Regulation of mitogen-activated protein kinases by sphingolipid products in oligodendrocytes

Sphingolipid products such as ceramide (cer), sphingosine (sph), and sphingosine-1-phosphate (SPP) are implicated in the regulation of cell growth and apoptosis. We have recently shown that cer, sph, and SPP differentially modulate ionic events in cultured oligodendrocytes (OLGs). Cer but not sph or SPP inhibits the inward rectifier (I-Kir) in OLGs. To further investigate the role of sphingolipid products in OLGs, we studied the effect of cer, sph, and SPP on OLG survival and on the regulation of mitogen-activated protein kinases (MAPKs). We found that cer, sph, and SPP differentially modulate OLG survival and activation of MAPK members. Cer causes OLG apoptosis, sph causes OLG lysis, and SPP does not affect OLG survival. Cer induces a preferential activation of p38 alpha, whereas sph and SPP induce a preferential activation of extracellular signal-regulated kinase 2 (ERK2) in OLGs. In addition, the effect of cer on p38 alpha activity is mimicked by the inhibition of I-Kir with Ba2+. In contrast, exposure to cer results in increased activity of ERK2 but not of p38 alpha in astrocytes. Cer-induced OLG apoptosis is attenuated by a p38 inhibitor, SB203580, and by expression of a p38 alpha dominant negative mutant. We conclude that p38 alpha is the mediator in cer-induced OLG apoptosis and that cer-induced I-Kir inhibition may contribute to the sustained activation of p38 alpha in OLGs.