2001 年 21 巻 1 号 p. 39-48
Generation of prostaglandins (PGs), which are involved in a wide variety of pathophysiological processes, is regulated by three sequential enzymatic reactions. This pathway is initiated by the release of arachidonic acid (AA) by phospholipase A2s (PLA2s), followed by its conversion to PGH2 by cyclooxygenases (COXs) and then to various biologically active PGs by terminal PG synthases (tPGSs) . PLA2 comprises a growing family of enzymes, among which cytosolic PLA2 (cPLA2) and several secretory PLA2s (sPLA2s) play a crucial role in the release of AA that is supplied to downstream COXs. Activation of cPLA2 is regulated primarily by perinuclear translocation in response to increased cytoplasmic Ca2+ levels and by dual phosphorylation that is under control of the MAP kinase pathway. sPLA2-mediated eicosanoid generation occurs by two distinct (heparan sulfate- or lipid interface dependent) mechanisms. The two COX isozymes, constitutive COX-1 and inducible COX-2, are functionally segregated in different phases of cell activation. COX-1 mediates the immediate PG generation, in which high levels of AA are released in a short time, whereas COX-2 is a prerequisite for the delayed PG generation, in which low levels of AA are gradually supplied. Furthermore, these COXs are differently coupled with tPGSs, which display unique tissue and subcellular distribution. Identification of two PGE2 synthases (PGESs) reveals that the constitutive, cytosolic PGES is functionally linked with only COX-1 and the inducible, perinuclear membrane-bound PGES favors COX-2 over COX-1. Overall, our results suggest that the amounts of AA released by cPLA2 or sPLA2 and subcellular localization of COXs and tPGSs crucially affect the functional coupling among the biosynthetic enzymes in the cascade.