Biological functions of Sphingolipids and their relevance to pathological phenomena

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Sphingosine 1-phosphate (S1P) have important roles in vascular and immune system, acting through a family of G-protein coupled receptor. In this decade, S1P and its receptor are emerged as a new target of drag discovery. In this research, we found different regulation of gene transcription between sphingosine kinase 1 and 2, and added new insights in the mechanism of S1P-pridution. Although S1P in the blood has been considered from platelet, we showed that the red blood cells could be new supplier of S1P. In the research of S1P-receptor, we revealed that C-terminal palmitation of S1P-receptor regulated agonist-stimulating internalization of S1P-receptor, leading to its cellular functions. The synthetic agonist of S1P-receptor, FTY-720, is a candidate of new immune suppressor, regulating lymphocyte migration. However, the detail working mechanisms of FTY-720 is not fully elucidated. We showed new metabolic pathway of FTY-720 which include the LPP-familly phosphatase.We also researched another bioactive sphingolipid, ceramide (Cer). We identified a new Cer-synthase, LAS3 (CerS3). The LAS3 could transfer longer fatty acid than LAS5 which was previously identified as Cer-sythase. Since one of the feature of sphingolipid is having long chain in its structure, LAS3 might be important for biosynthesis of long-chain sphingolipid. One the other hand, we also researched ceramide kinase (CERK), newly discovered Cer-metabolizing enzyme, and demonstrated that CERK was highly expressed at Purkinje cell in cerebellum, and might be involved in emotional behavior using CERK-knock out mice.As described above, we revealed new mechanisms and functions in S1P, S1P-receptor, Cer, and Cer-metabolite through this research.