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Article Dans Une Revue Drug News perspect. Année : 2004

Vascular sphingosine-1-phosphate S1P1 and S1P3 receptors

Christian Waeber
  • Fonction : Auteur
Salvatore Salomone
  • Fonction : Auteur

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.
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Dates et versions

hal-02266274 , version 1 (13-08-2019)

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  • HAL Id : hal-02266274 , version 1
  • PUBMED : 15334188

Citer

Christian Waeber, Nicolas Blondeau, Salvatore Salomone. Vascular sphingosine-1-phosphate S1P1 and S1P3 receptors. Drug News perspect., 2004, 17. ⟨hal-02266274⟩
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