Molecular Mechanism of production and secretion of platelet-derived bioactive lysolipids

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The receptors for serum-borne lysophospholipid mediators such as sphingosine1-phosphate (S1P) and lysophosphatidic acid (LPA) was identified in these several years and their physiological and pathophysiological roles have been strongly concerned. These bioactive lipids were observed to be released from activated platelets, but the detailed mechanism of their production, secretion and degradation have not been thoroughly studied. Therefore, in this three years Japan-USA research project, we have tried to clarify the molecular mechanism of production, secretion, and degradation of these bioactive lysolipids in the strong collaboration between Japanese and American groups.Through the collaboration we tried and found the following results. (1) Blood S1P is derived mainly from stimulated platelets and LPA is partially released from stimulated platelets but mostly produced in the blood by phospholipases which are released from activated platelets with the aids of lysophospholipase D. (2) We partially purified the responsible phospholipases which produce the lysophospholipids from the blood phospholipids. (3) The involvement of ABC transporter in S1P releasing from platelets was found but we could not determine the specific ABC transporter involved. (4) We identified for the first time a sphingolipid transporter RSB 1, a ATP-dependent new type of six transmembrane transporter, which can exclude the over-loaded DHS and PHS from yeast cells (5) We determined the molecular mechanism of ligand-receptor interaction utilizing computational model of Edg-6 (S1P6)/S1P interaction.By these collaboration studies we enriched our knowledge how the metabolism and functions of the blood-borne bioactive lysolipids such as LPA and S1P are regulated, indicating the importance of the regulations of these lysolipids in blood vessel biology and pathology.