OXE receptor

Target id: 271

Nomenclature: OXE receptor

Family: Leukotriene receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     OXE receptor has curated GtoImmuPdb data

Gene and Protein Information
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
hGPCR48 [14] | R527 [13] | TG1019 [9] | GPR170 | 5-oxo-ETE receptor | oxoeicosanoid (OXE) receptor 1
Database Links
Specialist databases
GPCRDB oxer1_human (Hs)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
5-oxo-C20:3
5-oxo-ETE
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  [9,13,26]

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 Affinity Units Reference
[3H]5-oxo-ETE Hs Agonist 8.4 pKd 25
pKd 8.4 (Kd 3.8x10-9 M) [25]
5-oxo-ETE 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 Hs Full agonist 8.0 pEC50 26
pEC50 8.0 (EC50 1x10-8 M) [26]
5-oxo-ODE Hs Full agonist 8.0 pEC50 4
pEC50 8.0 (EC50 1x10-8 M) [4]
5-oxo-15-HETE Hs Full agonist 7.7 pEC50 21,32,34,37
pEC50 7.7 (EC50 2x10-8 M) [21,32,34,37]
5S-HPETE Hs Full agonist 7.0 pEC50 10
pEC50 7.0 (EC50 1x10-7 M) [10]
5S-HETE 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 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 Affinity Units Reference
5-(6-chloro-2-hexyl-1H-indol-1-yl)-5-oxo-valeric acid Hs Antagonist 6.4 pIC50 7
pIC50 6.4 (IC50 4x10-7 M) [7]
5-oxo-12-HETE 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 Affinity Units Reference
Gue1654 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
Transducer Effector/Response
Gi/Go family Phospholipase C stimulation
References:  1,10
Secondary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate 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
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
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
Degranulation
Species:  Human
Tissue:  Neutrophils, eosinophils
Response measured:  Release of beta-glucuronidase and lysozyme (neutrophils) and eosinophil peroxidase and arylsulfatase (eosinophils)
References:  22-23
Calcium mobilization
Species:  Human
Tissue:  Neutrophils, eosinophils, basophils
Response measured:  Increased cytosolic calcium levels
References:  11,20,29,32,37
Actin polymerization
Species:  Human
Tissue:  Neutrophils, eosinophils, monocytes
Response measured:  Formation of F-actin
References:  5,30,38
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
Functional Assay Comments
5-oxo-ETE-induced degranulation is modest unless cells are pretreated with cytokines (G-CSF or GM-CSF).
Physiological Functions
Transendothelial migration in vitro
Species:  Human
Tissue:  Eosinophils
References:  6
GM-CSF release in vitro
Species:  Human
Tissue:  Monocytes
References:  39
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
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
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

Show »

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: 149-157. [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 Gi/o. J. Biol. Chem.277: 31459-31465. [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 Med11 (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: 129-134. [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: 505-515. [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: 17821-17828. [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. Acta1736 (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 Lett5 (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. Blood93 (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: 9280-9286. [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: 15029-15036. [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]

Contributors

Show »

How to cite this page

William Powell, Joshua Rokach, Magnus Bäck, Sven-Erik Dahlén, Jeffrey Drazen, Jilly F. Evans, G. Enrico Rovati, Takao Shimizu, Charles N. Serhan, Takehiko Yokomizo.
Leukotriene receptors: OXE receptor. Last modified on 16/03/2017. Accessed on 23/02/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=271.