Signaling events mediating activation of brain ethanolamine plasmalogen hydrolysis by ceramide.
Ceramide is a lipid second messenger that acts on multiple-target enzymes, some of which are involved in other signal-transduction systems. We have previously demonstrated that endogenous ceramide modifies the metabolism of brain ethanolamine plasmalogens. The mechanism involved was studied. On the basis of measurements of breakdown products, specific inhibitor effects, and previous findings, we suggest that a plasmalogen-selective phospholipase A2 is the ceramide target. Arachidonate-rich pools of the diacylphosphatidylethanolamine subclass were also affected by ceramide, but the most affected were plasmalogens. Concomitantly with production of free arachidonate, increased 1-O-arachidonoyl ceramide formation was observed. Quinacrine (phospholipase A2 inhibitor) and 1-O-octadecyl-2-O-methyl-rac-glycerol-3-phosphocholine (CoA-independent transacylase inhibitor) prevented all of these ceramide-elicited effects. Therefore, phospholipase and transacylase activities are tightly coupled. Okadaic acid (phosphatase 2A inhibitor) and PD 98059 (mitogen-activated protein kinase inhibitor) modified basal levels of ceramide and sphingomyelinase-induced accumulation of ceramide, respectively. Therefore, they provided no evidence to determine whether there is a sensitive enzyme downstream of ceramide. The evidence shows that there are serine-dependent and thiol-dependent enzymes downstream of ceramide generation. Furthermore, experiments with Ac-DEVD-CMK (caspase-3 specific inhibitor) have led us to conclude that caspase-3 is downstream of ceramide in activating the brain plasmalogen-selective phospholipase A2.
Latorre
Eduardo
E
Departamento de Bioquímica y Biología Molecular I, Facultad de Químicas, Universidad Complutense de Madrid, Madrid, Spain.
Collado
M Pilar
MP
Fernández
Inmaculada
I
Aragonés
M Dolores
MD
Catalán
R Edgardo
RE
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism* / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006868:Hydrolysis; D008297:Male; D019319:Okadaic Acid / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D010742:Phospholipid Ethers / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010955:Plasmalogens / Q000378:metabolism*; D054648:Protein Phosphatase 2; D011796:Quinacrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D061945:Caspase Inhibitors; D002518:Ceramides; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D005419:Flavonoids; C064769:N-acetylsphingosine; D010742:Phospholipid Ethers; D010955:Plasmalogens; C020791:phosphatidal ethanolamines; D019319:Okadaic Acid; C026659:edelfosine; D010741:Phospholipases A; D054467:Phospholipases A2; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D013108:Sphingomyelin Phosphodiesterase; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D011796:Quinacrine; D013110:Sphingosine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one