Sphingosine-1-phosphate receptor explained

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.

Discovery

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]

Function

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]

Subtypes

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.

Receptor G protein-coupled receptor superfamily Agonists Antagonists
S1PR1
  • Gi/Go family
  • W146 (CAS# 909725-62-8)[15]
  • VPC 23019 (CAS# 449173-19-7)[16]
S1PR2
  • Gs family
  • Gq/G11 family
  • G12/G13 family
  • S1P
  • JTE 013 (547756-93-4)[17]
  • AB1 (1463912-49-3)[18]
S1PR3
  • Gi/Go family
  • Gq/G11 family
  • G12/G13 family
  • S1P
  • Fingolimod (162359-55-9)
  • VPC 23019 (CAS# 449173-19-7)
S1PR4
  • Gi/Go family
  • G12/G13 family
  • S1P
  • Fingolimod (162359-55-9)
  • CYM 50260 (CAS# 1355026-60-6)[19]
  • CYM 50308 (CAS# 1345858-76-5)[20]
  • JTE 013 (547756-93-4)[21]
S1PR5
  • Gi/Go family
  • G12/G13 family
  • S1P
  • Fingolimod (162359-55-9)
  • Ozanimod (1306760-87-1)

Notes and References

  1. Hla T, Maciag T . 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 . June 1990 . 10.1016/S0021-9258(19)38849-0 . 2160972 . free .
  2. Okazaki H, Ishizaka N, Sakurai T, Kurokawa K, Goto K, Kumada M, Takuwa Y . Molecular cloning of a novel putative G protein-coupled receptor expressed in the cardiovascular system . Biochem. Biophys. Res. Commun. . 190 . 3 . 1104–9 . February 1993 . 8382486 . 10.1006/bbrc.1993.1163 .
  3. MacLennan AJ, Browe CS, Gaskin AA, Lado DC, Shaw G . Cloning and characterization of a putative G-protein coupled receptor potentially involved in development . Mol. Cell. Neurosci. . 5 . 3 . 201–9 . June 1994 . 8087418 . 10.1006/mcne.1994.1024 . 34088289 .
  4. Gräler MH, Bernhardt G, Lipp M . EDG6, a novel G-protein-coupled receptor related to receptors for bioactive lysophospholipids, is specifically expressed in lymphoid tissue . Genomics . 53 . 2 . 164–9 . October 1998 . 9790765 . 10.1006/geno.1998.5491 .
  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 . Characterization of a novel sphingosine 1-phosphate receptor, Edg-8 . J. Biol. Chem. . 275 . 19 . 14281–6 . May 2000 . 10799507 . 10.1074/jbc.275.19.14281 . free .
  6. Sharma, N. Sphingosine-1-phosphate suppresses TLR-induced CXCL8 secretion from human T cells. . J Leukoc Biol . 93. 4 . 521–528 . 2013. 23345392 . 10.1189/jlb.0712328. etal.
  7. Clemens JJ, Davis MD, Lynch KR, Macdonald TL . 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 . August 2005 . 15982878 . 10.1016/j.bmcl.2005.05.097 .
  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 . 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 . December 2004 . 15615513 . 10.1021/jm0492507 .
  9. Cahalan SM, Gonzalez-Cabrera PJ, Sarkisyan G, Nguyen N, Schaeffer MT, Huang L, Yeager A, Clemons B, Scott F, Rosen H . Actions of a picomolar short-acting S1P1 agonist in S1P1-eGFP knock-in mice . Nat. Chem. Biol. . 7 . 5 . 254–6 . May 2011 . 21445057 . 3430385 . 10.1038/nchembio.547 .
  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 . Full pharmacological efficacy of a novel S1P1 agonist that does not require S1P-like headgroup interactions . Mol. Pharmacol. . 74 . 5 . 1308–18 . November 2008 . 18708635 . 2575047 . 10.1124/mol.108.049783 .
  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 . Discovery of CS-2100, a potent, orally active and S1P3-sparing S1P1 agonist . Bioorg. Med. Chem. Lett. . 22 . 4 . 1788–92 . February 2012 . 22264485 . 10.1016/j.bmcl.2011.12.019 .
  12. Groves. Aran. Kihara. Yasuyuki. Chun. Jerold. 2013-05-15. Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. Journal of the Neurological Sciences. 328. 1–2. 9–18. 10.1016/j.jns.2013.02.011. 1878-5883. 3640626. 23518370.
  13. Scott. F. L.. Clemons. B.. Brooks. J.. Brahmachary. E.. Powell. R.. Dedman. H.. Desale. H. G.. Timony. G. A.. Martinborough. E.. June 2016. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. British Journal of Pharmacology. 173. 11. 1778–1792. 10.1111/bph.13476. 1476-5381. 4867749. 26990079.
  14. Web site: Ponesimod. PubChem. pubchem.ncbi.nlm.nih.gov. en. 2019-08-14.
  15. 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 . Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo . Nat. Chem. Biol. . 2 . 8 . 434–41 . August 2006 . 16829954 . 10.1038/nchembio804 . 13023611 .
  16. Davis MD, Clemens JJ, Macdonald TL, Lynch KR . Sphingosine 1-phosphate analogs as receptor antagonists . J. Biol. Chem. . 280 . 11 . 9833–41 . March 2005 . 15590668 . 10.1074/jbc.M412356200 . free .
  17. Parrill AL, Sardar VM, Yuan H . 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 . October 2004 . 15271292 . 10.1016/j.semcdb.2004.05.006 .
  18. Web site: AB1 CAS:1463912-49-3 Probechem Biochemicals. www.probechem.com. 2019-08-13.
  19. Guerrero M, Urbano M, Zhao J, Crisp M, Chase P, Hodder P, Schaeffer MT, Brown S, Rosen H, Roberts E . 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 . January 2012 . 22119461 . 3248976 . 10.1016/j.bmcl.2011.10.096 .
  20. Urbano M, Guerrero M, Velaparthi S, Crisp M, Chase P, Hodder P, Schaeffer MT, Brown S, Rosen H, Roberts E . 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 . November 2011 . 21982495 . 3209756 . 10.1016/j.bmcl.2011.09.049 .
  21. Long. Jaclyn S.. Fujiwara. Yuko. Edwards. Joanne. Tannahill. Claire L.. Tigyi. Gabor. Pyne. Susan. Pyne. Nigel J.. 2010-11-12. Sphingosine 1-Phosphate Receptor 4 Uses HER2 (ERBB2) to Regulate Extracellular Signal Regulated Kinase-1/2 in MDA-MB-453 Breast Cancer Cells. The Journal of Biological Chemistry. 285. 46. 35957–35966. 10.1074/jbc.M110.117945. 0021-9258. 2975218. 20837468. free .

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