The sphingomyelin cycle and the second messenger function of ceramide.

It is now well established that glycerophospholipids and their metabolic products (such as diacylglycerol (DAG), inositol trisphosphate, eicosanoids, and platelet-activating factor) function in signal transduction and cell regulation (14). On the other hand, a role for membrane sphingolipids in signal transduction has not been well appreciated although sphingolipids exhibit even greater structural diversity and complexity than glycerolipids (5-7). Much of the current understanding of sphingolipid structure and function, however, has focused on the carbohydrate headgroups of the glycosphingolipids (8). The discovery of inhibition of protein kinase C by sphingosine (9) directed attention to the lipid components of sphingolipids and suggested the hypothesis that sphingolipid-derived products may function as second messengers (6). Evidence in support of this hypothesis came with the recent elucidation of the sphingomyelin (SM) cycle and the physiologic functions of ceramide (10, 11). Current results show that the action of a number of extracellular agents results in early activation of a sphingomyelinase that cleaves membrane SM resulting in the formation of ceramide. In turn, ceramide has emerged as a potential mediator of the effects of these extracellular agents on cell growth, differentiation, and apoptosis. In cells, ceramide has been shown to modulate protein phosphorylation, the activity of protein kinases, the levels of the c-myc protooncogene, the nuclear factor KB, the activity of phospholipase A2, and prostaglandin release. In uitro, ceramide activates a serindthreonine protein phosphatase with evidence beginning to implicate this phosphatase in the cellular mechanism of action of ceramide. Where examined, the effects of ceramide show structural and stereospecificity commensurate with physiologic roles for the naturally occurring D-eythro-ceramide. Therefore, these studies are beginning to define a novel ceramide-dependent pathway of signal transduction (Fig. 1). This minireview will highlight these developments in our understanding of the SM cycle and the physiologic function of ceramide and its mechanism of action.