FIGURE 1. Intracellular regulation of ceramide, sphingosine and sphingosine-1-phosphate.

A variety of cell receptor agonists and environmental stimuli sequentially and/or selectively activate sphingomyelinases (that cleave the phosphocholine group of sphingomyelin to yield ceramide), ceramidases (that cleave the fatty acid chain of ceramide to form SPH), and sphingosine kinases (that phosphorylate SPH in its primary hydroxyl group to form S1P). Consequently, the levels of ceramide, SPH, S1P, or a combination of these lipids are elevated in cells [10]. All of them are bioactive lipids that can activate or inhibit various signaling pathways by affecting key signaling proteins. The actions of ceramide and SPH in many cell systems oppose those of S1P. S1P can act as a second messenger inside cells. Although the exact targets are unknown, it has been reported to affect a variety of calcium channels. S1P can be exported outside cells by transporters and bind a family of GPCR coupled receptors (S1P_1-5) present at the plasma membrane. Some isoforms of sphingomyelinase, ceramidase, and sphingosine kinase can be secreted under certain conditions, and the activation of these secreted enzymes can generate sphingolipid metabolites in the extracellular environment. Enzymes involved in the degradation of S1P (S1P phosphatases and S1P lyase) are also critical for the fine-tuning of S1P levels inside and outside cells. For clarity, the generation of sphingolipid metabolites is depicted at the inner leaflet of the plasma membrane, probably the major active signaling pool, but other intracellular membrane locations are possible (see reviews for more details [2, 10, 107, 108]).