The sphingosine-1-phosphate receptors are a class of G protein-coupled receptors that are targets of the lipid signalling molecule Sphingosine-1-phosphate (S1P). They are divided into five subtypes: S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5.
An Overview of Sphingosine 1 Phosphate Receptor (S1PR)
Sphingosine 1 phosphate (S1P) is a biologically active sphingolipid medium. Most of the S1P in the blood exists in the form of binding to high-density lipoprotein and plasma proteins. Sphingosine 1 phosphate receptor (S1PR) is a member of the G protein-coupled receptor (GPCR) family, which is mainly coupled with the G protein α subtype. Structural features of the S1PR include a small extracellular N-terminus (30 to 50 residues), 7 helical transmembrane domains, and an intracellular C-terminus. S1PRs are a class of receptors that are selectively activated by active lipids in GPCRs, such as prostaglandins, leukotrienes, endogenous cannabinoids, free fatty acids, and phospholipids. S1PR exerts different biological functions by activating multiple intracellular signaling pathways. Its functions include regulation of cell migration, proliferation, apoptosis and intracellular calcium mobilization, expression of inflammatory and adhesion molecules, and regulation of angiogenesis, vascular tone, and permeability.
Major types of S1PR
S1PR can be divided into five subtypes of specific transmembrane GPCRs receptor: S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5.
Inhibition of S1PR
Numerous studies in recent years have yielded a variety of drugs that are capable of selectively inhibiting or stimulating S1PR to vary degrees. In 2010, the US FDA approved the drug Gilenya (FTY720) for the treatment of multiple sclerosis. This sphingolipid analog, as a prodrug, is rapidly phosphorylated into a biologically active form by the action of the enzyme. Phosphorylated Gilenya is a potential agonist of S1PR. The structural modification of Gilenya resulted in a new selective S1PR prodrug agonist SYL978, which showed significant agonistic activity on the S1PR in vitro.
S1PR and diseases
S1PRs play an important role in the proliferation and metastasis of various malignant tumor cells. The expression of S1PR and changes in the expression levels of related enzymes will lead to changes in S1P levels, which play an important role in the development of tumors. S1P1 promotes multiple types of cancer migration, invasion, and angiogenesis. S1PR can be used as a new target for tumor therapy.
Brinkmann, V. (2007). Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacology & therapeutics, 115(1), 84-105.