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OXE receptor

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 271

Nomenclature: OXE receptor

Family: Leukotriene receptors

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 7 423 2p21 OXER1 oxoeicosanoid receptor 1 2
Previous and Unofficial Names Click here for help
hGPCR48 [14] | R527 [13] | TG1019 [9] | GPR170 | 5-oxo-ETE receptor | oxoeicosanoid (OXE) receptor 1
Database Links Click here for help
Specialist databases
GPCRDB oxer1_human (Hs)
Other databases
Alphafold
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands Click here for help
5-oxo-C20:3
5-oxo-ETE
5-oxo-20-HETE
5-oxo-12-HETE
5-oxo-15-HETE
5-oxo-ODE
5S-HETE
5S-HPETE
Comments: 5-Oxo-ETE and 5-oxo-C20:3 are the most potent endogenous agonists
Potency order of endogenous ligands
5-oxo-ETE, 5-oxo-C20:3, 5-oxo-ODE > 5-oxo-15-HETE > 5S-HPETE > 5S-HETE  [8-9,13,25-26,33,37]

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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
[3H]5-oxo-ETE Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Agonist 8.4 pKd 25
pKd 8.4 (Kd 3.8x10-9 M) [25]
5-oxo-ETE Small molecule or natural product Ligand is endogenous in the given species Hs Full agonist 8.3 – 8.5 pEC50 8,25-26,33,37
pEC50 8.3 – 8.5 (EC50 5x10-9 – 3.1x10-9 M) [8,25-26,33,37]
5-oxo-C20:3 Small molecule or natural product Ligand is endogenous in the given species Hs Full agonist 8.0 pEC50 26
pEC50 8.0 (EC50 1x10-8 M) [26]
5-oxo-ODE Small molecule or natural product Ligand is endogenous in the given species Hs Full agonist 8.0 pEC50 4
pEC50 8.0 (EC50 1x10-8 M) [4]
5-oxo-15-HETE Small molecule or natural product Ligand is endogenous in the given species Hs Full agonist 7.7 pEC50 21,32,34,37
pEC50 7.7 (EC50 2x10-8 M) [21,32,34,37]
5S-HPETE Small molecule or natural product Ligand is endogenous in the given species Hs Full agonist 7.0 pEC50 10
pEC50 7.0 (EC50 1x10-7 M) [10]
5S-HETE Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 6.5 – 7.2 pEC50 10,21,32
pEC50 6.5 – 7.2 (EC50 3x10-7 – 6x10-8 M) [10,21,32]
5-oxo-20-HETE Small molecule or natural product Ligand is endogenous in the given species Hs Full agonist 6.5 pEC50 34
pEC50 6.5 (EC50 3.4x10-7 M) [34]
Agonist Comments
There are some discrepancies in the relative potencies of 5-oxo-ETE vs 5-oxo-15-HETE (5-oxo-ETE more potent [21,32]; equipotent [37]).
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
S‐Y048 Small molecule or natural product Hs Antagonist 10.7 pIC50 43
pIC50 10.7 (IC50 2x10-11 M) [43]
Description: Inhibition of 5‐oxo‐ETE‐induced calcium mobilization in human neutrophils.
5-(6-chloro-2-hexyl-1H-indol-1-yl)-5-oxo-valeric acid Small molecule or natural product Hs Antagonist 6.4 pIC50 7
pIC50 6.4 (IC50 4x10-7 M) [7]
5-oxo-12-HETE Small molecule or natural product Ligand is endogenous in the given species Hs Antagonist 6.3 pIC50 31
pIC50 6.3 (IC50 5x10-7 M) [31]
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
Gue1654 Small molecule or natural product Hs Negative ~6.0 pIC50 1
pIC50 ~6.0 (IC50 ~1x10-6 M) [1]
Allosteric Modulator Comments
Gue1654 inhibits most responses to 5-oxo-ETE (mediated by blocking Gβγ signalling) but not Gαi-mediated inhibition of adenylyl cyclase [1].
Immunopharmacology Comments
Activation of oxoeicosanoid receptor, OXER1, by products of 5-lipoxygenase enzyme activity has downstream effects on inflammation and immunity [8]. The OXER1 agonist 5-oxo-ETE acts as a chemoattractant for eosinophils [35] (e.g. in asthmatic airways [12]) and basophils [40]. OXER1 antagonists are being investigated for potential in eosinophilic diseases such as allergic rhinitis and asthma [27]
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Phospholipase C stimulation
References:  1,10
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Adenylyl cyclase inhibition
