Many different cell types release arachidonic acid in response to stimulation. This important fatty acid is the precursor of biologically active eicosanoids such as prostaglandins, thromboxane and leukotrienes. In fact, the rate limiting step in eicosanoids production is the liberation of arachidonic acid. Although the steps involved in the release of arachidonic acid are complex and not fully understood, the main one involves phospholipase A2 (PLA2) activation and translocation to the compartments where the substrate is located. The PLA2 enzyme system is also important in the generation of platelet-activating factor (PAF). Leukotrienes, prosta-glandins, thromboxane, prostacyclin and PAF are important lipid mediators with diverse biological activities. The cytosolic form of phospholipase A2 (cPLA2), which has an apparent molecular weight of 85 kDa mediates the production of agonist-induced arachidonic acid release and plays an essential role in the release of platelet-activating factor. Activation of cPLA2 requires both the phosphorylation of the enzyme and an increase in the concentration of intracellular free calcium. The release of arachidonic acid and the generation of PAF in intact cells require that the phosphorylated cPLA2 be translocated to the compartments where the substrates are localized.
The kinases that phosphorylate cytosolic phospholipase A2 include the p42 (erk2), p44 (erk1) mitogen-activated protein kinase (MAPK), p38 MAP kinase, and other still unidentified kinases. The kinase or kinases that phosphorylate cPLA2 in intact cells following stimulation depend on the type of the stimulus used. This lipase is phosphorylated on different sites including serine 505. This phosphorylation is required for activity. However it is not clear if the phosphorylation on the other sites is required for activity. In unstimulated cells, cPLA2 is found mostly in the cytosol, and is translocated, upon stimulation, to various compartments such as nuclear envelope and endoplasmic reticulum. Depending on cell type, the released arachidonic acid is metabolized either by the cyclooxygenase enzyme system to release prostaglandins, prostacycline and thromboxane or by the lipo-oxygenase enzyme system to generate various forms of leukotriens.
Buy this Article