Regulation of distribution of extracellular Edg receptor family ligands and their physiological roles

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We examined the regulation of distribution of extracellular sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA), and their physiological roles. (1) S1P as a mediator of lipoprotein actions in vascular cells : We showed a good correlation between HDL-S1P and HDL-cholesterol. In order to identify the receptor subtypes involved in HDL and S1P actions in vascular endothelial cells, we used antis enseoligonucleotides or siRNA specific S1P receptor subtypes and demonstrated that cell survival is mainly mediated by S1P1, cell migration is by both S1P1 and S1P3, and inhibition of TNF-α-induced adhesion molecule expression is by mainly S1P1. In vascular smooth muscle cells, it was shown that S1P2 receptor mediates cAMP accumulation and inhibition of cell migration. These results suggest that S1P receptors are useful therapeutic targets for vascular diseases. (2) Characterization of an LPA receptor antagonist and its application : We characterized Ki16425 as an LPA receptor antagonist and showed that this drug is effective for inhibiting motility of cancer cells such as pancreatic cancer cells and glioma cells. (3) Role of lipid mediator in central nervous system : We identified autotaxin, a lysophospholipase D, as a neurite retraction factor in cerebrospinal fluid. (4) A novel function of lysolipid receptors : We demonstrated that TDAG8, which has been shown to be a receptor for lipid molecule psychosine, senses extracellular proton or pH, resulting in activation of adenylyl cyclase. We also demonstrated by using siRNA techniques that extracellular acidic pH induces prostaglandin production and cAMP accumulation through OGR1, one of GPCRs with a similar primary structure to TDAG8, in human vascular SMC. Thus, OGR1 family GPCRs are functional receptors for sensing extracellular pH.