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S1P4 receptor

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Target id: 278

Nomenclature: S1P4 receptor

Family: Lysophospholipid (S1P) receptors

Contents:

Gene and Protein Information Click here for help
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 Click here for help
edg6 | endothelial differentiation, G protein-coupled receptor 6
Database Links Click here for help
Specialist databases
GPCRdb s1pr4_human (Hs), s1pr4_mouse (Mm)
Other databases
Alphafold O95977 (Hs), Q9Z0L1 (Mm)
ChEMBL Target CHEMBL3230 (Hs)
Ensembl Gene ENSG00000125910 (Hs), ENSMUSG00000044199 (Mm), ENSRNOG00000005370 (Rn)
Entrez Gene 8698 (Hs), 13611 (Mm), 314649 (Rn)
Human Protein Atlas ENSG00000125910 (Hs)
KEGG Gene hsa:8698 (Hs), mmu:13611 (Mm), rno:314649 (Rn)
OMIM 603751 (Hs)
Pharos O95977 (Hs)
RefSeq Nucleotide NM_003775 (Hs), NM_010102 (Mm), NM_001108075 (Rn)
RefSeq Protein NP_003766 (Hs), NP_034232 (Mm), NP_001101545 (Rn)
UniProtKB O95977 (Hs), Q9Z0L1 (Mm)
Wikipedia S1PR4 (Hs)
Natural/Endogenous Ligands Click here for help
dihydrosphingosine 1-phosphate
sphingosine 1-phosphate
sphingosylphosphorylcholine
Comments: Sphingosine 1-phosphate exhibits greater potency than sphingosylphosphorylcholine
Potency order of endogenous ligands
sphingosine 1-phosphate > dihydrosphingosine 1-phosphate  [33]

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
VPC03090-P Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.8 pKd 21
⤷ pKd 7.8 (Kd 1.73x10-8 M) [21]
AFD(R) Small molecule or natural product Click here for species-specific activity table Hs Agonist 8.3 – 8.4 pEC50 3,27
⤷ pEC50 8.3 – 8.4 [3,27]
mocravimod-phosphate Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Mm Agonist 8.0 pEC50 30
⤷ pEC50 8.0 [30]
fingolimod-phosphate Small molecule or natural product Click here for species-specific activity table Hs Agonist 6.6 – 9.2 pEC50 3,13,25,27,36
⤷ pEC50 6.6 – 9.2 [3,13,25,27,36]
VPC03090-P Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.8 pEC50 21
⤷ pEC50 7.8 (EC50 1.77x10-8 M) [21]
sphingosine 1-phosphate Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 7.2 – 8.1 pEC50 6,25,27
⤷ pEC50 7.2 – 8.1 (EC50 6.7x10-8 M) [6,25,27]
CYM-50308 Small molecule or natural product Hs Agonist 7.3 pEC50 32
⤷ pEC50 7.3 (EC50 5.6x10-8 M) [32]
fingolimod-phosphate Small molecule or natural product Click here for species-specific activity table Mm Agonist 7.2 pEC50 3,30
⤷ pEC50 7.2 [3,30]
sphingosine 1-phosphate Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Mm Agonist 7.1 pEC50 27
⤷ pEC50 7.1 (EC50 7.5x10-8 M) [27]
etrasimod Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand 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] Small molecule or natural product Primary target of this compound Hs Agonist 6.7 – 6.8 pEC50 19
⤷ pEC50 6.8 (EC50 1.54x10-7 M) [19]
Description: In a cAMP assay.
pEC50 6.7 (EC50 2x10-7 M) [19]
Description: In a GTPγS binding assay.
siponimod Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 6.1 pEC50 31
⤷ pEC50 6.1 (EC50 7.5x10-7 M) [31]
Description: In a GTPγS binding assay
ASP4058 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist 5.6 pEC50 36
⤷ pEC50 5.6 (EC50 2.3x10-6 M) [36]
Description: In a GTPγS binding assay.
AUY954 Small molecule or natural product Click here for species-specific activity table Mm Agonist 5.0 – 6.0 pEC50 25
⤷ pEC50 5.0 – 6.0 [25]
ozanimod Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist <5.1 pEC50 29
⤷ pEC50 <5.1 (EC50 >7.865x10-6 M) [29]
Description: In a β-arrestin assay.
compound 43 [PMID: 26751273] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist >4.4 pEC50 10
⤷ pEC50 >4.4 (EC50 <3.981x10-5 M) [10]
Description: In an aequorin calcium accumulation assay.
phytosphingosine 1-phosphate Small molecule or natural product Hs Agonist 8.8 pIC50 6
⤷ pIC50 8.8 [6]
dihydrosphingosine 1-phosphate Small molecule or natural product Click here for species-specific activity table Hs Agonist 8.0 pIC50 6
⤷ pIC50 8.0 [6]
compound 26 [PMID: 16190743] Small molecule or natural product Click here for species-specific activity table Hs Agonist 7.2 pIC50 24
⤷ pIC50 7.2 [24]
sphingosine 1-phosphate Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 6.1 – 7.0 pIC50 3,6
⤷ pIC50 6.1 – 7.0 [3,6]
ponesimod Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand 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
SLB736 Small molecule or natural product Hs Agonist - - 18
⤷ [18]
View species-specific agonist tables
Agonist Comments
The EC50 was determined by physiometer functional characterization of the human S1P4 receptor expressed in CHO cells.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CYM-50358 Small molecule or natural product Hs Antagonist 7.6 pIC50 7,17
⤷ pIC50 7.6 (IC50 2.5x10-8 M) [7,17]
Cell Type Associations
Immuno Cell Type:  Granulocytes
Cell Ontology Term:   eosinophil (CL:0000771)
neutrophil (CL:0000775)
Comment:  Eosinophils express all S1P receptors except S1P2R.
A missense variant of S1P4 receptor in humans correlates with decreased circulating neutrophils.
References:  8,20
Immuno Cell Type:  B cells
Comment:  Expressed by peritoneal B1a, B1b, and B2 B cells.
References:  22
Immuno Cell Type:  T cells
Cell Ontology Term:   T-helper 17 cell (CL:0000899)
Comment:  Affects Th17 differentiation.
References:  28
Immuno Cell Type:  Dendritic cells
Cell Ontology Term:   dendritic cell (CL:0000451)
Comment:  Affects dendritic cell migration to lymph nodes.
References:  11
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family
G12/G13 family 		Adenylyl cyclase inhibition
Comments:  Activation of Cdc42 [23].
References:  16,23
Tissue Distribution Click here for help
Spleen, peripheral leukocytes, lung, thymus, lymph node, bone marrow
Species:  Human
Technique:  Northern blot
References:  15
Lung and spleen
Species:  Mouse
Technique:  Northern blot
References:  9
Naive T cell and regulatory T cell
Species:  Mouse
Technique:  RT-PCR
References:  34
Expression Datasets Click here for help

