Vascular sphingosine-1-phosphate S1P1 and S1P3 receptors
Résumé
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 and
GPR12. These receptors are coupled to different intracellular second messenger systems, including
stimulation 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 multiplicity
and pleiotropic signaling mechanisms, S1P influences numerous cell functions. S1P1, S1P2 and S1P3
receptors are the major S1P receptor subtypes in the cardiovascular system, where they mediate the
effects of S1P released from platelets, and possibly other tissues (such as brain). Thus S1P1 and S1P3
receptors enhance endothelial and vascular smooth muscle cell proliferation and migration, playing a key
role in developmental and pathological angiogenesis. In contrast, S1P2 receptors inhibit migration of these
cell types, probably because of their unique stimulatory effect on a GTPase-activating protein inhibiting
the activity of Rac. S1P receptors can also cause relaxation and constriction of blood vessels. The former
effect is mediated by Pertussis toxin sensitive receptors (possibly S1P1) located on the endothelium and
stimulating phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase (eNOS). The
vasoconstricting effect of S1P is likely to be mediated by S1P2 and/or S1P3 receptors, via Rho/Rho kinase
and is more potent in coronary and cerebral blood vessels. Finally, S1P also protects endothelial cells
from apoptosis through activation of phosphatidylinositol 3-kinase/Akt/eNOS via S1P1 and S1P3
receptors. 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 selective
agents.