Phospholipase A2 stimulation
Other - See Comments
Comments:  Stimulation of PI3K [10,19], ERK [10,15,22] and p38 [15] MAP kinases.
References:  1,9-10,22
Tissue Distribution Click here for help
Liver, kidney, peripheral leukocytes, lung, spleen, placenta, small intestine, colon, skeletal muscle, heart
Species:  Human
Technique:  Northern blot
References:  9
Kidney, liver, placenta, peripheral blood leukocytes
Species:  Human
Technique:  Northern blot
References:  13
Eosinophils, neutrophils, lung macrophages, T cells, differentiated brochial epithelial cells
Species:  Human
Technique:  RT-PCR
References:  13
Prostate cancer cell lines (PC3, LNCaP and DU145 cells)
Species:  Human
Technique:  Western blot, RT-PCR, Northern blot and immunocytochemistry
References:  36
Prostate tumor tissue
Species:  Human
Technique:  Immunohistochemistry
References:  36
MDA-MB-231 and MCF7 breast cancer cell lines; SKOV3 ovarian cancer cell line
Species:  Human
Technique:  RT-PCR
References:  24
H295R adrenocortical cells
Species:  Human
Technique:  Western blot and RT-PCR
References:  3
Basophils
Species:  Human
Technique:  RT-PCR
References:  11,40
Functional Assays Click here for help
Actin polymerization
Species:  Human
Tissue:  Neutrophils, eosinophils, monocytes
Response measured:  Formation of F-actin
References:  5,30,38
Calcium mobilization
Species:  Human
Tissue:  Neutrophils, eosinophils, basophils
Response measured:  Increased cytosolic calcium levels
References:  11,20,29,32,37
Degranulation
Species:  Human
Tissue:  Neutrophils, eosinophils
Response measured:  Release of beta-glucuronidase and lysozyme (neutrophils) and eosinophil peroxidase and arylsulfatase (eosinophils)
References:  22-23
Shape change
Species:  Human
Tissue:  Eosinophils, neutrophils, basophils
Response measured:  Induces a shape change (detected by flow cytometry)
References:  40
CD11b expression
Species:  Human
Tissue:  Neutrophils, eosinophils, basophils
Response measured:  Stimulates surface expression of CD11b
References:  17,29-30
L-selectin shedding
Species:  Human
Tissue:  Eosinophils
Response measured:  Loss of L-selectin from the cell surface
References:  29
CD69 expression
Species:  Human
Tissue:  Eosinophils
Response measured:  Increased surface expression of CD69
References:  42
Functional Assay Comments
5-oxo-ETE-induced degranulation is modest unless cells are pretreated with cytokines (G-CSF or GM-CSF).
Physiological Functions Click here for help
Stimulation of the respiratory burst (superoxide production) in vitro
Species:  Human
Tissue:  Eosinophils and neutrophils
References:  5,22
Chemotaxis in vitro
Species:  Human
Tissue:  Eosinophils, neutrophils, monocytes, basophils
References:  11,28,32,37-38,40
Transendothelial migration in vitro
Species:  Human
Tissue:  Eosinophils
References:  6
GM-CSF release in vitro
Species:  Human
Tissue:  Monocytes
References:  39
Cancer cell proliferation in vitro
Species:  Human
Tissue:  Tumor cell lines (prostate, breast, ovarian)
References:  24,41
Steroidogenesis in vitro
Species:  Human
Tissue:  H295R adrenocortical cells
References:  3
Tissue eosinophilia in vivo
Species:  Human
Tissue:  Skin
References:  18
Physiological Functions Comments
To undergo the respiratory burst in response to 5-oxo-ETE neutrophils must first be pretreated with cytokines (G-CSF or GM-CSF) [22].
Physiological Consequences of Altering Gene Expression Comments
Since there is no ortholog of OXER1 in mice, gene knockout studies cannot be done in this species.
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphisms
Species:  Human
Description:  Two SNPs downstream from OXER1 (rs930421 and rs6719977) are associated with attention deficit hyperactivity disorder
SNP accession: 
References:  16
General Comments
There are no mouse or rat orthologues of OXER1.

