Modulation of the activity of cytosolic phospholipase A2α (cPLA2α) by cellular sphingolipids and inhibition of cPLA2α by sphingomyelin

Abstract

This article is available online at http://www.jlr.org Arachidonic acid (AA) is a precursor of eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, playing an important role in several physiological functions ( 1 ). The biosynthesis of these AA metabolites occurs mainly through the activation of phospholipase A2 (PLA2) in response to a wide variety of stimuli such as cytokines, growth factors, and neurotransmitters ( 2 ). PLA2 catalyzes hydrolysis of the sn-2 position of glycerophospholipids to release free AA. Mammalian cells have structurally diverse forms of PLA2 including secretory PLA2, Ca 2+ -independent PLA2, and cytosolic PLA2 (cPLA2) ( 3, 4 ). Among these PLA2s, the 85 kDa cPLA2, specifi cally cPLA2 ␣ , is highly selective for glycerophospholipids containing AA. cPLA2 ␣ is regulated mainly by an increase in the intracellular Ca 2+ concentrations ([Ca 2+ ]i) and by the phosphorylation on serine residues by mitogen-activated protein kinase (MAPK) ( 3, 4 ). The binding of Ca 2+ to the C2 domain of cPLA2 ␣ triggers translocation of cPLA2 ␣ from the cytosol to the perinuclear region including the Golgi apparatus, endoplasmic reticulum (ER), and nuclear envelope. cPLA2 ␣ can be phosphorylated at Ser 505 , Ser 515 , and Ser 727 , which increases its intrinsic enzymatic activity 2-to 3-fold in vitro ( 5-8 ). Abstract

The Role of Sphingolipids in Arachidonic Acid Metabolism

“…Our laboratory has reported that SM inhibits the activity of cPLA 2 a and the release of AA (15). In that report, we showed that A23187-induced AA release was increased in LY-A cells that are defective in the ceramide transport protein CERT for SM synthesis, compared with that in control cells.…”

Lactosylceramide Interacts with and Activates Cytosolic Phospholipase A2α

“…Using this culture system, we determined whether the reduction in the cellular glycosphingolipid level affected the release of AA from cells. We previously reported that stimulation of CHO-W11A cells with A23187 or PAF induces cPLA 2 ␣-dependent AA release (11). As shown in Fig.…”

“…Thus, TNF-␣ activates cPLA 2 ␣ through the production of glycosphingolipids, especially LacCer. Previously, we reported that sphingomyelin disturbs the binding of cPLA 2 ␣ to glycerophospholipids and inhibits the release of AA (11). Numerous reports have shown that sphingomyelin is hydrolyzed to ceramide by sphingomyelinase in response to TNF-␣ (9,29,30).…”

Role of sphingomyelinases in neurological disorders

“…Interactions or crosstalk between sphingomyelin-and phosphatidylcholine-derived lipid mediators are closely associated with cell proliferation, differentiation, apoptosis, migration, and cell survival [18,74]. Sphingomyelin has a role in regulating cPLA 2 -dependent release of arachidonic acid by inhibiting the binding of cPLA 2 to glycerophospholipids [75]. In contrast, sphingomyelin-derived ceramide and ceramide 1-phosphate stimulate cPLA 2 , and in return, arachidonic acid can stimulate sphingomyelinases to generate ceramide [76,77].…”