Sphingosine-1-phosphate receptor

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.


In 1990, S1PR1 was the first member of the S1P receptor family to be cloned from endothelial cells.[1] Later, S1PR2 and S1PR3 were cloned from rat brain and a human genomic library respectively.[2][3] Finally, S1P4 and S1PR5 were cloned from in vitro differentiated human dendritic cells and rat cDNA library.[4][5]


The sphingosine-1-phosphate receptors regulate fundamental biological processes such as cell proliferation, angiogenesis, migration, cytoskeleton organization, endothelial cell chemotaxis, immune cell trafficking and mitogenesis. Sphingosine-1-phosphate receptors are also involved in immune-modulation and directly involved in suppression of innate immune responses from T cells.[6]


Sphingosine-1-phosphate (S1P) receptors are divided into five subtypes: S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5.

They are expressed in a wide variety of tissues, with each subtype exhibiting a different cell specificity, although they are found at their highest density on leukocytes. S1PR1, 2 and 3 receptors are expressed ubiquitously. The expression of S1PR4 and S1PR5 are less widespread. S1PR4 is confined to lymphoid and hematopoietic tissues whereas S1PR5 primarily located in the white matter of the central nervous system (CNS) and spleen.

G protein interactions and selective ligands

The sphingosine-1-phosphate (S1P) is the endogenous agonist for the five subtypes.

ReceptorG protein-coupled receptor superfamilyAgonistsAntagonists
  • Gi/Go family
  • S1P
  • TC-SP 14 (CAS# 1257093-40-5)[7]
  • SEW 2871 (CAS# 256414-75-2)[8]
  • RP 001 hydrochloride (CAS# 1306761-53-4)[9]
  • CYM 5442 hydrochloride (CAS# 1094042-01-9)[10]
  • CS 2100 (CAS# 913827-99-3)[11]
  • W146 (CAS# 909725-62-8)[12]
  • VPC 23019 (CAS# 449173-19-7)[13]
  • Gs family
  • Gq/G11 family
  • G12/G13 family
  • S1P
  • JTE 013 (547756-93-4)[14]
  • Gi/Go family
  • Gq/G11 family
  • G12/G13 family
  • S1P
  • VPC 23019 (CAS# 449173-19-7)[13]
  • Gi/Go family
  • G12/G13 family
  • S1P
  • CYM 50260 (CAS# 1355026-60-6)[15]
  • CYM 50308 (CAS# 1345858-76-5)[16]
  • Gi/Go family
  • G12/G13 family
  • S1P