References

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1. Blättermann S, Peters L, Ottersbach PA, Bock A, Konya V, Weaver CD, Gonzalez A, Schröder R, Tyagi R, Luschnig P et al.. (2012) A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer. Nat Chem Biol, 8 (7): 631-8. [PMID:22634634]

2. Brink C, Dahlén SE, Drazen J, Evans JF, Hay DW, Rovati GE, Serhan CN, Shimizu T, Yokomizo T. (2004) International Union of Pharmacology XLIV. Nomenclature for the oxoeicosanoid receptor. Pharmacol Rev, 56 (1): 149-57. [PMID:15001665]

3. Cooke M, Di Cónsoli H, Maloberti P, Cornejo Maciel F. (2013) Expression and function of OXE receptor, an eicosanoid receptor, in steroidogenic cells. Mol Cell Endocrinol, 371 (1-2): 71-8. [PMID:23159987]

4. Cossette C, Patel P, Anumolu JR, Sivendran S, Lee GJ, Gravel S, Graham FD, Lesimple A, Mamer OA, Rokach J et al.. (2008) Human neutrophils convert the sebum-derived polyunsaturated fatty acid Sebaleic acid to a potent granulocyte chemoattractant. J Biol Chem, 283 (17): 11234-43. [PMID:18287092]

5. Czech W, Barbisch M, Tenscher K, Schöpf E, Schröder JM, Norgauer J. (1997) Chemotactic 5-oxo-eicosatetraenoic acids induce oxygen radical production, Ca2+-mobilization, and actin reorganization in human eosinophils via a pertussis toxin-sensitive G-protein. J Invest Dermatol, 108 (1): 108-12. [PMID:8980298]

6. Dallaire MJ, Ferland C, Pagé N, Lavigne S, Davoine F, Laviolette M. (2003) Endothelial cells modulate eosinophil surface markers and mediator release. Eur Respir J, 21 (6): 918-24. [PMID:12797482]

7. Gore V, Patel P, Chang CT, Sivendran S, Kang N, Ouedraogo YP, Gravel S, Powell WS, Rokach J. (2013) 5-Oxo-ETE receptor antagonists. J Med Chem, 56 (9): 3725-32. [PMID:23581530]

8. Grant GE, Rokach J, Powell WS. (2009) 5-Oxo-ETE and the OXE receptor. Prostaglandins Other Lipid Mediat, 89 (3-4): 98-104. [PMID:19450703]

9. Hosoi T, Koguchi Y, Sugikawa E, Chikada A, Ogawa K, Tsuda N, Suto N, Tsunoda S, Taniguchi T, Ohnuki T. (2002) Identification of a novel human eicosanoid receptor coupled to G(i/o). J Biol Chem, 277 (35): 31459-65. [PMID:12065583]

10. Hosoi T, Sugikawa E, Chikada A, Koguchi Y, Ohnuki T. (2005) TG1019/OXE, a Galpha(i/o)-protein-coupled receptor, mediates 5-oxo-eicosatetraenoic acid-induced chemotaxis. Biochem Biophys Res Commun, 334 (4): 987-95. [PMID:16039985]

11. Iikura M, Suzukawa M, Yamaguchi M, Sekiya T, Komiya A, Yoshimura-Uchiyama C, Nagase H, Matsushima K, Yamamoto K, Hirai K. (2005) 5-Lipoxygenase products regulate basophil functions: 5-Oxo-ETE elicits migration, and leukotriene B(4) induces degranulation. J Allergy Clin Immunol, 116 (3): 578-85. [PMID:16159627]

12. Jones CE. (2005) The OXE receptor: a new therapeutic approach for asthma?. Trends Mol Med, 11 (6): 266-70. [PMID:15949767]

13. Jones CE, Holden S, Tenaillon L, Bhatia U, Seuwen K, Tranter P, Turner J, Kettle R, Bouhelal R, Charlton S, Nirmala NR, Jarai G, Finan P. (2003) Expression and characterization of a 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid receptor highly expressed on human eosinophils and neutrophils. Mol Pharmacol, 63: 471-477. [PMID:12606753]

14. Koike D, Obinata H, Yamamoto A, Takeda S, Komori H, Nara F, Izumi T, Haga T. (2006) 5-Oxo-eicosatetraenoic acid-induced chemotaxis: identification of a responsible receptor hGPCR48 and negative regulation by G protein G(12/13). J Biochem, 139 (3): 543-9. [PMID:16567419]

15. Langlois A, Chouinard F, Flamand N, Ferland C, Rola-Pleszczynski M, Laviolette M. (2009) Crucial implication of protein kinase C (PKC)-delta, PKC-zeta, ERK-1/2, and p38 MAPK in migration of human asthmatic eosinophils. J Leukoc Biol, 85 (4): 656-63. [PMID:19164129]

