Signaling events mediating activation of brain ethanolamine plasmalogen hydrolysis by ceramide

Abstract

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 A 2 is the ceramide target. Arachidonaterich 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 A 2 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 sphingomyelinaseinduced 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 A 2 .

Inhibitors of Brain Phospholipase A2Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders

“…Other glycosphingolipids, such as cerebrosides and sulfatides, have no effect. However, ceramide markedly stimulates PlsEtn-PLA 2 activity in a time-and dose-dependent manner (Latorre et al, 2003). Treatment of rat brain slices with Staphylococcus aureus sphingomyelinase or C2-ceramide produces a marked decrease in PlsEtn levels, suggesting stimulation of PlsEtn-PLA 2 activity.…”

“…Treatment of rat brain slices with Staphylococcus aureus sphingomyelinase or C2-ceramide produces a marked decrease in PlsEtn levels, suggesting stimulation of PlsEtn-PLA 2 activity. Bromoenol lactone, a potent inhibitor of iPLA 2 , does not affect this stimulation, but quinacrine and gangliosides, nonspecific inhibitors of PlsEtn-PLA 2 , completely block it (Latorre et al, 2003;Yang et al, 1994a,b). These studies have led to the suggestion that the degradation of plasmalogen by PlsEtn-PLA 2 is a receptormediated process Farooqui et al, 2003a;Latorre et al, 2003) and may involve an interaction between plasmalogen metabolism and sphingolipid metabolism.…”

Role of sphingomyelinases in neurological disorders

“…The P2X7 purinergic receptor affects levels of several lipid messengers including arachidonic acid, diacylglycerol, phosphatidic acid, and ceramide via modulation of phospholipases A 2 , C, D, and N-SMase [79]. Sphingomyelinase and ceramide decrease the levels of plasmalogen, a vinylether group containing phospholipid, which acts as an antioxidant through the action of plasmalogenselective PLA 2 (iPLA 2 ) [80,81]. Decrease in plasmalogens induced by sphingomyelinase or ceramide is inhibited by quinacrine and bromoenol lactone, which are inhibitors of iPLA 2 [81,82].…”

Studies on Plasmalogen-Selective Phospholipase A2 in Brain

“…The cause of the increased PlsEtn-PLA 2 activity is not fully understood. However, it is becoming increasingly evident that ceramide, a lipid mediator of sphingolipid metabolism, stimulates PlsEtn-PLA 2 activity in a dose-dependent manner [13]. So increase in PlsEtn-PLA 2 activity may be due to the accumulation of ceramide in brain from AD patients [14,15].…”