浓度下，高亲和力拮抗剂对突变型V2Rs的功能拯救最为有效。由于OPC31260和OPC41061在临床上是安全的，它们是缓解NDI的有希望的候选药物。此外，由于许多其他疾病是由内质网保留的gpcr引起的，细胞渗透性拮抗剂可用，我们发现高亲和力拮抗剂优越，预计对这些疾病的药物治疗发展很重要。
Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 292: F253-F260, 2007. First published August 22, 2006; doi:10.1152/ajprenal.00247.2006.-Intracellular retention of a functional vasopressin V2 receptor (V2R) is a major cause of congenital nephrogenic diabetes insipidus (NDI) and rescue of V2R mutants by nonpeptide antagonists may restore their basolateral membrane (BM) localization and function. However, the criteria for efficient functional rescue of G protein-coupled receptor (GPCR) mutants at clinically feasible antagonist concentrations are unknown. We found that the four nonpeptide antagonists SR49059, OPC31260, OPC41061, and SR121463B induced maturation and rescued the BM expression of eight of nine different V2R mutants, stably expressed in physiologically relevant polarized cells. The extent of maturation and rescued BM expression correlated with the antagonists' concentration and affinity for the V2R. Displacement of the antagonists by AVP and subsequent cAMP generation inversely correlated with the antagonists' affinities for the V2R but is partially influenced by antagonist-specific aspects. Despite limited increases in maturation and cell-surface expression of V2R mutants, the low-affinity SR49059 optimally induced functional rescue at high concentrations, due to its easy displacement by vasopressin. At clinically feasible antagonist concentrations, however, only the high-affinity antagonists OPC31260 and OPC41061 induced functional rescue, as at these concentrations the extent of BM expression became limited. In conclusion, functional rescue of mutant V2Rs at clinically feasible concentrations is most effective with high-affinity antagonists. As OPC31260 and OPC41061 are clinically safe, they are promising candidates to relieve NDI. Moreover, as numerous other diseases are caused by endoplasmic reticulum-retained GPCRs for which cell-permeable antagonists become available, our finding that high-affinity antagonists are superior is anticipated to be important for pharmacotherapy development of these diseases.