16. Lasky-Su J, Neale BM, Franke B, Anney RJ, Zhou K, Maller JB, Vasquez AA, Chen W, Asherson P, Buitelaar J et al.. (2008) Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations. Am J Med Genet B Neuropsychiatr Genet, 147B (8): 1345-54. [PMID:18821565]

17. Monneret G, Boumiza R, Gravel S, Cossette C, Bienvenu J, Rokach J, Powell WS. (2005) Effects of prostaglandin D(2) and 5-lipoxygenase products on the expression of CD203c and CD11b by basophils. J Pharmacol Exp Ther, 312 (2): 627-34. [PMID:15388786]

18. Muro S, Hamid Q, Olivenstein R, Taha R, Rokach J, Powell WS. (2003) 5-oxo-6,8,11,14-eicosatetraenoic acid induces the infiltration of granulocytes into human skin. J Allergy Clin Immunol, 112 (4): 768-74. [PMID:14564360]

19. Norgauer J, Barbisch M, Czech W, Pareigis J, Schwenk U, Schröder JM. (1996) Chemotactic 5-oxo-icosatetraenoic acids activate a unique pattern of neutrophil responses. Analysis of phospholipid metabolism, intracellular Ca2+ transients, actin reorganization, superoxide-anion production and receptor up-regulation. Eur J Biochem, 236 (3): 1003-9. [PMID:8665888]

20. O'Flaherty JT, Cordes J, Redman J, Thomas MJ. (1993) 5-Oxo-eicosatetraenoate, a potent human neutrophil stimulus. Biochem Biophys Res Commun, 192 (1): 129-34. [PMID:8386504]

21. O'Flaherty JT, Cordes JF, Lee SL, Samuel M, Thomas MJ. (1994) Chemical and biological characterization of oxo-eicosatetraenoic acids. Biochim Biophys Acta, 1201 (3): 505-15. [PMID:7803484]

22. O'Flaherty JT, Kuroki M, Nixon AB, Wijkander J, Yee E, Lee SL, Smitherman PK, Wykle RL, Daniel LW. (1996) 5-Oxo-eicosanoids and hematopoietic cytokines cooperate in stimulating neutrophil function and the mitogen-activated protein kinase pathway. J Biol Chem, 271 (30): 17821-8. [PMID:8663432]

23. O'Flaherty JT, Kuroki M, Nixon AB, Wijkander J, Yee E, Lee SL, Smitherman PK, Wykle RL, Daniel LW. (1996) 5-Oxo-eicosatetraenoate is a broadly active, eosinophil-selective stimulus for human granulocytes. J Immunol, 157 (1): 336-42. [PMID:8683135]

24. O'Flaherty JT, Rogers LC, Paumi CM, Hantgan RR, Thomas LR, Clay CE, High K, Chen YQ, Willingham MC, Smitherman PK et al.. (2005) 5-Oxo-ETE analogs and the proliferation of cancer cells. Biochim Biophys Acta, 1736 (3): 228-36. [PMID:16154383]

25. O'Flaherty JT, Taylor JS, Thomas MJ. (1998) Receptors for the 5-oxo class of eicosanoids in neutrophils. J Biol Chem, 273 (49): 32535-41. [PMID:9829988]

26. Patel P, Cossette C, Anumolu JR, Gravel S, Lesimple A, Mamer OA, Rokach J, Powell WS. (2008) Structural requirements for activation of the 5-oxo-6E,8Z, 11Z,14Z-eicosatetraenoic acid (5-oxo-ETE) receptor: identification of a mead acid metabolite with potent agonist activity. J Pharmacol Exp Ther, 325 (2): 698-707. [PMID:18292294]

27. Patel P, Reddy CN, Gore V, Chourey S, Ye Q, Ouedraogo YP, Gravel S, Powell WS, Rokach J. (2014) Two Potent OXE-R Antagonists: Assignment of Stereochemistry. ACS Med Chem Lett, 5 (7): 815-9. [PMID:25050171]

28. Powell WS, Chung D, Gravel S. (1995) 5-Oxo-6,8,11,14-eicosatetraenoic acid is a potent stimulator of human eosinophil migration. J Immunol, 154 (8): 4123-32. [PMID:7706749]

