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. 

Contents

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
lpC1
endothelial differentiation, G-protein-coupled receptor 6
endothelial differentiation, lysophosphatidic acid G-protein-coupled receptor, 6
Edg6_predicted
LOC314649
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
lpC1
S1P4
AI790342
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Natural/Endogenous Ligands
sphingosine 1-phosphate
sphingosylphosphorylcholine
Comments: sphingosine 1-phosphate exhibits greater potency than sphingosylphosphorylcholine
Rank order of potency
sphingosine 1-phosphate > dihydrosp​hingosine​-1-phosph​ate > sphingosylphosphorylcholine  [15]
Agonists
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

REFERENCES

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 25/07/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=278.

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