Regulation of extracellular S1P concentration and mechanisms of the lipid receptor subtype-specific actions

细胞外 S1P 浓度的调节和脂质受体亚型特异性作用的机制

基本信息

批准号：
12480185
负责人：
OKAJIMA Fumikazu
金额：
$ 9.22万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

Sphingosine 1-phosphate (S1P) exerts a variety of cellular responses including proliferation, differentiation, adhesion, motility and apoptosis through G-protein-coupled S1P receptors (Edg-I, -3, -5, -6, -8). Here, we established a novel quantitative method for S1P and investigated its function and action mechanisms. (1) We established a novel quantitative method for S1P based on the ligand competition on S1P receptor Edg-1. We found that the tight binding of S1P to the lipoproteins especially HDL may interferes with S1P binding to its receptors and thereby might protect the cells from "over-activation" of S1P receptors. (2) It is well known that HDL is inversely correlated with the risk of cardiovascular disease, such as atherosclerosis. The pharmacological and molecular biological analyzes demonstrated that S1P is a major component of HDL in the lipoprotein-induced endothelial cell migration and survival. The HDL or lipid-induced actions may be mediated through the lipid receptors, S1P_1/Edg-1 and S1P_3 /Edg-3.(3) In rat type I astrocytes and C6 glioma cells, we found a differential roles of Edg-1 (stimulation of Erk/bFGF system) and Edg-5 (increase in intracellular calcium concentration and stimulation phospholipase C and D). We also found that HDL mimicked these actions and their actions are mediated by S1P/S1P receptors. Thus, S1P might partially mediate lipoprotein-induced cholesterol metabolism-independent neural cell functions in the central nervous system

1-磷酸鞘氨酸（S1P）通过G蛋白偶联的S1P受体（EDG -I，-3，-5，-5，-6，-8）发挥各种细胞反应，包括增殖，分化，粘附，运动和凋亡。在这里，我们建立了一种用于S1P的新型定量方法，并研究了其功能和动作机制。（1）我们基于S1P受体EDG-1的配体竞争建立了一种新的S1P定量方法。我们发现，S1P与脂蛋白特别HDL的紧密结合可能会干扰S1P与其受体结合，从而可以保护细胞免受S1P受体的“过度激活”的影响。（2）众所周知，HDL与心血管疾病（例如动脉粥样硬化）的风险成反比。药理和分子生物学分析表明，S1P是脂蛋白诱导的内皮细胞迁移和存活中HDL的主要组成部分。 The HDL or lipid-induced actions may be mediated through the lipid receptors, S1P_1/Edg-1 and S1P_3 /Edg-3.(3) In rat type I astrocytes and C6 glioma cells, we found a differential roles of Edg-1 (stimulation of Erk/bFGF system) and Edg-5 (increase in intracellular calcium concentration and stimulation phospholipase C and D).我们还发现，HDL模仿了这些动作，它们的作用是由S1P/S1P受体介导的。因此，S1P可能部分介导脂蛋白诱导的胆固醇代谢与中枢神经系统中的神经细胞功能