Cellular components that functionally interact with signaling phospholipase A(2)S

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 (PC) biosynthesis. Arachidonic acid (AA) released by cPL A(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. Vimenti n, an intermediate filament component, acts as a functional perinuclear ada pter for cPLA(2), in which the C2 domain of cPLA(2) associates with the hea d domain of vimentin in a Ca2+-sensitive manner. The heparin-binding signal ing sPLA(2)-IIA, IID and V bind the glycosylphosphatidylinositol-anchored h eparan sulfate proteoglycan glypican, which plays a role in sorting of thes e isozymes into caveolae and perinuclear compartments. Phospholipid scrambl ase, which facilitates transbilayer movement of anionic phospholipids, rend ers the cellular membranes more susceptible to signaling sPLA(2)s. There is functional cooperation between cPLA(2) and signaling sPLA(2)s in that prio r activation of cPLA(2) is required for the signaling sPLA(2)s to act prope rly. 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 ca pable of releasing AA from intact cells in the absence of cofactors. This p roperty is attributed to its ability to avidly hydrolyze zwitterionic phosp hatidylcholine, 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 cofac tors and interfacial binding to membrane phospholipids, which differ accord ing to cell type, stimuli, secretory processes, and subcellular distributio ns. (C) 2000 Elsevier Science B.V. All rights reserved.