Signal Transduction and Arachidonic Acid Metabolism in the Aid Drug of Development

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We have investigated the broad and basic problems about the signal transduction and arachidonic acid metabolism in the aid of drug development, focused on following three points ;1. Studies on signal transduction for initiating arachidonic acid metabolism.(1) A gene cloning for group ll phospholipase A2 was performed, and a proteinous enzyme inhibitor was isolated (lnoue). (2) PGE stimulated phospnorylation of smg p21 of G protein through activated A kinase (Takai). (3) A serum-dependent growth decreased a new type of nuclear G protein in 3T3 cells (Natori). (4) Synthesis of PAF in neutrophil and of TNF in macrophage was inhibited by a-Linoleate in rats. (5) Arachidonic acid stimulated a translocation of a new proteinous factor from cytoplasm to membrane, which activated NADPH oxidase (Ishibashi).2. Screening of new compounds acting on inhibition of arachidonic acid metabolism.(1) Furavonoid derivative, cirsillol, selectively inhibited 5-lipoxygenase (Yamamoto).(2) TMK-688 inhibited both 5-lipoxygenase and receptor-mediated hitamine action (Murata).3. Receptors for arachidonic acid metabolites. (1) TAX2 receptor was isolated and its gene was cloned from human platelets (Narumiya). (2) LTD4 recrptor from guinea pig lung was solubilized and characterized, and cDNA for PAF was cloned (Shimizu).(3) Receptor for PGD2 was controlled by phosphorylation-dephosphorylation reaction (ichikawa). (4) Translocation of membrane Gia into cytosol acted on down regulation of thrombin-stimulated mast cells (Ichikawa).