The endothelial cell differentiation gene (Edg) family of G-protein coupled receptors (GPCR) function as receptors for Lysophosphatidic acid (LPA) and structurally related sphingosine-1-phosphate (S1P). LPA and S1P are predominantly released by activated platelets and are present in blood plasma and serum, mainly bound to albumin and lipoprotein. Both LPA and S1P mediate similar biological cell responses including cell proliferation, migration, differentiation and apoptosis. LPA is a multifunctional signalling molecule that is involved in multiple biological processes including inflammation, platelet activation, wound healing and tissue regeneration (1). S1P also elicits a wide variety of responses by cells and regulates a wide range of biological process including cell proliferation, angiogenesis, cardiac development, immunity and cell motility (2). Dysregulation of S1P signalling is thought to contribute to the pathology of a wide range of diseases including cancer, diabetes, atherosclerosis, osteoporosis and progression of autoimmune conditions such as multiple sclerosis (3).
The diverse actions of LPA and S1P are mediated primarily through the binding of Edg receptors, and the regulation of various signalling pathways. Edg receptors are developmentally regulated and differentially expressed in cells, tissues and organs. Two subfamilies of Edg receptors exist based on their structure and function. The S1P receptor subfamily comprises Edg1, Edg3, Edg5, Edg6 and Edg8, which have been re-named spingosine-1-phosphate receptors S1P1, S1P3, S1P2, S1P4 and S1P5 respectively. Whereas the LPA receptor subfamily comprise Edg2, Edg4 and Edg7, which have been re-named lysophosphatidic acid receptors LPA1, LPA2 and LPA3 respectively.
Three Edg/LPA receptors have been identified for LPA. LPA1 (Edg2), is widely expressed. It is found in most tissues with the highest expression in brain and heart. On binding with LPA, LPA1 (Edg2) couples to heterotrimeric G proteins Gi/o, Gq/11 and G12/13. Loss of LPA1 receptor function has been linked to a range of pathological conditions including cancer, neuropathic pain and male infertility (4). LPA2 (Edg4) is predominantly found in the testes, prostate, pancreas, spleen and thymus. Whereas LPA3 (Edg7) is found in testes, prostate, pancreas, heart and lung. LPA2 (Edg4) and LPA3 (Edg7) couple G-proteins Gi/o and Gq to activate similar signalling pathways to LPA1 (Edg2). Like LPA1 (Edg2), LPA2 (Edg4) also couples G12/13.
Five Edg/S1P receptors have been identified which bind S1P. S1P1 (Edg1), S1P3 (Edg3), S1P2 (Edg5), S1P4 (Edg6) and S1P5 (Edg8) couple to multiple types of G proteins and mediate effects through ras and MAP kinase, rho, phospholipase C (PLC), and protein tyrosine kinases. S1P1 (Edg1) is widely expressed in most tissues. On binding S1P, S1P1 (Edg1) couples to G protein Gi/o, and mediates activation of Ras-MAP Kinase, Ca2+ mobilization, activation of PLC, and inhibition of adenylate cyclase (5). Loss of the receptor affects a wide range of processes including angiogenesis, neurogenesis, embryonic development and lymphocyte trafficking (4).
S1P2 (Edg5) and S1P3 (Edg3) are widely expressed in most tissues in adults and some embryonic tissues. On binding S1P, S1P2 (Edg5) can couple G-proteins Gi/o, Gs, Gq and G12/13 and is involved in cell proliferation and motility. Deletion of the S1P2 (Edg5) gene has been linked to cellular defects affecting hair cells, defects in vascularization and promotes angiogenesis in pathological conditions (4). S1P3 (Edg3) can couple Gi/o, Gq and G12/13, on binding S1P, but predominantly couples Gq leading to an increase in [Ca2+]i and PLC. Studies suggest that S1P3 (Edg3) regulates a variety of cell types and biological processes including regulating lymphoid endothelial cells, endothelial progenitor cells, myocardial perfusion and regulation of heart rate in rodents. (4).
S1P4 (Edg6) is primarily expressed in lymphoid tissue (6) and couples G-protein Gs, Gq and G12/13. S1P5 (Edg8) is expressed in the brain and spleen tissue and can couple G-proteins Gs, Gq and G12/13. Deletion of S1P5 (Edg8) is reported to affect the trafficking of natural killer cells.