  1. Hla T, Maciag T (June 1990). "An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors". J. Biol. Chem. 265 (16): 9308–13. PMID 2160972.
  2. Okazaki H, Ishizaka N, Sakurai T, Kurokawa K, Goto K, Kumada M, Takuwa Y (February 1993). "Molecular cloning of a novel putative G protein-coupled receptor expressed in the cardiovascular system". Biochem. Biophys. Res. Commun. 190 (3): 1104–9. doi:10.1006/bbrc.1993.1163. PMID 8382486.
  3. MacLennan AJ, Browe CS, Gaskin AA, Lado DC, Shaw G (June 1994). "Cloning and characterization of a putative G-protein coupled receptor potentially involved in development". Mol. Cell. Neurosci. 5 (3): 201–9. doi:10.1006/mcne.1994.1024. PMID 8087418.
  4. Gräler MH, Bernhardt G, Lipp M (October 1998). "EDG6, a novel G-protein-coupled receptor related to receptors for bioactive lysophospholipids, is specifically expressed in lymphoid tissue". Genomics. 53 (2): 164–9. doi:10.1006/geno.1998.5491. PMID 9790765.
  5. Im DS, Heise CE, Ancellin N, O'Dowd BF, Shei GJ, Heavens RP, Rigby MR, Hla T, Mandala S, McAllister G, George SR, Lynch KR (May 2000). "Characterization of a novel sphingosine 1-phosphate receptor, Edg-8". J. Biol. Chem. 275 (19): 14281–6. doi:10.1074/jbc.275.19.14281. PMID 10799507.
  6. Sharma, N; et al. (2013). "Sphingosine-1-phosphate suppresses TLR-induced CXCL8 secretion from human T cells". J Leukoc Biol. 93 (4): 521–528. doi:10.1189/jlb.0712328. PMID 23345392.
  7. Clemens JJ, Davis MD, Lynch KR, Macdonald TL (August 2005). "Synthesis of 4(5)-phenylimidazole-based analogues of sphingosine-1-phosphate and FTY720: discovery of potent S1P1 receptor agonists". Bioorg. Med. Chem. Lett. 15 (15): 3568–72. doi:10.1016/j.bmcl.2005.05.097. PMID 15982878.
  8. Hale JJ, Lynch CL, Neway W, Mills SG, Hajdu R, Keohane CA, Rosenbach MJ, Milligan JA, Shei GJ, Parent SA, Chrebet G, Bergstrom J, Card D, Ferrer M, Hodder P, Strulovici B, Rosen H, Mandala S (December 2004). "A rational utilization of high-throughput screening affords selective, orally bioavailable 1-benzyl-3-carboxyazetidine sphingosine-1-phosphate-1 receptor agonists". J. Med. Chem. 47 (27): 6662–5. doi:10.1021/jm0492507. PMID 15615513.
  9. Cahalan SM, Gonzalez-Cabrera PJ, Sarkisyan G, Nguyen N, Schaeffer MT, Huang L, Yeager A, Clemons B, Scott F, Rosen H (May 2011). "Actions of a picomolar short-acting S1P₁ agonist in S1P₁-eGFP knock-in mice". Nat. Chem. Biol. 7 (5): 254–6. doi:10.1038/nchembio.547. PMC 3430385. PMID 21445057.
  10. Gonzalez-Cabrera PJ, Jo E, Sanna MG, Brown S, Leaf N, Marsolais D, Schaeffer MT, Chapman J, Cameron M, Guerrero M, Roberts E, Rosen H (November 2008). "Full pharmacological efficacy of a novel S1P1 agonist that does not require S1P-like headgroup interactions". Mol. Pharmacol. 74 (5): 1308–18. doi:10.1124/mol.108.049783. PMC 2575047. PMID 18708635.
  11. Nakamura T, Asano M, Sekiguchi Y, Mizuno Y, Tamaki K, Kimura T, Nara F, Kawase Y, Shimozato T, Doi H, Kagari T, Tomisato W, Inoue R, Nagasaki M, Yuita H, Oguchi-Oshima K, Kaneko R, Watanabe N, Abe Y, Nishi T (February 2012). "Discovery of CS-2100, a potent, orally active and S1P3-sparing S1P1 agonist". Bioorg. Med. Chem. Lett. 22 (4): 1788–92. doi:10.1016/j.bmcl.2011.12.019. PMID 22264485.
  12. Sanna MG, Wang SK, Gonzalez-Cabrera PJ, Don A, Marsolais D, Matheu MP, Wei SH, Parker I, Jo E, Cheng WC, Cahalan MD, Wong CH, Rosen H (August 2006). "Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo". Nat. Chem. Biol. 2 (8): 434–41. doi:10.1038/nchembio804. PMID 16829954.
  13. 1 2 Davis MD, Clemens JJ, Macdonald TL, Lynch KR (March 2005). "Sphingosine 1-phosphate analogs as receptor antagonists". J. Biol. Chem. 280 (11): 9833–41. doi:10.1074/jbc.M412356200. PMID 15590668.
  14. Parrill AL, Sardar VM, Yuan H (October 2004). "Sphingosine 1-phosphate and lysophosphatidic acid receptors: agonist and antagonist binding and progress toward development of receptor-specific ligands". Semin. Cell Dev. Biol. 15 (5): 467–76. doi:10.1016/j.semcdb.2004.05.006. PMID 15271292.
  15. Guerrero M, Urbano M, Zhao J, Crisp M, Chase P, Hodder P, Schaeffer MT, Brown S, Rosen H, Roberts E (January 2012). "Discovery, design and synthesis of novel potent and selective sphingosine-1-phosphate 4 receptor (S1P₄-R) agonists". Bioorg. Med. Chem. Lett. 22 (1): 537–42. doi:10.1016/j.bmcl.2011.10.096. PMC 3248976. PMID 22119461.
  16. Urbano M, Guerrero M, Velaparthi S, Crisp M, Chase P, Hodder P, Schaeffer MT, Brown S, Rosen H, Roberts E (November 2011). "Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype". Bioorg. Med. Chem. Lett. 21 (22): 6739–45. doi:10.1016/j.bmcl.2011.09.049. PMC 3209756. PMID 21982495.
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