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Stimulation of calcium-sensing receptor truncate human (1-84) parathyroid hormone amino-terminally

刺激钙敏感受体截短人 (1-84) 甲状旁腺激素氨基末端

基本信息

批准号：
18591033
负责人：
IMANISHI Yasuo
金额：
$ 2.53万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Cinacalcet HC1 (cinacalcet), a calcimimetic compound which activates calcium-sensing receptor (CaR), has a magnificent effect of decreasing circulating PTH levels in both primary and secondary hyperparathyroidisms. Cinacalcet also suppressed the PTH secretion in vitro in primary cultured human parathyroid cells. Recently increasing extracellular Ca^<2+> concentration reported not only to suppress (1-84) PTH secretion but also to accelerate amino-terminal (N-terminal) truncation of (1-84) PTH in vitro. Our objective was to determine whether activation of CaR would enhance this truncation activity. N-terminally truncated fragments were detectable with commercially available intact PTH (I-PTH) assays, but not with the bio-intact PTH (Bio-PTH) assays, which detected only the (1-84) PTH. Suppression of PTH secretion by increasing the extracellular Ca^<2+> concentration (0.5-3.0 mM) or cinacalcet (10-1000 nM) was more evident with the Bio-PTH assay than with I-PTH assay for both cultured parathyroid cells prepared from parathyroid adenomas and uremia-associated secondary hyperparathyroidism in vitro. The Bio-PTH/I-PTH ratio, which is the ratio of (1-84) PTH to the sum of (1-84) PTH and N-terminally truncated fragments, decreased in response to increase both in extracellular Ca^<2+> and cinacalcet concentrations. These findings suggest that the N-terminal truncation is enhanced by stimulation of CaR to suppress (1-84) PTH secretion and to generate N-terminally truncated PTH fragments.

西那卡塞盐酸盐（西那卡塞），一种激活钙敏感受体（CaR）的拟钙化合物，在原发性和继发性甲状旁腺功能亢进症中具有降低循环PTH水平的显著作用。西那卡塞还在体外抑制原代培养的人甲状旁腺细胞中的PTH分泌。最近报道，细胞外Ca^<2+>浓度的增加不仅抑制了（1-84）PTH的分泌，而且在体外加速了（1-84）PTH氨基端（N-末端）的截短。我们的目的是确定是否激活钙受体将增强这种截断活动。N-末端截短片段可通过市售完整PTH（I-PTH）检测试剂盒检测到，但不能通过仅检测（1-84）PTH的生物完整PTH（Bio-PTH）检测试剂盒检测到。对于从体外甲状旁腺腺瘤和尿毒症相关继发性甲状旁腺功能亢进中制备的培养甲状旁腺细胞，通过增加细胞外Ca^2+浓度（0.5-3.0 mM）或西那卡塞（10-1000 nM）抑制PTH分泌的作用，Bio-PTH测定法比I-PTH测定法更明显。Bio-PTH/I-PTH比值，即（1- 84）PTH与（1- 84）PTH和N-末端截短片段之和的比值，随着细胞外Ca^2+和西那卡塞浓度的增加而降低。这些发现表明，N-末端截短通过刺激CaR而增强，从而抑制（1-84）PTH分泌并产生N-末端截短的PTH片段。