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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [37]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family [3,45], the receptors are currently designated as S1P1R through S1P5R [3,30,45]. Their gene nomenclature has been codified as human S1PR1, S1PR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and S1pr1, S1pr2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function. All S1P receptors (S1PRs) have been knocked-out in mice constitutively and in some cases, conditionally.
S1PRs, particularly S1P1, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P1 in multiple cell types [5,19]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems.
Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P1R activation [38-39]. The structures of S1P1 [29,40,64,66], S1P2 [12], S1P3[43,68], and S1P5 [41,67] are solved, and confirmed aspects of ligand binding, specificity, and receptor activation, determined previously through biochemical and genetic studies [4,29]. Fingolimod (FTY720), the first FDA-approved drug to target any of the lysophospholipid receptors, binds as a phosphorylated metabolite to four of the five S1PRs, and was the first oral therapy for multiple sclerosis (MS) [13]. Second-generation S1PR modulators siponimod, ozanimod, and ponesimod that target S1P1 and S1P5 are also FDA approved for the treatment of various MS forms [3,45]. In 2021, ozanimod became the first S1PR modulator to be FDA approved for the treatment of ulcerative colitis [56]. The mechanisms of action of fingolimod and other S1PR-modulating drugs now in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [14,26-27,54].
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* Key recommended reading is highlighted with an asterisk
* Cartier A, Hla T. (2019) Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Science, 366 (6463). DOI: 10.1126/science.aar5551 [PMID:31624181]
* Chew WS, Wang W, Herr DR. (2016) To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling. Pharmacol Res, 113 (Pt A): 521-532. [PMID:27663260]
* Chun J, Hla T, Lynch KR, Spiegel S, Moolenaar WH. (2010) International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature. Pharmacol Rev, 62 (4): 579-87. [PMID:21079037]
Kihara Y, Mizuno H, Chun J. (2015) Lysophospholipid receptors in drug discovery. Exp Cell Res, 333 (2): 171-7. [PMID:25499971]
Mutoh T, Rivera R, Chun J. (2012) Insights into the pharmacological relevance of lysophospholipid receptors. Br J Pharmacol, 165 (4): 829-44. [PMID:21838759]
O'Sullivan C, Dev KK. (2013) The structure and function of the S1P1 receptor. Trends Pharmacol Sci, 34 (7): 401-12. [PMID:23763867]
* Pyne NJ, Pyne S. (2017) Sphingosine 1-Phosphate Receptor 1 Signaling in Mammalian Cells. Molecules, 22 (3). [PMID:28241498]
* Rosen H, Stevens RC, Hanson M, Roberts E, Oldstone MB. (2013) Sphingosine-1-phosphate and its receptors: structure, signaling, and influence. Annu Rev Biochem, 82: 637-62. [PMID:23527695]
Spiegel S, Milstien S. (2011) The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol, 11 (6): 403-15. [PMID:21546914]
* Yanagida K, Hla T. (2017) Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient. Annu Rev Physiol, 79: 67-91. [PMID:27813829]
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Subcommittee members:
Jerold Chun (Chairperson)
Victoria Blaho
Yasuyuki Kihara
Danielle Jones (Editorial assistant to chairperson) |
Other contributors:
Deron Herr |
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
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The FDA-approved immunomodulator fingolimod (FTY720) is phosphorylated in vivo [1] to generate an agonist with activity at S1P1, S1P3, S1P4 and S1P5 receptors [7,44]. Many of the physiological consequences of fingolimod-phosphate administration, as well as those of other currently described S1P1 agonists, may involve functional antagonism via ubiquitination and subsequent degradation of S1P1 [3,48]. Additionally, receptor specificities of the different compounds may depend on the functional assay system utilized and from which species the receptor sequence originated.