y analogy to inositol (1,4,5)trisphosphate [Ins(1,4,5)P 3 ] and diacylglycerol (DAG), sphingoid-based lipids (sphingolipids) were initially considered to exert their effects as second messenger molecules. This was based on the finding that DAG activates protein kinase C (PKC) (both the classical and novel isozyme variant), whereas lysosphingolipids competitively inhibit this enzyme. Cloning of endothelial differentiation genes EDG1, EDG3, EDG5 and EDG6, which are specific G-protein-coupled receptors for sphingosine-1-phosphate (S1P) 1 , and the secretion of S1P by stimulated platelets and mast cells, shifted attention to their 'outside in' mediator function 2 .
In the traditional model of eukaryotic membranes, lipids are considered as 'solvents' for proteins. The asymmetrical distribution of the outer versus the inner leaflet and a distinct lateral organization of the structure suggests a further role for glycosphingolipids in the function and architecture of rafts [detergent-resistant membranes, glycosphingolipid-enriched membranes (GEMs), or microdomains]. In rafts, glycosphingolipids are specifically enriched in the exoplasmic leaflet, with glycerolipids in the cytoplasmic leaflet and cholesterol in the inner spaces 3 .
Sphingolipids: second messenger molecules and 'outside in' mediators
Ceramide, a second messenger in lymphocytes
A prototype molecule for the second messenger role of sphingolipids is ceramide. The transition from regarding these molecules as membrane constituents to regarding them as signals is illustrated best in neutrophils, where ceramide accumulates during phagocytosis, particularly as ceramide-1-phosphate (C1P). Elevated levels of this phospholipid promote the fusion of liposomes, which is now attributed to the signaling character, rather than the membrane V