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Study on mechanism of newly found reverse signaling system in platelets

新发现的血小板反向信号系统机制研究

基本信息

批准号：
10672047
负责人：
SUGATANI Junko
金额：
$ 2.05万
依托单位：
University of Shizuoka
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

Platelet-activating factor (PAF) is one of the most potent platelet agonists that promote platelet aggregation through its specific receptor. The binding of PAF to platelet receptors triggers intracellular responses such as activation of phospholipase C, D and AィイD22ィエD2 and many kinases and increases in cytosolic CaィイD12+ィエD1 concentration, which have been considered to occur transiently in association with platelet aggregation and serotonin secretion. The present study demonstrates that human and rabbit platelets fully aggregated by PAF were rapidly disaggregated by the PAF receptor antagonists. Accordingly, continuous binding of PAF to its receptor is considered to be necessary for prolonged platelet aggregation, which may be mediated through an unknown signaling system for a long-term cell response rather than a transient signaling system (Ref. 1). Most of PAF bound to platelets was metabolized extracellularly by ecto-type PAF acetylhydrolase. In order to clarify in more detail the binding behavior of PAF to its receptor, we investigated effects of intracellular signal transduction inhibitors such as many phosphatase inhibitors and kinase inhibitors on platelet disaggregation. The results suggested the presence of newly found reverse signaling system, which causes shape change and disaggregation of platelets. In addition, we found that extracellular CaィイD12+ィエD1 blocker nucleoside 5'-alkylphosphates (Ref. 5).

血小板活化因子（PAF）是最强的血小板激动剂之一，通过其特异性受体促进血小板聚集。PAF与血小板受体的结合引发细胞内反应，如磷脂酶C、D和A β D22、D β D2和许多激酶的活化以及胞浆Ca β D12+ D β D1浓度的增加，这些反应被认为与血小板聚集和5-羟色胺分泌有关。本研究表明，人和兔血小板完全聚集的PAF迅速解聚的PAF受体拮抗剂。因此，认为PAF与其受体的持续结合是延长血小板聚集所必需的，这可能是通过未知的信号系统而不是瞬时信号系统介导的长期细胞应答（参考文献1）。与血小板结合的PAF大部分通过胞外型PAF乙酰水解酶在细胞外代谢。为了更详细地阐明PAF与其受体的结合行为，我们研究了细胞内信号转导抑制剂如多种磷酸酶抑制剂和激酶抑制剂对血小板解聚的影响。结果表明，存在新发现的反向信号系统，导致血小板的形状变化和解聚。此外，我们发现细胞外Ca ~（2+）D_12 + Ca ~（2+）D_1阻断剂核苷5 '-烷基磷酸盐（参考文献5）。