Murakami M, Nakatani Y, Kuwata H, Kudo I
Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, 142-8555, Tokyo, Japan.
Biochim Biophys Acta. 2000 Oct 31;1488(1-2):159-66. doi: 10.1016/s1388-1981(00)00118-9.
Accumulating evidence has suggested that cytosolic phospholipase A(2) (cPLA(2)) and several secretory PLA(2) (sPLA(2)) isozymes are signaling PLA(2)s that are functionally coupled with downstream cyclooxygenase (COX) isozymes for prostaglandin (PG) biosynthesis. Arachidonic acid (AA) released by cPLA(2) and sPLA(2)s is supplied to both COX-1 and COX-2 in the immediate, and predominantly to COX-2 in the delayed, PG-biosynthetic responses. Vimentin, an intermediate filament component, acts as a functional perinuclear adapter for cPLA(2), in which the C2 domain of cPLA(2) associates with the head domain of vimentin in a Ca(2+)-sensitive manner. The heparin-binding signaling sPLA(2)-IIA, IID and V bind the glycosylphosphatidylinositol-anchored heparan sulfate proteoglycan glypican, which plays a role in sorting of these isozymes into caveolae and perinuclear compartments. Phospholipid scramblase, which facilitates transbilayer movement of anionic phospholipids, renders the cellular membranes more susceptible to signaling sPLA(2)s. There is functional cooperation between cPLA(2) and signaling sPLA(2)s in that prior activation of cPLA(2) is required for the signaling sPLA(2)s to act properly. cPLA(2)-derived AA is oxidized by 12/15-lipoxygenase, the products of which not only augment the induction of sPLA(2) expression, but also cause membrane perturbation, leading to increased cellular susceptibility to the signaling sPLA(2)s. sPLA(2)-X, a heparin-non-binding sPLA(2) isozyme, is capable of releasing AA from intact cells in the absence of cofactors. This property is attributed to its ability to avidly hydrolyze zwitterionic phosphatidylcholine, a major phospholipid in the outer plasma membrane. sPLA(2)-V can also utilize this route in several cell types. Taken together, the AA-releasing function of sPLA(2)s depends on the presence of regulatory cofactors and interfacial binding to membrane phospholipids, which differ according to cell type, stimuli, secretory processes, and subcellular distributions.
越来越多的证据表明，胞质磷脂酶A2（cPLA2）和几种分泌型磷脂酶A2（sPLA2）同工酶是信号磷脂酶A2，它们在功能上与下游环氧化酶（COX）同工酶偶联，参与前列腺素（PG）的生物合成。cPLA2和sPLA2释放的花生四烯酸（AA）在即时PG生物合成反应中同时供应给COX-1和COX-2，在延迟的PG生物合成反应中主要供应给COX-2。波形蛋白是一种中间丝成分，作为cPLA2的功能性核周衔接蛋白，其中cPLA2的C2结构域以Ca2+敏感的方式与波形蛋白的头部结构域结合。肝素结合信号sPLA2-IIA、IID和V与糖基磷脂酰肌醇锚定的硫酸乙酰肝素蛋白聚糖磷脂酰肌醇蛋白聚糖结合，后者在将这些同工酶分选到小窝和核周区室中起作用。促进阴离子磷脂跨双层移动的磷脂翻转酶使细胞膜更容易受到信号sPLA2的影响。cPLA2和信号sPLA2之间存在功能协同作用，即信号sPLA2要正常发挥作用需要cPLA2预先激活。cPLA2衍生的AA被12/15-脂氧合酶氧化，其产物不仅增强sPLA2表达的诱导，还会引起膜扰动，导致细胞对信号sPLA2的敏感性增加。sPLA2-X是一种不与肝素结合的sPLA2同工酶，能够在没有辅因子的情况下从完整细胞中释放AA。这种特性归因于其能够 avidly水解两性离子磷脂酰胆碱，这是质膜外的一种主要磷脂。sPLA2-V在几种细胞类型中也可以利用这条途径。综上所述，sPLA2的AA释放功能取决于调节辅因子的存在以及与膜磷脂的界面结合，这因细胞类型、刺激、分泌过程和亚细胞分布而异。
