S1P<sub>5</sub> receptor | Lysophospholipid (S1P) receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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S1P5 receptor

target has curated data in GtoImmuPdb

Target id: 279

Nomenclature: S1P5 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

Contents:

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 398 19p13.2 S1PR5 sphingosine-1-phosphate receptor 5
Mouse 7 400 9 A4 S1pr5 sphingosine-1-phosphate receptor 5
Rat 7 400 8q13 S1pr5 sphingosine-1-phosphate receptor 5
Previous and Unofficial Names
edg8 | NRG-1 | endothelial differentiation G protein-coupled receptor 8 | nerve growth factor-regulated G-protein-coupled receptor 1
Database Links
Specialist databases
GPCRDB s1pr5_human (Hs), s1pr5_mouse (Mm), s1pr5_rat (Rn)
Other databases
ChEMBL Target CHEMBL2274 (Hs)
DrugBank Target Q9H228 (Hs)
Ensembl Gene ENSG00000180739 (Hs), ENSMUSG00000045087 (Mm), ENSRNOG00000020901 (Rn)
Entrez Gene 53637 (Hs), 94226 (Mm), 60399 (Rn)
Human Protein Atlas ENSG00000180739 (Hs)
KEGG Gene hsa:53637 (Hs), mmu:94226 (Mm), rno:60399 (Rn)
OMIM 605146 (Hs)
RefSeq Nucleotide NM_030760 (Hs), NM_053190 (Mm), NM_021775 (Rn)
RefSeq Protein NP_110387 (Hs), NP_444420 (Mm), NP_068543 (Rn)
UniProtKB Q9H228 (Hs), Q91X56 (Mm), Q9JKM5 (Rn)
Wikipedia S1PR5 (Hs)
Natural/Endogenous Ligands
sphingosine 1-phosphate
sphingosylphosphorylcholine
Comments: Sphingosine 1-phosphate exhibits greater potency than sphingosylphosphorylcholine
Potency order of endogenous ligands
sphingosine 1-phosphate > dihydrosphingosine 1-phosphate  [15]

