S1P<sub>4</sub> receptor | Lysophospholipid (S1P) receptors | IUPHAR Guide to IMMUNOPHARMACOLOGY

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S1P4 receptor

Target id: 278

Nomenclature: S1P4 receptor

Family: Lysophospholipid (S1P) receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: ON :     S1P4 receptor has curated data in GtoImmuPdb

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 > sphingosylphosphorylcholine  [22]

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 Affinity Units Reference
VPC03090-P Hs Full agonist 7.8 pKd 14
pKd 7.8 (Kd 1.73x10-8 M) [14]
AFD(R) Hs Agonist 8.3 – 8.4 pEC50 3,18
pEC50 8.3 – 8.4 [3,18]
KRP 203-phosphate Mm Agonist 8.0 pEC50 20
pEC50 8.0 [20]
FTY720-phosphate Hs Agonist 6.6 – 9.2 pEC50 8,17-18,25
pEC50 6.6 – 9.2 [8,17-18,25]
VPC03090-P Hs Full agonist 7.8 pEC50 14
pEC50 7.8 (EC50 1.77x10-8 M) [14]
sphingosine 1-phosphate Hs Agonist 7.2 – 8.1 pEC50 5,17-18
pEC50 7.2 – 8.1 (EC50 6.7x10-8 M) [5,17-18]
FTY720-phosphate Mm Agonist 7.2 pEC50 3,20
pEC50 7.2 [3,20]
sphingosine 1-phosphate Mm Agonist 7.1 pEC50 18
pEC50 7.1 (EC50 7.5x10-8 M) [18]
etrasimod Hs Agonist 6.8 pEC50 4
pEC50 6.8 (EC50 1.47x10-7 M) [4]
Description: In a β-arrestin recruitment assay.
compound 5c [PMID: 27894870] Hs Agonist 6.7 – 6.8 pEC50 12
pEC50 6.8 (EC50 1.54x10-7 M) [12]
Description: In a cAMP assay.
pEC50 6.7 (EC50 2x10-7 M) [12]
Description: In a GTPγS binding assay.
siponimod Hs Agonist 6.1 pEC50 21
pEC50 6.1 (EC50 7.5x10-7 M) [21]
Description: In a GTPγS binding assay
ASP4058 Hs Agonist 5.6 pEC50 25
pEC50 5.6 (EC50 2.3x10-6 M) [25]
Description: In a GTPγS binding assay.
AUY954 Mm Agonist 5.0 – 6.0 pEC50 17
pEC50 5.0 – 6.0 [17]
ozanimod Hs Agonist <5.1 pEC50 19
pEC50 <5.1 (EC50 >7.865x10-6 M) [19]
Description: In a β-arrestin assay.
compound 43 [PMID: 26751273] Hs Agonist >4.4 pEC50 7
pEC50 >4.4 (EC50 <3.981x10-5 M) [7]
Description: In an aequorin calcium accumulation assay.
phytosphingosine 1-phosphate Hs Agonist 8.8 pIC50 5
pIC50 8.8 [5]
dihydrosphingosine 1-phosphate Hs Agonist 8.0 pIC50 5
pIC50 8.0 [5]
compound 26 [PMID: 16190743] Hs Agonist 7.2 pIC50 16
pIC50 7.2 [16]
sphingosine 1-phosphate Hs Agonist 6.1 – 7.0 pIC50 3,5
pIC50 6.1 – 7.0 [3,5]
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.
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family
G12/G13 family
Adenylate cyclase inhibition
Comments:  Activation of Cdc42 [15].
References:  11,15
Tissue Distribution
Spleen, peripheral leukocytes, lung, thymus, lymph node, bone marrow
Species:  Human
Technique:  Northern blot
References:  10
Lung and spleen
Species:  Mouse
Technique:  Northern blot
References:  6
Naive T cell and regulatory T cell
Species:  Mouse
Technique:  RT-PCR
References:  23
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:  11,15
Cell proliferation, cytokine production
Species:  Mouse
Tissue:  D10G4.1 mouse Th2 cells and EL4.IL-2 expressing S1P4
Response measured: 
References:  24
Physiological Consequences of Altering Gene Expression
Loss of S1P4 partially decreased the neutrophilia and inflammation in S1P lyase-deficient mice
Species:  Mouse
Tissue:  Neutrophil
Technique:  Gene knockouts
References:  1
Abnormal megakaryocyte morphology, a defect in platelet repopulation
Species:  Mouse
Tissue:  Megakaryocytes, platelets
Technique:  Gene knockouts
References:  9
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: 847-856. [PMID:12110609]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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]

22. 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]

23. 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]

24. 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]

25. 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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How to cite this page

Yasuyuki Kihara, Victoria Blaho, Hirotaka Mizuno, Jerold Chun.
Lysophospholipid (S1P) receptors: S1P4 receptor. Last modified on 20/02/2018. Accessed on 16/01/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=278.