Nomenclature: S1P4 receptor

Family: Lysophospholipid (S1P) receptors

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing. 


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
endothelial differentiation, G-protein-coupled receptor 6
endothelial differentiation, lysophosphatidic acid G-protein-coupled receptor, 6
endothelial differentiation, G-protein-coupled receptor 6 (predicted)
endothelial differentiation, lysophosphatidic acid G-protein-coupled receptor 6
endothelial differentiation, lysophosphatidic acid G-protein-coupled receptor 6 (predicted)
sphingosine 1-phosphate receptor 4
sphingosine-1-phosphate receptor 4
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Reference Database
PharmGKB Gene
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
UniGene Hs.
Natural/Endogenous Ligands
sphingosine 1-phosphate
Comments: sphingosine 1-phosphate exhibits greater potency than sphingosylphosphorylcholine
Rank order of potency
sphingosine 1-phosphate > dihydrosp​hingosine​-1-phosph​ate > sphingosylphosphorylcholine  [15]
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 7.76 pKd 9
pKd 7.76 (Kd 1.73x10-8 M) [9]
AFD(R) Hs Agonist 8.3 – 8.4 pEC50 2,13
pEC50 8.3 – 8.4 [2,13]
KRP 203-phosphate Mm Agonist 8.0 pEC50 14
pEC50 8.0 [14]
FTY720-phosphate Hs Agonist 6.6 – 9.22 pEC50 5,12-13
pEC50 6.6 – 9.22 [5,12-13]
VPC03090-P Hs Full agonist 7.75 pEC50 9
pEC50 7.75 (EC50 1.77x10-8 M) [9]
sphingosine 1-phosphate Hs Agonist 7.17 – 8.07 pEC50 3,12-13
pEC50 7.17 – 8.07 (EC50 6.7x10-8 M) [3,12-13]
FTY720-phosphate Mm Agonist 7.15 pEC50 2,14
pEC50 7.15 [2,14]
sphingosine 1-phosphate Mm Agonist 7.12 pEC50 13
pEC50 7.12 (EC50 7.5x10-8 M) [13]
AUY954 Mm Agonist 5.0 – 6.0 pEC50 12
pEC50 5.0 – 6.0 [12]
phytosphingosine 1-phosphate Hs Agonist 8.8 pIC50 3
pIC50 8.8 [3]
dihydrosp​hingosine​-1-phosph​ate Hs Agonist 8.0 pIC50 3
pIC50 8.0 [3]
compound 26 [PMID:16190743] Hs Agonist 7.15 pIC50 11
pIC50 7.15 [11]
sphingosine 1-phosphate Hs Agonist 6.1 – 7.0 pIC50 2-3
pIC50 6.1 – 7.0 [2-3]
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 [10].
References:  8,10
Tissue Distribution
Spleen, peripheral leukocytes, lung, thymus, lymph node, bone marrow
Species:  Human
Technique:  Northern blot
References:  7
Lung and spleen
Species:  Mouse
Technique:  Northern blot
References:  4
Naive T cell and regulatory T cell
Species:  Mouse
Technique:  RT-PCR
References:  16
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:  8,10
Cell proliferation, cytokine production
Species:  Mouse
Tissue:  D10G4.1 mouse Th2 cells and EL4.IL-2 expressing S1P4
Response measured: 
References:  17
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:  6
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
Available Assays
DiscoveRx PathHunter® CHO-K1 EDG6 β-Arrestin Cell Line (Cat no. 93-0227C2) more info


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. 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]

3. 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]

4. 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]

5. 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]

6. 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]

7. 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. Genomics53 (2): 164-9. [PMID:9790765]

8. 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]

9. 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]

10. 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 Cells8 (8): 685-97. [PMID:12875654]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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. Blood95 (8): 2624-9. [PMID:10753843]

16. 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]

17. 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]

To cite this database page, please use the following:

Jerold Chun, Yasuyuki Kihara, Chido Mpamhanga.
Lysophospholipid (S1P) receptors: S1P4 receptor. Last modified on 05/06/2014. Accessed on 20/10/2014. IUPHAR database (IUPHAR-DB),

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