S1P<sub>4</sub> receptor | Lysophospholipid (S1P) receptors | IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

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S1P4 receptor

Target id: 278

Nomenclature: S1P4 receptor

Family: Lysophospholipid (S1P) receptors

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 384 19p13.3 S1PR4 sphingosine-1-phosphate receptor 4
Mouse 7 386 10 C1 S1pr4 sphingosine-1-phosphate receptor 4
Rat 7 413 7q11 S1pr4 sphingosine-1-phosphate receptor 4
Previous and Unofficial Names
edg6 | endothelial differentiation, G protein-coupled receptor 6
Database Links
Specialist databases
GPCRDB s1pr4_human (Hs), s1pr4_mouse (Mm)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Natural/Endogenous Ligands
sphingosine 1-phosphate
Comments: Sphingosine 1-phosphate exhibits greater potency than sphingosylphosphorylcholine
Potency order of endogenous ligands
sphingosine 1-phosphate > dihydrosphingosine 1-phosphate  [26]

Download all structure-activity data for this target as a CSV file

Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
VPC03090-P Hs Full agonist 7.8 pKd 17
pKd 7.8 (Kd 1.73x10-8 M) [17]
AFD(R) Hs Agonist 8.3 – 8.4 pEC50 3,21
pEC50 8.3 – 8.4 [3,21]
KRP 203-phosphate Mm Agonist 8.0 pEC50 23
pEC50 8.0 [23]
fingolimod-phosphate Hs Agonist 6.6 – 9.2 pEC50 3,10,20-21,29
pEC50 6.6 – 9.2 [3,10,20-21,29]
VPC03090-P Hs Full agonist 7.8 pEC50 17
pEC50 7.8 (EC50 1.77x10-8 M) [17]
sphingosine 1-phosphate Hs Agonist 7.2 – 8.1 pEC50 6,20-21
pEC50 7.2 – 8.1 (EC50 6.7x10-8 M) [6,20-21]
CYM-50308 Hs Agonist 7.3 pEC50 25
pEC50 7.3 (EC50 5.6x10-8 M) [25]
fingolimod-phosphate Mm Agonist 7.2 pEC50 3,23
pEC50 7.2 [3,23]
sphingosine 1-phosphate Mm Agonist 7.1 pEC50 21
pEC50 7.1 (EC50 7.5x10-8 M) [21]
etrasimod Hs Agonist 6.8 pEC50 4-5
pEC50 6.8 (EC50 1.47x10-7 M) [4-5]
Description: In a β-arrestin recruitment assay.
compound 5c [PMID: 27894870] Hs Agonist 6.7 – 6.8 pEC50 15
pEC50 6.8 (EC50 1.54x10-7 M) [15]
Description: In a cAMP assay.
pEC50 6.7 (EC50 2x10-7 M) [15]
Description: In a GTPγS binding assay.
siponimod Hs Agonist 6.1 pEC50 24
pEC50 6.1 (EC50 7.5x10-7 M) [24]
Description: In a GTPγS binding assay
ASP4058 Hs Agonist 5.6 pEC50 29
pEC50 5.6 (EC50 2.3x10-6 M) [29]
Description: In a GTPγS binding assay.
AUY954 Mm Agonist 5.0 – 6.0 pEC50 20
pEC50 5.0 – 6.0 [20]
ozanimod Hs Agonist <5.1 pEC50 22
pEC50 <5.1 (EC50 >7.865x10-6 M) [22]
Description: In a β-arrestin assay.
compound 43 [PMID: 26751273] Hs Agonist >4.4 pEC50 9
pEC50 >4.4 (EC50 <3.981x10-5 M) [9]
Description: In an aequorin calcium accumulation assay.
phytosphingosine 1-phosphate Hs Agonist 8.8 pIC50 6