29. Powell WS, Gravel S, Halwani F. (1999) 5-oxo-6,8,11,14-eicosatetraenoic acid is a potent stimulator of L-selectin shedding, surface expression of CD11b, actin polymerization, and calcium mobilization in human eosinophils. Am J Respir Cell Mol Biol, 20 (1): 163-70. [PMID:9870930]

30. Powell WS, Gravel S, Halwani F, Hii CS, Huang ZH, Tan AM, Ferrante A. (1997) Effects of 5-oxo-6,8,11,14-eicosatetraenoic acid on expression of CD11b, actin polymerization, and adherence in human neutrophils. J Immunol, 159 (6): 2952-9. [PMID:9300719]

31. Powell WS, Gravel S, Khanapure SP, Rokach J. (1999) Biological inactivation of 5-oxo-6,8,11,14-eicosatetraenoic acid by human platelets. Blood, 93 (3): 1086-96. [PMID:9920859]

32. Powell WS, Gravel S, MacLeod RJ, Mills E, Hashefi M. (1993) Stimulation of human neutrophils by 5-oxo-6,8,11,14-eicosatetraenoic acid by a mechanism independent of the leukotriene B4 receptor. J Biol Chem, 268 (13): 9280-6. [PMID:8387490]

33. Powell WS, Gravelle F, Gravel S. (1992) Metabolism of 5(S)-hydroxy-6,8,11,14-eicosatetraenoic acid and other 5(S)-hydroxyeicosanoids by a specific dehydrogenase in human polymorphonuclear leukocytes. J Biol Chem, 267 (27): 19233-41. [PMID:1326548]

34. Powell WS, MacLeod RJ, Gravel S, Gravelle F, Bhakar A. (1996) Metabolism and biologic effects of 5-oxoeicosanoids on human neutrophils. J Immunol, 156 (1): 336-42. [PMID:8598482]

35. Powell WS, Rokach J. (2013) The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor. Prog Lipid Res, 52 (4): 651-65. [PMID:24056189]

36. Sarveswaran S, Ghosh J. (2013) OXER1, a G protein-coupled oxoeicosatetraenoid receptor, mediates the survival-promoting effects of arachidonate 5-lipoxygenase in prostate cancer cells. Cancer Lett, 336 (1): 185-95. [PMID:23643940]

37. Schwenk U, Schröder JM. (1995) 5-Oxo-eicosanoids are potent eosinophil chemotactic factors. Functional characterization and structural requirements. J Biol Chem, 270 (25): 15029-36. [PMID:7797484]

38. Sozzani S, Zhou D, Locati M, Bernasconi S, Luini W, Mantovani A, O'Flaherty JT. (1996) Stimulating properties of 5-oxo-eicosanoids for human monocytes: synergism with monocyte chemotactic protein-1 and -3. J Immunol, 157 (10): 4664-71. [PMID:8906847]

39. Stamatiou PB, Chan CC, Monneret G, Ethier D, Rokach J, Powell WS. (2004) 5-oxo-6,8,11,14-eicosatetraenoic acid stimulates the release of the eosinophil survival factor granulocyte/macrophage colony-stimulating factor from monocytes. J Biol Chem, 279 (27): 28159-64. [PMID:15136573]

40. Sturm GJ, Schuligoi R, Sturm EM, Royer JF, Lang-Loidolt D, Stammberger H, Amann R, Peskar BA, Heinemann A. (2005) 5-Oxo-6,8,11,14-eicosatetraenoic acid is a potent chemoattractant for human basophils. J Allergy Clin Immunol, 116 (5): 1014-9. [PMID:16275369]

41. Sundaram S, Ghosh J. (2006) Expression of 5-oxoETE receptor in prostate cancer cells: critical role in survival. Biochem Biophys Res Commun, 339 (1): 93-8. [PMID:16289380]

42. Urasaki T, Takasaki J, Nagasawa T, Ninomiya H. (2001) Pivotal role of 5-lipoxygenase in the activation of human eosinophils: platelet-activating factor and interleukin-5 induce CD69 on eosinophils through the 5-lipoxygenase pathway. J Leukoc Biol, 69 (1): 105-12. [PMID:11200053]

43. Ye Q, Chourey S, Reddy CN, Wang R, Cossette C, Gravel S, Slobodchikova I, Vuckovic D, Rokach J, Powell WS. (2020) Novel highly potent OXE receptor antagonists with prolonged plasma lifetimes that are converted to active metabolites in vivo in monkeys. Br J Pharmacol, 177 (2): 388-401. [PMID:31655025]

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