FIGURE 1.

Schematic representation of S1PRs signaling activation in the cardiovascular system. Ceramide is catabolized by ceramidase to produce sphingosine that, in turn, is phosphorylated by sphingosine kinases 1 and 2 (SphK1 and 2) to generate the sphingosine 1-phosphate (S1P). Cellular S1P concentrations are regulated by the balance between its synthesis and de-phosphorylation mediated by S1P phosphatases (SPP). In the cytosol, S1P can also be irreversibly cleaved into trans-2-hexadecenal and ethanolamine phosphate or can be exported out of cells through the “inside-out” mechanism where it can bind three different receptors (S1PR_1-3). Activation of S1PR₁ induces negative inotropic effects via G protein (Gi) activation and decreased cAMP concentration. Moreover, S1PR₁ is able to positively affect endothelial function and to confer protection to the heart, via activation of the mitogen-activated protein kinase 1 and 2 (ERK) and the protein kinase B (Akt). Both S1PR₂ and S1PR₃ activate Gi, Gq, and G12/13 appear to collaborate in providing cardioprotection and in regulating cardiac hypertrophy. However, while S1PR₂ is involved in endothelial dysfunction and promotion of fibroblasts function, S1PR₃ appears to influence the vascular tone and induce bradycardia.