pIC50 8.8 [6]
dihydrosphingosine 1-phosphate Hs Agonist 8.0 pIC50 6
pIC50 8.0 [6]
compound 26 [PMID: 16190743] Hs Agonist 7.2 pIC50 19
pIC50 7.2 [19]
sphingosine 1-phosphate Hs Agonist 6.1 – 7.0 pIC50 3,6
pIC50 6.1 – 7.0 [3,6]
ponesimod Hs Partial agonist 5.7 pIC50 2
pIC50 5.7 (IC50 1.956x10-6 M) [2]
Description: In a radioligand binding assay using membranes from CHO cells expressing human S1P4
View species-specific agonist tables
Agonist Comments
The EC50 was determined by physiometer functional characterization of the human S1P4 receptor expressed in CHO cells.
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CYM-50358 Hs Antagonist 7.6 pIC50 7,14
pIC50 7.6 (IC50 2.5x10-8 M) [7,14]
Immunopharmacology Comments
In the immune system S1P receptors regulate immune cell trafficking and mitogenesis, are involved in immune-modulation, and suppression of innate immune T cell responses.
Cell Type Associations
Immuno Cell Type:  Granulocytes
Cell Ontology Term:   eosinophil (CL:0000771)
Comment:  Eosinophils express all S1P receptors except S1P2R.
References:  16
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family
G12/G13 family
Adenylate cyclase inhibition
Comments:  Activation of Cdc42 [18].
References:  13,18
Tissue Distribution
Spleen, peripheral leukocytes, lung, thymus, lymph node, bone marrow
Species:  Human
Technique:  Northern blot
References:  12
Lung and spleen
Species:  Mouse
Technique:  Northern blot
References:  8
Naive T cell and regulatory T cell
Species:  Mouse
Technique:  RT-PCR
References:  27
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Cell migration
Species:  Human
Tissue:  CHO cells stably expressing S1P4
Response measured:  Migration
References:  13,18
Cell proliferation, cytokine production
Species:  Mouse
Tissue:  D10G4.1 mouse Th2 cells and EL4.IL-2 expressing S1P4
Response measured: 
References:  28
Physiological Consequences of Altering Gene Expression
Abnormal megakaryocyte morphology, a defect in platelet repopulation
Species:  Mouse
Tissue:  Megakaryocytes, platelets
Technique:  Gene knockouts
References:  11
Loss of S1P4 partially decreased the neutrophilia and inflammation in S1P lyase-deficient mice
Species:  Mouse
Tissue:  Neutrophil
Technique:  Gene knockouts
References:  1
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
S1pr4+|S1pr4tm1Dgen S1pr4tm1Dgen/S1pr4+
involves: 129P2/OlaHsd * C57BL/6
MGI:1333809  MP:0009142 decreased prepulse inhibition
S1pr4tm1Dgen S1pr4tm1Dgen/S1pr4tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:1333809  MP:0006207 embryonic lethality during organogenesis