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

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
sphingosine 1-phosphate Rn Agonist 8.7 pKd 15
⤷ pKd 8.7 [15]
VPC03090-P Hs Partial agonist 8.6 pKd 18
⤷ pKd 8.6 (Kd 2.3x10-9 M) [18]
siponimod Hs Agonist 9.0 pEC50 9-10,27
⤷ pEC50 9.0 (EC50 9.8x10-10 M) [9-10,27]
Description: In a GTPγS binding assay
fingolimod-phosphate Hs Agonist 8.2 – 9.5 pEC50 2,7,22
⤷ pEC50 8.2 – 9.5 [2,7,22]
AFD(R) Hs Agonist 8.0 – 9.7 pEC50 2,23
⤷ pEC50 8.0 – 9.7 [2,23]
VPC03090-P Hs Partial agonist 8.6 pEC50 18
⤷ pEC50 8.6 (EC50 2.4x10-9 M) [18]
A-971432 Hs Agonist 8.2 – 8.4 pEC50 6,12
⤷ pEC50 8.4 (EC50 4.1x10-9 M) [12]
Description: In a forskolin-induced cAMP inhibition assay in S1P5-transfected CHO cells.
pEC50 8.2 (EC50 5.7x10-9 M) [6,12]
Description: In a GTPγS assay using membranes from S1P5-transfected HEK293 cells.
RP-101075 Hs Agonist 8.2 pEC50 25
⤷ pEC50 8.2 (EC50 5.9x10-9 M) [25]
Description: As measured in a GTPγS assay.
sphingosine 1-phosphate Hs Agonist 7.4 – 8.9 pEC50 2,14,22-23
⤷ pEC50 7.4 – 8.9 [2,14,22-23]
ASP4058 Hs Agonist 8.1 pEC50 29
⤷ pEC50 8.1 (EC50 7.5x10-9 M) [29]
Description: In a GTPγS binding assay.
sphingosine 1-phosphate Mm Agonist 7.8 – 7.9 pEC50 14,23
⤷ pEC50 7.8 – 7.9 (EC50 1.6x10-8 M) [14,23]
compound 43 [PMID: 26751273] Hs Agonist 7.8 pEC50 5
⤷ pEC50 7.8 (EC50 1.66x10-8 M) [5]
Description: In an aequorin calcium accumulation assay.
ozanimod Hs Agonist 7.3 – 8.0 pEC50 21,24
⤷ pEC50 8.0 (EC50 1.1x10-8 M) [24]
Description: In a GTPγS assay.
pEC50 7.3 (EC50 5.52x10-8 M) [21]
etrasimod Hs Agonist 7.6 pEC50 3
⤷ pEC50 7.6 (EC50 2.44x10-8 M) [3]
Description: In a β-arrestin recruitment assay.
VPC44116 Hs Partial agonist 7.5 pEC50 8
⤷ pEC50 7.5 [8]
AUY954 Mm Agonist 6.5 pEC50 22
⤷ pEC50 6.5 [22]
AUY954 Hs Agonist 6.5 pEC50 22
⤷ pEC50 6.5 (EC50 3.4x10-7 M) [22]
fingolimod-phosphate Hs Agonist 9.2 pIC50 7
⤷ pIC50 9.2 (IC50 6x10-10 M) [7]
compound 26 [PMID: 16190743] Hs Agonist 9.0 pIC50 19
⤷ pIC50 9.0 [19]
ponesimod Hs Partial agonist 6.8 pIC50 1
⤷ pIC50 6.8 (IC50 1.42x10-7 M) [1]
Description: In a radioligand binding assay using membranes from CHO cells expressing human S1P5
fingolimod Hs Agonist 5.7 pIC50 11
⤷ pIC50 5.7 (IC50 2.1x10-6 M) [11]
View species-specific agonist tables
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:  13
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family
G12/G13 family 		Adenylate cyclase inhibition
Comments:  Activation of MAPK [20].
References:  15,20
Tissue Distribution
Brain, spleen, embryo (day 7 and 17)
Species:  Human
Technique:  Northern blot
References:  14
CD56dim NK cells
Species:  Human
Technique:  RT-PCR
References:  28
Brain, spleen, peripheral blood leukocytes, placenta, lung, aorta, and fetal spleen
Species:  Human
Technique:  Northern blot
References:  14
Ly6C− monocytes
Species:  Mouse
Technique:  RT-PCR
References:  4
Corpus callosum, anterior commissure, fimbria, and white matter of the cerebellum
Species:  Mouse
Technique:  in situ hybridisation
References:  16
Spleen, intestine, brain, vas def, testis, adrenal
Species:  Mouse
Technique:  Northern blot, in situ hybridisation
References:  15
NK cell
Species:  Mouse
Technique:  RT-PCR
References:  28
NG2-positive oligodendrocyte progenitor cells
Species:  Rat
Technique:  Immunocytochemistry
References:  26
Brain, spleen
Species:  Rat
Technique:  Northern blot
References:  15
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:  Mouse
Tissue:  Oligodendrocytes, NK cells, monocytes
Response measured:  Migration
References:  4,16,28
Cell survival
Species:  Mouse
Tissue:  Oligodendrocytes
Response measured:  Survival
References:  16
Physiological Consequences of Altering Gene Expression
Aberrant NK cell homing during steady-state conditions in knockout mice.
Species:  Mouse
Tissue:  NK cell
Technique:  Gene knockouts
References:  28
Loss of process retraction in knockout pre-oligodendrocytes
Species:  Mouse
Tissue:  Preoligodendrocytes
Technique:  Gene knockouts
References:  16
Lacking the egress of Ly6C− monocytes from the bone marrow in knockout mice
Species:  Mouse
Tissue:  Peripheral Ly6C− monocytes
Technique:  Gene knockouts
References:  4
Egress of NK cells from lymph nodes and bone marrow
Species:  Mouse
Tissue:  NK cells
Technique:  Gene knockouts
References:  17
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
S1pr5tm1Club S1pr5tm1Club/S1pr5tm1Club
involves: 129P2/OlaHsd * C57BL/6J		 MGI:2150641  MP:0003690 abnormal glial cell physiology PMID: 15703400 
S1pr5tm1Jch S1pr5tm1Jch/S1pr5tm1Jch
involves: 129P2/OlaHsd * C57BL/6		 MGI:2150641  MP:0008053 abnormal NK cell differentiation PMID: 19808259 

References

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1. 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]

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. 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]

4. Debien E, Mayol K, Biajoux V, Daussy C, De Aguero MG, Taillardet M, Dagany N, Brinza L, Henry T, Dubois B et al.. (2013) S1PR5 is pivotal for the homeostasis of patrolling monocytes. Eur. J. Immunol., 43 (6): 1667-75. [PMID:23519784]

5. 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]

6. Di Pardo A, Castaldo S, Amico E, Pepe G, Marracino F, Capocci L, Giovannelli A, Madonna M, van Bergeijk J, Buttari F et al.. (2018) Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington's disease. Hum. Mol. Genet., 27 (14): 2490-2501. [PMID:29688337]

