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

1-磷酸鞘氨醇（Sphingosine 1-phosphate，S1 P）通过G蛋白偶联的S1 P受体（Edg-I，-3，-5，-6，-8）发挥多种细胞反应，包括增殖、分化、粘附、运动和凋亡。本文建立了一种新的S1 P定量方法，并对其功能和作用机制进行了研究。(1)我们建立了一种基于配体竞争作用于S1 P受体Edg-1的定量分析方法。我们发现，S1 P与脂蛋白尤其是HDL的紧密结合可能会干扰S1 P与其受体的结合，从而可能保护细胞免受S1 P受体的“过度激活”。(2)众所周知，HDL与心血管疾病如动脉粥样硬化的风险呈负相关。药理学和分子生物学分析表明，S1 P是HDL在脂蛋白诱导的内皮细胞迁移和存活中的主要成分。HDL或脂质诱导的作用可以通过脂质受体S1P_1/Edg-1和S1P_3 /Edg-3介导。(3)在大鼠I型星形胶质细胞和C6胶质瘤细胞中，我们发现Edg-1（Erk/bFGF系统的刺激）和Edg-5（细胞内钙浓度增加和刺激磷脂酶C和D）的不同作用。我们还发现HDL模拟这些作用，并且它们的作用是由S1 P/S1 P受体介导的。因此，S1 P可能部分介导脂蛋白诱导的胆固醇代谢非依赖性中枢神经系统神经细胞功能

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