Sphingosine-1-phosphate receptor signalling in the heart

Abstract

The five known members of the sphingosine-1-phosphate (S1P) receptor family exhibit diverse tissue expression profiles and couple to distinct G-protein-mediated signalling pathways. S1P1, S1P2, and S1P3 receptors are all present in the heart, but the ratio of these subtypes differs for various cardiac cells. The goal of this review is to summarize data concerning which S1P receptor subtypes regulate cardiac physiology and pathophysiology, which G-proteins and signalling pathways they couple to, and in which cell types they are expressed. The available information is based on studies using a lamentably limited set of pharmacological agonists/antagonists, but is complemented by work with S1P receptor subtype-specific knockout mice and sphingosine kinase knockout mice. In cardiac myocytes, the S1P1 receptor subtype is the predominant subtype expressed, and the activation of this receptor inhibits cAMP formation and antagonizes adrenergic receptor-mediated contractility. The S1P3 receptor, while expressed at lower levels, mediates the bradycardic effect of S1P agonists. Studies using knockout mice indicate that S1P2 and S1P3 receptors play a major role in mediating cardioprotection from ischaemia/reperfusion injury in vivo. S1P receptors are also involved in remodelling, proliferation, and differentiation of cardiac fibroblasts, a cell type in which the S1P3 receptor predominates. Receptors for S1P are also present in endothelial and smooth muscle cells where they mediate peripheral vascular tone and endothelial responses, but the role of this regulatory system in the cardiac vasculature is unknown. Further understanding of the contributions of each cell and receptor subtype to cardiac function and pathophysiology should expedite consideration of the endogenous S1P signalling pathway as a therapeutic target for cardiovascular disease.

Figure 1

S1P receptor-mediated signalling in the heart. Activation of the S1P₁ receptor induces negative inotropy through effects of G_αi to decrease cAMP concentration and effects of G_βγ on ion channels. The S1P₂ receptor is the primary receptor for mediating Rho activation and this receptor mediated pathway may participate in cardioprotection. The S1P₃ receptor is the primary receptor coupling to PLC and the activation of this receptor also results in bradycardia. While the S1P₂ and S1P₃ receptors appear to collaborate in providing cardioprotection from ischaemia reperfusion injury in vivo, the S1P₁ receptor has been suggested to be cardioprotective in the isolated cardiomyocytes.