7. 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]

8. Foss FW, Snyder AH, Davis MD, Rouse M, Okusa MD, Lynch KR, Macdonald TL. (2007) Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists. Bioorg. Med. Chem., 15 (2): 663-77. [PMID:17113298]

9. Gates E. (1998) A complement to care. Nurs Times, 94 (9): 55-7. [PMID:9735753]

10. Gergely P, Nuesslein-Hildesheim B, Guerini D, Brinkmann V, Traebert M, Bruns C, Pan S, Gray NS, Hinterding K, Cooke NG et al.. (2012) The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br. J. Pharmacol., 167 (5): 1035-47. [PMID:22646698]

11. Hale JJ, Lynch CL, Neway W, Mills SG, Hajdu R, Keohane CA, Rosenbach MJ, Milligan JA, Shei GJ, Parent SA et al.. (2004) A rational utilization of high-throughput screening affords selective, orally bioavailable 1-benzyl-3-carboxyazetidine sphingosine-1-phosphate-1 receptor agonists. J. Med. Chem., 47 (27): 6662-5. [PMID:15615513]

12. Hobson AD, Harris CM, van der Kam EL, Turner SC, Abibi A, Aguirre AL, Bousquet P, Kebede T, Konopacki DB, Gintant G et al.. (2015) Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P5) Agonist for the Potential Treatment of Neurodegenerative Disorders. J. Med. Chem., 58 (23): 9154-70. [PMID:26509640]

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. Im DS, Clemens J, Macdonald TL, Lynch KR. (2001) Characterization of the human and mouse sphingosine 1-phosphate receptor, S1P5 (Edg-8): structure-activity relationship of sphingosine1-phosphate receptors. Biochemistry, 40 (46): 14053-60. [PMID:11705398]

15. Im DS, Heise CE, Ancellin N, O'Dowd BF, Shei GJ, Heavens RP, Rigby MR, Hla T, Mandala S, McAllister G et al.. (2000) Characterization of a novel sphingosine 1-phosphate receptor, Edg-8. J. Biol. Chem., 275 (19): 14281-6. [PMID:10799507]

16. Jaillard C, Harrison S, Stankoff B, Aigrot MS, Calver AR, Duddy G, Walsh FS, Pangalos MN, Arimura N, Kaibuchi K et al.. (2005) Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J. Neurosci., 25 (6): 1459-69. [PMID:15703400]

17. Jenne CN, Enders A, Rivera R, Watson SR, Bankovich AJ, Pereira JP, Xu Y, Roots CM, Beilke JN, Banerjee A et al.. (2009) T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow. J. Exp. Med., 206 (11): 2469-81. [PMID:19808259]

18. 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]

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. Malek RL, Toman RE, Edsall LC, Wong S, Chiu J, Letterle CA, Van Brocklyn JR, Milstien S, Spiegel S, Lee NH. (2001) Nrg-1 belongs to the endothelial differentiation gene family of G protein-coupled sphingosine-1-phosphate receptors. J. Biol. Chem., 276 (8): 5692-9. [PMID:11069896]

21. Martinborough E, Boehm MF, Yeager AR, Tamiya J, Huang L, Brahmachary E, Moorjani M, Timony GA, Brooks JL, Peach R et al.. (2011) Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis. Patent number: US20110172202 A1. Assignee: Martinborough E, Boehm MF, Yeager AR, Tamiya J, Huang L, Brahmachary E, Moorjani M, Timony GA, Brooks JL, Peach R et al.. Priority date: 13/11/2009. Publication date: 14/07/2011.

22. 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]

23. 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]

24. 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]

25. Taylor Meadows KR, Steinberg MW, Clemons B, Stokes ME, Opiteck GJ, Peach R, Scott FL. (2018) Ozanimod (RPC1063), a selective S1PR1 and S1PR5 modulator, reduces chronic inflammation and alleviates kidney pathology in murine systemic lupus erythematosus. PLoS ONE, 13 (4): e0193236. [PMID:29608575]

26. Terai K, Soga T, Takahashi M, Kamohara M, Ohno K, Yatsugi S, Okada M, Yamaguchi T. (2003) Edg-8 receptors are preferentially expressed in oligodendrocyte lineage cells of the rat CNS. Neuroscience, 116 (4): 1053-62. [PMID:12617946]

27. 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]

28. Walzer T, Chiossone L, Chaix J, Calver A, Carozzo C, Garrigue-Antar L, Jacques Y, Baratin M, Tomasello E, Vivier E. (2007) Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor. Nat. Immunol., 8 (12): 1337-44. [PMID:17965716]

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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