Vascular sphingosine-1-phosphate S1P1 and S1P3 receptors

Description

The sphingolipid sphingosine-1-phosphate (S1P) acts on five subtypes of G protein coupled receptors,termed S1P1 (formerly Endothelial Differentiation Gene-1, Edg-1), S1P2 (Edg-5), S1P3 (Edg-3), S1P4(Edg-6) and S1P5 (edg-8), and possibly several other "orphan" receptors, such as GPR3, GPR6 andGPR12. These receptors are coupled to different intracellular second messenger systems, includingstimulation of adenylate cyclase, phospholipase C, phosphatidylinositol 3-kinase/protein kinase Akt,MAP kinases, as well as Rho- and Ras-dependent pathways. Consistently with this receptor multiplicityand pleiotropic signaling mechanisms, S1P influences numerous cell functions. S1P1, S1P2 and S1P3receptors are the major S1P receptor subtypes in the cardiovascular system, where they mediate theeffects of S1P released from platelets, and possibly other tissues (such as brain). Thus S1P1 and S1P3receptors enhance endothelial and vascular smooth muscle cell proliferation and migration, playing a keyrole in developmental and pathological angiogenesis. In contrast, S1P2 receptors inhibit migration of thesecell types, probably because of their unique stimulatory effect on a GTPase-activating protein inhibitingthe activity of Rac. S1P receptors can also cause relaxation and constriction of blood vessels. The formereffect is mediated by Pertussis toxin sensitive receptors (possibly S1P1) located on the endothelium andstimulating phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase (eNOS). Thevasoconstricting effect of S1P is likely to be mediated by S1P2 and/or S1P3 receptors, via Rho/Rho kinaseand is more potent in coronary and cerebral blood vessels. Finally, S1P also protects endothelial cellsfrom apoptosis through activation of phosphatidylinositol 3-kinase/Akt/eNOS via S1P1 and S1P3receptors. The variety of these effects, taken together with the existence of multiple receptor subtypes,provides an abundance of therapeutic targets that currently still awaits the development of selectiveagents.

Abstract

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