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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 Click here for help
Cell migration
Species:  Human
Tissue:  CHO cells stably expressing S1P4
Response measured:  Migration
References:  16,23
Cell proliferation, cytokine production
Species:  Mouse
Tissue:  D10G4.1 mouse Th2 cells and EL4.IL-2 expressing S1P4
Response measured: 
References:  35
Physiological Consequences of Altering Gene Expression Click here for help
Abnormal megakaryocyte morphology, a defect in platelet repopulation
Species:  Mouse
Tissue:  Megakaryocytes, platelets
Technique:  Gene knockouts
References:  14
Loss of S1P4 partially decreased the neutrophilia and inflammation in S1P lyase-deficient mice
Species:  Mouse
Tissue:  Neutrophil
Technique:  Gene knockouts
References:  1
S1P4 receptor signaling suppresses macrophage and neutrophil migration.
Species:  Mouse
Tissue:  Whole animal
Technique:  Gene knockouts.
References:  12
S1P4 receptor deficiency reduces DC migration and Th17 differentiation.
Species:  Mouse
Tissue:  Whole animal
Technique:  Gene knockouts
References:  28
Loss of S1P4 impairs splenic germinal center response to sepsis.
Species:  Mouse
Tissue:  Spleen
Technique:  Gene knockout
References:  26
Hemizygous deletion of S1P4 attenuates high-fat diet-induced hepatic inflammation and nonalcoholic steatohepatitis.
Species:  Mouse
Tissue:  Liver
Technique:  Hemizygous gene knockout
References:  18
Phenotypes, Alleles and Disease Models Click here for help 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
Biologically Significant Variants Click here for help
Type:  Missense mutation
Species:  Human
Description:  Neutropenia, generalized leukopenia
Amino acid change:  Arg365Leu
SNP accession:  rs3746072

References

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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. CHARGE Consortium Hematology Working Group. (2016) Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits. Nat Genet, 48 (8): 867-76. [PMID:27399967]

9. 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]

10. 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]

11. Dillmann C, Mora J, Olesch C, Brüne B, Weigert A. (2015) S1PR4 is required for plasmacytoid dendritic cell differentiation. Biol Chem, 396 (6-7): 775-82. [PMID:25720060]

12. Fettel J, Kühn B, Guillen NA, Sürün D, Peters M, Bauer R, Angioni C, Geisslinger G, Schnütgen F, Meyer Zu Heringdorf D et al.. (2019) Sphingosine-1-phosphate (S1P) induces potent anti-inflammatory effects in vitro and in vivo by S1P receptor 4-mediated suppression of 5-lipoxygenase activity. FASEB J, 33 (2): 1711-1726. [PMID:30188757]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. Hong CH, Ko MS, Kim JH, Cho H, Lee CH, Yoon JE, Yun JY, Baek IJ, Jang JE, Lee SE et al.. (2022) Sphingosine 1-Phosphate Receptor 4 Promotes Nonalcoholic Steatohepatitis by Activating NLRP3 Inflammasome. Cell Mol Gastroenterol Hepatol, 13 (3): 925-947. [PMID:34890841]

19. 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]

20. 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]

21. 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]

22. Kleinwort A, Lührs F, Heidecke CD, Lipp M, Schulze T. (2018) S1P Signalling Differentially Affects Migration of Peritoneal B Cell Populations In Vitro and Influences the Production of Intestinal IgA In Vivo. Int J Mol Sci, 19 (2). [PMID:29382132]

23. 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]

24. 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]

25. 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]

26. Riese J, Hähnel C, Menz J, Hannemann M, Khabipov A, Lührs F, Schulze T. (2022) S1PR4 deficiency results in reduced germinal center formation but only marginally affects antibody production. Front Immunol, 13: 1053490. [PMID:36532028]

27. 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]

28. Schulze T, Golfier S, Tabeling C, Räbel K, Gräler MH, Witzenrath M, Lipp M. (2011) Sphingosine-1-phospate receptor 4 (S1P₄) deficiency profoundly affects dendritic cell function and TH17-cell differentiation in a murine model. FASEB J, 25 (11): 4024-36. [PMID:21825036]

29. 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]

30. 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]

31. 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]

32. 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]

33. 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]

34. 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]

35. 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]

36. 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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