An update on the biology of sphingosine 1-phosphate receptors

Abstract

Sphingosine 1-phosphate (S1P) is a membrane-derived lysophospholipid that acts primarily as an ex-tracellular signaling molecule. Signals initiated by S1P are transduced by five G protein-coupled receptors, named S1P1-5 Cellular and temporal expression of the S1P receptors (S1PRs) determine their specific roles in various organ systems, but they are particularly critical for regulation of the cardiovascular, immune, and nervous systems, with the most well-known contributions of S1PR signaling being modulation of vascular barrier function, vascular tone, and regulation of lymphocyte trafficking. However, our knowledge of S1PR biology is rapidly increasing as they become attractive therapeutic targets in several diseases, such as chronic inflammatory pathologies, autoimmunity, and cancer. Understanding how the S1PRs regulate interactions between biological systems will allow for greater efficacy in this novel therapeutic strategy as well as characterization of complex physiological networks. Because of the rapidly expanding body of research, this review will focus on the most recent advances in S1PRs.

Keywords: activation; endothelium; immune cells; immunity; migration; nervous system; vascular permeability.

Fig. 1.

Synthesis and export of S1P. S1P synthesis primarily begins with metabolism of membrane SM. Once synthesized, S1P can be irreversibly degraded to phosphoethanolamine and hexadecenal by S1P lyase, or actively transported out of the cell. Once outside of the cell, S1P is found bound to ApoM or albumin. Spns2, spinster 2.

Fig. 2.

Expression of S1PRs and responses by endothelial cells. Endothelial cells express S1P₁, S1P₂, and S1P₃ protein. Endothelial cells may express different S1PRs depending on activation status.

Fig. 3.

Expression of S1PRs and responses by cells of the acquired immune system. T cells express S1P₁ and S1P₄, B cells express S1P₁, S1P₂, S1P₃, and S1P₄, and NK cells express S1P₁ and S1P₅. Cells do not necessarily express all of the illustrated S1PRs at one time, but may have differential expression during different stages of maturation or activation.

Fig. 4.

Expression of S1PRs and responses by cells of the innate immune system. Monocytes and/or macrophages express S1P_1–4, neutrophils express S1P₁, S1P₃, and S1P₄, eosinophils and MCs express all S1PRs, and DCs express S1P₁, S1P₃, and S1P₄. Cells do not necessarily express all of the illustrated S1PRs at one time, but may have differential expression during different stages of maturation or activation.

Fig. 5.

Expression of S1PRs and responses by neural cells. Neural progenitors express S1P₁ and S1P₂, neurons express S1P₁ and S1P₃, oligodendrocytes express S1P₁ and S1P₅, and astrocytes express S1P₁ and S1P₂. S1P₁ couples exclusively to G_αi. S1P₂ and S1P₃ can couple to G_αi, G_α12/13, or G_αq, and S1P₅ can couple to G_αi or G_α12/13. Cells do not necessarily express all of the illustrated S1PRs at one time, but may have differential expression during different stages of maturation or activation.