2019 Volume 18 Issue 7 Pages 333-340
Sphingosine-1-phosphate (S1P) exerts pleiotropic biological activities including the development of the vasculature and the nervous system, regulation of vascular barrier integrity and lymphocyte trafficking. Many, if not all, of these S1P actions are mediated by five members of the G proteincoupled S1P receptors (S1P1~S1P5) with overlapping but distinct coupling to heterotrimeric G proteins. Another striking feature of the S1P signaling system is the presence of a steep concentration gradient of S1P between the blood and the perivascular surrounding tissues. The major target cells of S1P are vascular cells and immune cells including lymphocytes and macrophages. The S1P signaling system regulates vascular development and barrier integrity, circulation and differentiation of lymphocytes, and migration and activation of macrophages. The synthetic compound FTY720, a sphingosine analogue, reduces circulating lymphocytes very effectively and has been approved as a novel therapeutic agent for multiple sclerosis. Further development of S1P receptor agonists and antagonists with improved receptor subtype-selectivity, inhibitors or modulators of sphingolipid-metabolizing enzymes, and their optimal drug delivery system are expected to provide novel therapeutic tactics.
