Effects of ceramide, ceramidase inhibition and expression of ceramide kinase on cytosolic phospholipase A2α; additional role of ceramide-1-phosphate in phosphorylation and Ca2+ signaling

Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8675, Japan.
Cellular Signalling (Impact Factor: 4.32). 03/2009; 21(3):440-7. DOI: 10.1016/j.cellsig.2008.11.014
Source: PubMed


Ceramide and the metabolites including ceramide-1-phosphate (C1P) and sphingosine are reported to regulate the release of arachidonic acid (AA) and/or phospholipase A(2) (PLA(2)) activity in many cell types including lymphocytes. Recent studies established that C1P, a product of ceramide kinase, interacts directly with Ca(2+) binding regions in the C2 domain of alpha type cytosolic PLA(2) (cPLA(2)alpha), leading to translocation of the enzyme from the cytosol to the perinuclear region in cells. However, a precise mechanism for C1P-induced activation of cPLA(2)alpha has not been well elucidated; such as the phosphorylation signal caused by the extracellular signal-regulated kinases (ERK1/2) pathway, a downstream of the protein kinase C activation with 4beta-phorbol myristate acetate (PMA), is required or not. In the present study, we showed that the increase in intracellular ceramide levels (exogenously added cell permeable ceramides and an inhibition of ceramidase by (1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol and the increase in C1P formation by transfection with the vector for human ceramide kinase significantly enhanced the Ca(2+) ionophore (A23187) -induced release of AA via cPLA(2)alpha's activation in CHO cells. Ceramides did not show additional effects on the release from the cells treated with the inhibitor of ceramidase. Ceramides and C2-C1P neither had effect on the intracellular mobilization of Ca(2+) nor the phosphorylation of cPLA(2)alpha in cells. A23187/PMA-induced release of AA was enhanced by ceramides and C2-C1P and by expression of ceramide kinase. Our findings suggest that C1P is a stimulatory factor on cPLA(2)alpha that is independent of the Ca(2+) signal and the PKC-ERK-mediated phosphorylation signal.

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    • "D-e-MAPP resulted in blockage of progestin and adiponectinreceptor (PAQR), involving SLs, and ceramidases downstream of PAQR signalling, an important hormone receptor related to pathological conditions, including obesity, diabetes and coronary artery disease (Kupchak et al., 2009). Other studies have shown D-e-MAPP, as well as exogenous short length acyl-ceramides, to enhance the A23187 (Ca 2+ ionophore)-induced release of arachidonic acid, associated with an increase of endogenous ceramide accumulation (Shimizu et al., 2009). Modifications of the structure of D-e-MAPP led to B13 ((1R,2R)-2- (N-tetradecanoylamino)-1- (4-nitrophenyl)-1,3- propanediol), a more water soluble form. "
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