While the role of the group IVA Ca2+-dependent cytosolic phospholipase A2α (cPLA2α) in arachidonic acid (AA) metabolism has been well documented, that of its paralogue, Ca2+-independent group IVC PLA2 (cPLA2γ), has remained uncertain. Here we show, using a transfection strategy, that cPLA2γ has the ability to increase the spontaneous and stimulus-induced release of cellular fatty acids. The AA released by cPLA2γ was metabolized further to prostaglandin E2 via cyclo-oxygenase-1 (COX-1) in the immediate response, and via COX-2 in the delayed response. Mutation of the putative catalytic-centre residue Ser82 abrogated the AA-releasing function of cPLA2γ both in vitro and in vivo. Confocal microscopy revealed that cPLA2γ was distributed in the perinuclear endoplasmic reticulum membranes. Mutating the C-terminal prenylation site of cPLA2γ abrogated its intracellular membrane localization and cellular AA-releasing function, without reducing its enzyme activity in vitro. Our results indicate that cPLA2γ is the second cPLA2 enzyme that contributes to cellular AA metabolism and phospholipid remodelling under appropriate conditions.

Abbreviations used: AA, arachidonic acid; COX, cyclo-oxygenase; ER, endoplasmic reticulum; FCS, fetal calf serum; HEK, human embryonic kidney; IL-1, interleukin-1; MAFP, methyl arachidonyl fluorophosphate; MAPK, mitogen-activated protein kinase; OA, oleic acid; PGE2, prostaglandin E2; PLA2, phospholipase A2; cPLA2, cytosolic phospholipase A2; iPLA2, Ca2+-independent PLA2; sPLA2, secretory PLA2; TBS, Tris-buffered saline; WT, wild-type.

This content is only available as a PDF.