Sphingosine-1-phosphate: an emerging therapeutic target

Sphingosine-1-phosphate (SPP) is a polar sphingolipid metabolite that has received increasing attention as both an extracellular mediator and an intracellular second messenger. SPP is the ligand of a family of specific cell surface G-protein coupled receptors (GPCR), known as the endothelial differentiation gene-1 (EDG-1) family. These receptors, which include EDG-1, -3, -5, -6 and -8, regulate diverse processes including cell migration, angiogenesis, vascular maturation, heart development, neurite retraction and soma rounding. In addition, abundant evidence indicates that SPP also acts as an intracellular lipid messenger, regulating calcium mobilisation, cell growth and survival. The relative intracellular level of SPP and ceramide, another sphingolipid metabolite associated with cell death and cell growth arrest, is an important factor in determining cell fate. Changes in SPP and ceramide have been implicated in a number of pathological conditions in which apoptosis plays an important role, including cancer and neurodegenerative disorders, as well as in atherosclerosis and allergic responses. This review will examine the biosynthesis, metabolism and potential functions of SPP in diverse diseases in order to illuminate targets for the pharmaceutical and therapeutic manipulation of SPP levels.