Structure, function and regulation of Ca²⁺‐sensitive cytosolic phospholipase A2 (cPLA2)

Abstract

The 85-kDa cytosolic PLA2 (cPLA2) is present in many cells and tissues and its unusual functional properties and catalytic mechanism are being elucidated. Notably, cPLA2 becomes catalytically active in the presence of free Ca 2+ concentrations as present in stimulated cells and preferentially cleaves arachidonic acid-containing phospholipids. A variety of agonists, growth factors and cytokines, as well as stressful stimuli activate cPLA2 to hydrolyze cellular phospholipids thereby liberating fatty acids and lysophospholipids and providing the precursor substrates for the biosynthesis of eicosanoids and platelet-activating factor. These products of cPLA2 contribute to inflammatory and degenerative disease states and cPLA2 is therefore an attractive target for the development of novel therapies.

Cellular and Molecular Pathways of Ischemic Neuronal Death

“…arachidonic acid) and lysophospholipids by catalyzing the cleavage of the free fatty acid from glycerophospholipids. Arachidonic acid is further utilized for the production of prostaglandins and leukotrienes with a concomitant production of superoxide (Kramer and Sharp, 1997;Sapirstein and Bonventre, 2000). The activation of cPLA2 may contribute to neuronal death in excitotoxicity and hypoxic-ischemia.…”

Evidence that cytosolic phospholipase A2 is down‐regulated by protein kinase C in intact human platelets stimulated with fluoroaluminate

“…The chelation of intracellular Ca 2 with BAPTA completely blocked the release of labelled AA in both thrombin-and AlF 3 4 -stimulated platelets, even when preincubated with GF 109203X (Fig. 2). 3.2. cPLA 2 inhibition and release of arachidonic acid AACOCF 3 (60 WM), a speci¢c cPLA 2 inhibitor, blocked the liberation of AA induced by AlF 3 4 even in the presence of GF 109203X (Fig.…”

“…Nowadays, there is a general consensus that the activation of the Ca 2 -dependent cytosolic phospholipase A 2 (cPLA 2 ) is required for receptor-mediated liberation of AA in several cell types including human platelets [1]. The activation of this enzyme requires Ca 2 -mediated translocation and phosphorylation [1^3] but, while the requirement of an increase of cytosolic Ca 2 concentration is considered to be essential for the activation of cPLA 2 , it is still unclear whether its phosphorylation is strictly required [3]. In addition, the identity of the kinase(s) involved in receptormediated phosphorylation of cPLA 2 in intact cells is not completely de¢ned.…”

Antiplatelet activity of BRX-018, (6aS,cis)-Malonic acid 3-acetoxy-6a9-bis-(2-methoxycarbonyl-acetoxy)-6,6a,7,11b-tetrahydro-indeno[2,1-c]chromen-10-yl ester methylester

“…The stimulation of platelets with different stimuli resulted in the early activation of Ca 2+ -dependent cytosolic phospholipase A 2 (PLA 2 ), which hydrolyzes AA from the membrane phospholipids of platelets [9,10]. The liberated AA is metabolized via cyclooxygenase (COX) pathway to form endoperoxides, prostaglandins (PH), and the final products, thromboxane (TX) A 2 [11,12].…”