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1. Allende ML, Bektas M, Lee BG, Bonifacino E, Kang J, Tuymetova G, Chen W, Saba JD, Proia RL. (2011) Sphingosine-1-phosphate lyase deficiency produces a pro-inflammatory response while impairing neutrophil trafficking. J. Biol. Chem., 286 (9): 7348-58. [PMID:21173151]

2. Bolli MH, Abele S, Binkert C, Bravo R, Buchmann S, Bur D, Gatfield J, Hess P, Kohl C, Mangold C et al.. (2010) 2-imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists. J. Med. Chem., 53 (10): 4198-211. [PMID:20446681]

3. Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P et al.. (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem., 277 (24): 21453-7. [PMID:11967257]

4. Buvinic S, Briones R, Huidobro-Toro JP. (2002) P2Y(1) and P2Y(2) receptors are coupled to the NO/cGMP pathway to vasodilate the rat arterial mesenteric bed. Br. J. Pharmacol., 136 (6): 847-56. [PMID:12110609]

5. Buzard DJ, Kim SH, Lopez L, Kawasaki A, Zhu X, Moody J, Thoresen L, Calderon I, Ullman B, Han S et al.. (2014) Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor. ACS Med Chem Lett, 5 (12): 1313-7. [PMID:25516790]

6. Candelore MR, Wright MJ, Tota LM, Milligan J, Shei GJ, Bergstrom JD, Mandala SM. (2002) Phytosphingosine 1-phosphate: a high affinity ligand for the S1P(4)/Edg-6 receptor. Biochem. Biophys. Res. Commun., 297 (3): 600-6. [PMID:12270137]

7. Cencetti F, Bernacchioni C, Tonelli F, Roberts E, Donati C, Bruni P. (2013) TGFβ1 evokes myoblast apoptotic response via a novel signaling pathway involving S1P4 transactivation upstream of Rho-kinase-2 activation. FASEB J., 27 (11): 4532-46. [PMID:23913862]

8. Contos JJ, Ye X, Sah VP, Chun J. (2002) Tandem genomic arrangement of a G protein (Gna15) and G protein-coupled receptor (s1p(4)/lp(C1)/Edg6) gene. FEBS Lett., 531 (1): 99-102. [PMID:12401211]

9. Demont EH, Bailey JM, Bit RA, Brown JA, Campbell CA, Deeks N, Dowell SJ, Eldred C, Gaskin P, Gray JR et al.. (2016) Discovery of Tetrahydropyrazolopyridine as Sphingosine 1-Phosphate Receptor 3 (S1P3)-Sparing S1P1 Agonists Active at Low Oral Doses. J. Med. Chem., 59 (3): 1003-20. [PMID:26751273]

10. Forrest M, Sun SY, Hajdu R, Bergstrom J, Card D, Doherty G, Hale J, Keohane C, Meyers C, Milligan J et al.. (2004) Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. J. Pharmacol. Exp. Ther., 309 (2): 758-68. [PMID:14747617]

11. Golfier S, Kondo S, Schulze T, Takeuchi T, Vassileva G, Achtman AH, Gräler MH, Abbondanzo SJ, Wiekowski M, Kremmer E et al.. (2010) Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine-1-phosphate receptor S1P4. FASEB J., 24 (12): 4701-10. [PMID:20686109]

12. Gräler MH, Bernhardt G, Lipp M. (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. [PMID:9790765]

13. Gräler MH, Grosse R, Kusch A, Kremmer E, Gudermann T, Lipp M. (2003) The sphingosine 1-phosphate receptor S1P4 regulates cell shape and motility via coupling to Gi and G12/13. J. Cell. Biochem., 89 (3): 507-19. [PMID:12761884]

14. Guerrero M, Urbano M, Velaparthi S, Zhao J, Schaeffer MT, Brown S, Rosen H, Roberts E. (2011) Discovery, design and synthesis of the first reported potent and selective sphingosine-1-phosphate 4 (S1P4) receptor antagonists. Bioorg. Med. Chem. Lett., 21 (12): 3632-6. [PMID:21570287]

15. Hur W, Rosen H, Gray NS. (2017) A benzo[b]thiophene-based selective type 4 S1P receptor agonist. Bioorg. Med. Chem. Lett., 27 (1): 1-5. [PMID:27894870]

16. Idzko M, Panther E, Corinti S, Morelli A, Ferrari D, Herouy Y, Dichmann S, Mockenhaupt M, Gebicke-Haerter P, Di Virgilio F et al.. (2002) Sphingosine 1-phosphate induces chemotaxis of immature and modulates cytokine-release in mature human dendritic cells for emergence of Th2 immune responses. FASEB J., 16 (6): 625-7. [PMID:11919175]

17. Kennedy PC, Zhu R, Huang T, Tomsig JL, Mathews TP, David M, Peyruchaud O, Macdonald TL, Lynch KR. (2011) Characterization of a sphingosine 1-phosphate receptor antagonist prodrug. J. Pharmacol. Exp. Ther., 338 (3): 879-89. [PMID:21632869]

