Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate

Abstract

Sphingosine 1-phosphate (S1P) influences heart rate, coronary artery caliber, endothelial integrity, and lymphocyte recirculation through five related high affinity G-protein-coupled receptors. Inhibition of lymphocyte recirculation by non-selective S1P receptor agonists produces clinical immunosuppression preventing transplant rejection but is associated with transient bradycardia. Understanding the contribution of individual receptors has been limited by the embryonic lethality of the S1P 1 knock-out and the unavailability of selective agonists or antagonists. A potent, S1P 1 -receptor selective agonist structurally unrelated to S1P was found to activate multiple signals triggered by S1P, including guanosine 5 -3-O-(thio)triphosphate binding, calcium flux, Akt and ERK1/2 phosphorylation, and stimulation of migration of S1P 1 -but not S1P 3 -expressing cells in vitro. The agonist also alters lymphocyte trafficking in vivo. Use of selective agonism together with deletant mice lacking S1P 3 receptor reveals that agonism of S1P 1 receptor alone is sufficient to control lymphocyte recirculation. Moreover, S1P 1 receptor agonist plasma levels are causally associated with induction and maintenance of lymphopenia. S1P 3 , and not S1P 1 , is directly implicated in sinus bradycardia. The sustained bradycardia induced by S1P receptor nonselective immunosuppressive agonists in wild-type mice is abolished in S1P 3 ؊/؊ mice, whereas S1P 1 -selective agonist does not produce bradycardia. Separation of receptor subtype usage for control of lymphocyte recirculation and heart rate may allow the identification of selective immunosuppressive S1P 1 receptor agonists with an enhanced therapeutic window. S1P 1 -selective agonists will be of broad utility in understanding cell functions in vitro, and vascular physiology in vivo, and the success of the chemical approach for S1P 1 suggests that selective tools for the resolution of function across this broad lipid receptor family are now possible.Sphingosine 1-phosphate (S1P), 1 through its high affinity G-protein-coupled receptors, is a physiological mediator with widespread effects upon multiple physiological systems (1). It regulates heart rate (2), coronary artery blood flow (3), blood pressure (4), endothelial integrity in lung (5, 6) and most recently has been shown to regulate the recirculation of lymphocytes (7-11). Many of the physiologically relevant functions occur in the low nanomolar range, including activation of endothelial nitric oxide synthase (12, 13), vasorelaxation (14), and inhibition of thymic egress and lymphocyte recirculation (11). Free plasma levels of S1P are tightly regulated by protein binding to albumin and high density lipoprotein to avoid the deleterious effects of systemic S1P receptor subtype activation at high concentrations of ligand, such as bradycardia and coronary artery vasospasm (3, 15). The choice of S1P, through its receptors, as an acute regulator of the number of blood lymphocytes may represent an interesting evolutionary choice by the immun...

Migration of CD4 T Cells and Dendritic Cells toward Sphingosine 1-Phosphate (S1P) Is Mediated by Different Receptor Subtypes: S1P Regulates the Functions of Murine Mature Dendritic Cells via S1P Receptor Type 3

“…SEW2871 has been reported to induce S1P 1 internalization and recycling but not receptor degradation (31), and long-term, in vivo treatment with SEW2871 induces a marked decrease in peripheral blood lymphocytes in mice (39). Like FTY720, SEW2871 reduces the circulating lymphocytes by sequestering lymphocytes into secondary lymphoid tissues and the thymus (39). We showed here that SEW2871 inhibits S1P-induced migration of CD4 T cells at concentrations that induce internalization of S1P 1 (Figs.…”

“…This demonstrates their immunosuppressive effects against several types of autoimmune disorders (18,20,39,47). DCs migrate to lymph nodes through afferent lymphatic vessels, whereas T cells do so via high endothelial venules (1,2).…”

“…Thus, it is likely that promotion or inhibition of CD4 T cell migration toward S1P depends on the magnitude of S1P 1 down-regulation by S1P, (S)-FTY720-P, or SEW2871. SEW2871 has been reported to induce S1P 1 internalization and recycling but not receptor degradation (31), and long-term, in vivo treatment with SEW2871 induces a marked decrease in peripheral blood lymphocytes in mice (39). Like FTY720, SEW2871 reduces the circulating lymphocytes by sequestering lymphocytes into secondary lymphoid tissues and the thymus (39).…”

Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes

“…Activation of this current can shorten action potential (AP) duration (APD), inhibit excitability by reducing Na ϩ current, and increase the minimum stimulus current needed to generate an AP (20,35,43). In mammalian in vivo experiments, S1P activation can induce a transient bradycardia (47). S1P receptor activation, through coupling to G proteins and generation of both direct and indirect (second-messenger mediated) responses, can also activate a number of distinct intracellular signaling pathways and result in altered calcium handling.…”

Ligand-gated Ion Channels

“…Rank order of potency S1P > dihydro-S1P > SPC (Okamoto et al, 1998, Ancellin andHla, 1999) S1P > dihydro-S1P > SPC (Okamoto et al, 1998, Ancellin andHla, 1999) S1P > dihydro-S1P > SPC (Okamoto et al, 1998) S1P > dihydro-S1P > SPC (Van Brocklyn et al, 2000) S1P > dihydro-S1P > SPC (Im et al, 2000) Selective agonists SEW2871 (Sanna et al, 2004), AUY954 (Pan et al, 2006) -…”