Regulatory Mechanism and Physiological Role of Cytosolic Phospholipase A2

Abstract

Cytosolic phospholipase A 2 a a (cPLA 2 a a) preferentially hydrolyzes phospholipids containing arachidonic acid and plays a key role in the biosynthesis of eicosanoids. This review discusses the essential features of cPLA 2 a a regulation and addresses new insights into the functional properties of this enzyme. Full activation of the enzyme requires Ca 2؉ binding to an N-terminal C2 domain and phosphorylation on serine residues. Ca 2؉ binding induces translocation of cPLA 2 a a from the cytosol to the perinuclear membranes. Serine phosphorylation is mediated by mitogen-activated protein kinases (MAPKs), Ca 2؉ /calmodulin-dependent protein kinase II, and MAPK-interacting kinase Mnk1. Interaction with proteins and lipids, which include vimentin, annexins, NADPH oxidase, phosphatidylcholine, phosphatidylinositol 4,5-bisphosphate (PIP 2 ), and ceramide-1-phosphate, can also modulate the activity of cPLA 2 a a. Recent evidence has established the physiological and pathological roles of cPLA 2 a a using cPLA 2 a a knockout mice. This enzyme has been implicated in fertility, striated muscle growth, renal concentration, postischemic brain injury, arthritis, inflammatory bone resorption, intestinal polyposis, pulmonary fibrosis, acute respiratory distress syndrome, and autoimmune encephalomyelitis. Now novel three paralogs, cPLA 2 b b, cPLA 2 g g, and cPLA 2 d d, have been identified in humans. cPLA 2 g g is distinct from others in that it is farnesylated and lacks the C2 domain. Biological roles for these new enzymes have not yet been defined.

Signaling Role for Lysophosphatidylcholine Acyltransferase 3 in Receptor-Regulated Arachidonic Acid Reacylation Reactions in Human Monocytes

“…Cell stimulation by a variety of agonist receptors leads to the activation of another PLA 2 form, the group IVA, calcium-dependent cytosolic PLA 2 a (cPLA 2 a), which then becomes the dominant PLA 2 involved in AA release (15)(16)(17)(18)(19). Under stimulation conditions, the rate of AA release clearly exceeds that of reincorporation into PLs, hence net accumulation of AA occurs that is followed by its conversion into different eicosanoids.…”

Altered Endothelin-1 Signaling in Production of Thromboxane A2 in Kupffer Cells from Bile Duct Ligated Rats

“…The primary means by which AA is released from membranes is the agonist induced activation of the calcium dependent group IV  isoform of cPLA 2 , due to its high specificity and selectivity for glycerophospholipids containing AA at the sn-2 position. Although the agonist induced activation of cPLA 2  has been established as the rate limiting step of eicosanoid biosynthesis (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), the deacylation of diacylglycerol (DAG) via DAG lipase also produces AA for the synthesis of eicosianoids. In addition, DAG lipase has been suggested to mediate the release of AA in KCs (56,62).…”

“…In the same model, we have also shown that the fibrotic stress primes KCs for the release of TXA 2 by inducing the upregulation of cytosolic phopholipase A 2 (cPLA 2 ), COX-2, and thromboxane synthase (TS) (10), the three key enzymes for its biosynthesis (11)(12)(13)(14)(15)(16). cPLA 2 is critical for the production of AA-derived eicosanoids due to its high specificity and selectivity for glycerophospholipids containing AA at the sn-2 position (17)(18)(19). The significance of cPLA 2 in eicosanoid production is further evident as cells and tissues from cPLA 2 -deficient mice fail to produce prostaglandins, leukotrienes, and thromboxanes (20,21).…”

“…The significance of cPLA 2 in eicosanoid production is further evident as cells and tissues from cPLA 2 -deficient mice fail to produce prostaglandins, leukotrienes, and thromboxanes (20,21). It is established that the primary function of cPLA 2  is to mediate agonist-induced release of AA for eicosanoid production (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). The regulation of cPLA 2 activity involves multiple components.…”

Effects of Synthetic Sphingosine-1-Phosphate Analogs on Cytosolic Phospholipase A2α–Independent Release of Arachidonic Acid and Cell Toxicity in L929 Fibrosarcoma Cells: the Structure–Activity Relationship

“…cPLA 2 α (group IVA) plays a pivotal role in providing AA because of its selectivity for phospholipds containing AA at the sn-2 position (4, 10). In group IV, cPLA 2 β (IVB), and cPLA 2 γ (IVC) require Ca 2+ for their activity, and newly identified isoforms of cPLA 2 including δ, ε, and ζ subtypes did not appear to have a preference for AA in phospholipids (10,11). So far, the Ca 2+ -independent PLA 2 (group VIA and VIB) family and some of the Group IV family show Ca 2+ -independent activity (12,13).…”