Regulation of mammalian physiology, development, and disease by the sphingosine 1-phosphate and lysophosphatidic acid receptors.

Abstract

The moniker lysophospholipid incorporates two broad families of membrane-derived lipids: the glycerophospholipids and the sphingolipids1. Primary representatives of these two arms are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), the majority of whose activities are mediated via multiple G-protein-coupled receptors with a high degree of specificity for either LPA or S1P 2,3. Unlike S1P, which is a single molecular species (2S-amino-1-(dihydrogen phosphate)-4E-octadecene-1,3R-diol), LPA (1-O-acyl-2-hydroxy-sn-glycero-3-phosphate) is actually a diverse group of molecules consisting of either a saturated (e.g. 16:0; 18:0) or unsaturated (e.g. 16:1; 18:1; 18:2; 20:4) fatty acid chain esterified at the sn-1 or sn-2 position of a glycerol backbone 4,5. This can also be modified to alkyl or alkenyl at the sn-1 position 6. Other bioactive members of the LP family include the LPA analogues cyclic phosphatidic acid (cPA), sphigosylphosphotidylcholine (SPC), lysophosphatidylcholine (LPC), lysophosphatidylserine (LPS), and lysophosphatidylinositol (LPI) 1,5,7. Numerous emerging reports indicate roles in mammalian biology for other, less well-characterized LP members, as well 8. In the past decade, our understanding of LP biology has expanded exponentially, fueled by the identification of LP receptors, generation and analysis of LPA and S1P-receptor knockout mice, and small molecule compounds functioning as receptor-specific agonists or antagonists 3,9,10. Specific receptors for LPA and S1P were cloned and characterized beginning only about 15 years ago. The description of the first LPAR was reported in 1996, and the orphan receptor EDG-1, which was cloned as an immediate-early gene from endothelial cells, was identified as the first S1P receptor in 1998 11-13. Since then, four more S1P receptors and at least five more LPA receptors have been identified 3. The two families have been best characterized in specific organ systems; namely, LPARs in the nervous system and cancer, and S1PR in vascular biology and immunology. That is not to say that their contributions in other fields are minor, only that they are incompletely understood.