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Mechanisms of cyclic ADP-ribose-induced Ca^<2+> mobilization and its physiological role

环ADP核糖诱导Ca^2动员机制及其生理作用

基本信息

批准号：
13671939
负责人：
MORITA Katsuya
金额：
$ 1.98万
依托单位：
Hiroshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671939/
关键词：
cyclic ADP-ribose (cADPR)ryanodine receptor channel Ca^<2+> mobilization Ca^<2+>-induced Ca^<2+> release cADPR antagonist, 8Br-cADPR FK506 FK506-binding protein (FKBP)anti-FKBP12 12.6 antibody cyclic ADP-ribose Ca^<2+>動員作用 FK506結合タ

项目摘要

The calcium channels/ryanodine receptors (RyRs) are potential/putative target of cyclic ADP-ribose (cADPR) action in many tissue systems. However, the regulation of its synthesis in response to cell stimulation, and the mechanisms by which cADPR activates RyRs, and its functional roles are still unclear. We have demonstrated that cADPR synthesis is stimulated by cAMP-dependent mechanism. There is increasing evidence indicating that FK506 binding proteins (FKBP)12/12.6 play an important role in the regulation of the RyRs channel gating. It is believed that dissociation from RyRs activates or delays their inactivation. The present study was designed to determine whether FKBP, an accessory protein of the RyRs, plays a role in cADPR-induced activation of RyR channels and whether the physiological relevance of cADPR to the messenger role in several cells (bovine adrenal chromaffin cells, canin parotide cells and human neutrophils) using a cADPR antagonist, 8Br-cADPR, and FK506 and rapamycin … More which bind to FKBPs and dissociate them from the RyRIn permeabilized cells, cADPR-induced Ca^<2+> release but not caffeine-and ryanodine -induced Ca^<2+> release was inhibited by a cADPR antagonist, 8Br-cADPR, and FK506 and rapamycin. Furthermore, anti-FKBP 12/12.6 antibody also attenuated the cADPR-induced Ca^<2+> release. The evidence suggests that cADPR may be the ligand for FKBP-RyR complex, resulting in a dynamic regulation of RyR-mediated Ca^<2+> release. ACh and fMLP causes biphasic intracellular free Ca^<2+> concentration ([Ca^<2+>]i) rise, an initial transient rise followed by sustained rise, in intact cells. 8Br-cADPR, FK506 and rapamycin but not cyclospolin A specifically reduced the sustained phases of stimulation-induced [Ca^<2+>]i rise, suggesting that cADPR contributes to sustained [Ca^<2+>]_i rise. 8Br-cADPR, FK506, and rapamycin reduced ACh-induced adrenal catecholamine release and fMLP-induced neutrophils migrationThese results provide evidence that the synthesis of cADPR is regulated by cell stimulation, and the cADPR/Ca^<2+>-induced Ca^<2+> release pathway forms a positive feedback to stimulation-induced response Less

钙通道/兰尼碱受体（RyR）是许多组织系统中环ADP-核糖（cADPR）作用的潜在/推定靶点。然而，其合成的调节响应于细胞刺激，和cADPR激活RyRs的机制，其功能作用仍然不清楚。我们已经证明，cADPR的合成是由cAMP依赖性机制刺激。越来越多的证据表明FK 506结合蛋白（FKBP）12/12.6在RyRs通道门控的调节中起重要作用。据信从RyR解离激活或延迟其失活。本研究旨在使用cADPR拮抗剂8 Br-cADPR、FK 506和雷帕霉素确定FKBP（RyR的辅助蛋白）是否在cADPR诱导的RyR通道激活中发挥作用，以及cADPR与几种细胞（牛肾上腺嗜铬细胞、犬腮腺细胞和人中性粒细胞）中信使作用的生理相关性 ...更多信息 cADPR拮抗剂8 Br-cADPR、FK 506和雷帕霉素可抑制cADPR诱导的Ca^2+释放，但不抑制咖啡因和兰尼碱诱导的Ca^2+释放。此外，抗FKBP 12/12.6抗体也减弱cADPR诱导的Ca^<2+>释放。这表明cADPR可能是FKBP-RyR复合物的配体，对RyR介导的Ca^2+释放具有动态调节作用。ACh和fMLP可引起完整细胞内游离Ca^2+浓度（[Ca^2+]i）的双相升高，即先短暂升高后持续升高。8Br-cADPR、FK 506和雷帕霉素特异性地降低刺激诱导的[Ca^2+]i升高的持续时相，而环孢素A则没有，表明cADPR有助于[Ca^2+] i的持续升高。8Br-cADPR、FK 506和雷帕霉素减少ACh诱导的肾上腺儿茶酚胺释放和fMLP诱导的中性粒细胞迁移这些结果提供了证据，证明cADPR的合成受细胞刺激的调节，cADPR/Ca^<2 +>诱导的Ca^<2+>释放途径对刺激诱导的反应形成正反馈。