18. Kohno T, Matsuyuki H, Inagaki Y, Igarashi Y. (2003) Sphingosine 1-phosphate promotes cell migration through the activation of Cdc42 in Edg-6/S1P4-expressing cells. Genes Cells, 8 (8): 685-97. [PMID:12875654]

19. Li Z, Chen W, Hale JJ, Lynch CL, Mills SG, Hajdu R, Keohane CA, Rosenbach MJ, Milligan JA, Shei GJ et al.. (2005) Discovery of potent 3,5-diphenyl-1,2,4-oxadiazole sphingosine-1-phosphate-1 (S1P1) receptor agonists with exceptional selectivity against S1P2 and S1P3. J. Med. Chem., 48 (20): 6169-73. [PMID:16190743]

20. Pan S, Mi Y, Pally C, Beerli C, Chen A, Guerini D, Hinterding K, Nuesslein-Hildesheim B, Tuntland T, Lefebvre S et al.. (2006) A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model. Chem. Biol., 13 (11): 1227-34. [PMID:17114004]

21. Sanna MG, Liao J, Jo E, Alfonso C, Ahn MY, Peterson MS, Webb B, Lefebvre S, Chun J, Gray N et al.. (2004) Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J. Biol. Chem., 279 (14): 13839-48. [PMID:14732717]

22. Scott FL, Clemons B, Brooks J, Brahmachary E, Powell R, Dedman H, Desale HG, Timony GA, Martinborough E, Rosen H et al.. (2016) Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1 ) and receptor-5 (S1P5 ) agonist with autoimmune disease-modifying activity. Br. J. Pharmacol., 173 (11): 1778-92. [PMID:26990079]

23. Song J, Matsuda C, Kai Y, Nishida T, Nakajima K, Mizushima T, Kinoshita M, Yasue T, Sawa Y, Ito T. (2008) A novel sphingosine 1-phosphate receptor agonist, 2-amino-2-propanediol hydrochloride (KRP-203), regulates chronic colitis in interleukin-10 gene-deficient mice. J. Pharmacol. Exp. Ther., 324 (1): 276-83. [PMID:17898319]

24. Urbano M, Guerrero M, Rosen H, Roberts E. (2013) Modulators of the Sphingosine 1-phosphate receptor 1. Bioorg. Med. Chem. Lett., 23 (23): 6377-89. [PMID:24125884]

25. Urbano M, Guerrero M, Velaparthi S, Crisp M, Chase P, Hodder P, Schaeffer MT, Brown S, Rosen H, Roberts E. (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. [PMID:21982495]

26. Van Brocklyn JR, Gräler MH, Bernhardt G, Hobson JP, Lipp M, Spiegel S. (2000) Sphingosine-1-phosphate is a ligand for the G protein-coupled receptor EDG-6. Blood, 95 (8): 2624-9. [PMID:10753843]

27. Wang W, Graeler MH, Goetzl EJ. (2004) Physiological sphingosine 1-phosphate requirement for optimal activity of mouse CD4+ regulatory T Cells. FASEB J., 18 (9): 1043-5. [PMID:15084513]

28. Wang W, Graeler MH, Goetzl EJ. (2005) Type 4 sphingosine 1-phosphate G protein-coupled receptor (S1P4) transduces S1P effects on T cell proliferation and cytokine secretion without signaling migration. FASEB J., 19 (12): 1731-3. [PMID:16046470]

29. Yamamoto R, Okada Y, Hirose J, Koshika T, Kawato Y, Maeda M, Saito R, Hattori K, Harada H, Nagasaka Y et al.. (2014) ASP4058, a novel agonist for sphingosine 1-phosphate receptors 1 and 5, ameliorates rodent experimental autoimmune encephalomyelitis with a favorable safety profile. PLoS ONE, 9 (10): e110819. [PMID:25347187]


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