Oxoeicosanoid receptor 1

Species and tissue distribution

Orthologs of OXER1 are found in various mammalian species including opossums and several species of fish; however, mice and rats lack a clear ortholog of OXER1. This represents an important hindrance to studies on the function of OXER1 since these two mammalian species are the most common and easiest models for investigating the in vivo functions of receptors in mammals and by extrapolation humans. Since mouse cells make and respond to members of the 5-HETE family of agonists, it is most likely that mice do have a receptor that substitutes for OXER1 by mediating their responses to this agonist family. Recently, A G protein-couple receptor of the hydroxy carboxylic acid subfamily, Niacin receptor 1, has been proposed to mediate the responses of mouse tissues to 5-oxo-ETE.

OXER1 is highly expressed by human white blood cells, particularly eosinophils and to a lesser extent neutrophils, basophils, and monocytes; by bronchoalveolar macrophages isolated from human bronchoalveolar lavage washings; and by the human H295R adrenocortical cell line. Various types of human cancer cells lines express OXER1; these include those of the prostate, breast, lung, ovaries, colon, and pancreas. OXER1 is also expressed by the human spleen, lung, liver, and kidney tissues. The exact cell types bearing OXER1 in these tissues has not been defined.

A recent study has found that cats express the OXER1 receptor for 5-oxo-ETE, that feline leukocytes, including eosinophils, have been found to synthesize and be very highly responsive to 5-oxo-ETE, and that 5-oxo-ETE is present in the bronchoalveolar lavage fluid from cats with experimentally induced asthma; these findings suggest that the 5-oxo-ETE/OXER1 axis may play an important role in feline asthma, a common condition in this species, and that felines could serve as a useful animal model to investigate the pathophysiological role of 5-oxo-ETE in asthma and other conditions.

Ligands

The OXER1 G protein-coupled receptor resembles the hydroxy carboxylic acid subfamily of G protein-coupled receptors, which besides GPR109A, niacin receptor 1, and niacin receptor 2 may include the recently defined receptor for 12-HETE, GPR31, not only in its amino acid sequence but also in the hydroxy-carboxylic acid nature of its cognate ligands. Naturally occurring ligands for OXER1 are long chain polyunsaturated fatty acids containing either a hydroxyl (i.e. -OH) or oxo (i.e. =O, keto) residue removed by 5 carbons from each of these acid's carboxy residue.

Agonists

OXER1 is known or presumed to bind and thereby be activated by the following endogenous arachidonic acid metabolites; 5-oxo-ETE5-oxo-15-hydroxy-ETE5-hydroperoxyicosatetraenoic acid (5-HpETE)5-HETE5,20-diHETE. OXER1 is also activated by metabolites of other polyunsaturated fatty acids that therefore may be categorized as members of the 5-oxo-ETE family of agonists; these agonists include 5(S)-oxo-6E,8Z,11Z-eicosatrienoic acid (a 5-LO metabolite of mead acid); 5(S)-hydroxy-6E,8Z-octadecadienoic acid and 5(S)-oxo-6E,8Z-octadecadienoic acid (5-LO metabolites of sebaleic acid, i.e. 5Z,8Z-octadecadienoic acid); and 5(S)-hydroxy-6E,8Z,11Z,14Z,17Z-eicosapentaenoic and 5-oxo-6E,8Z,11Z,14Z,17Z-eicosapentaenoic acids (5-LO metabolites of the n-3 polyunsaturated fatty acid, eicosapentaenoic acid).

Antagonists

5-Oxo-12(S)-hydroxy-HETE and its 8-trans isomer, 5-oxo-12(S)-hydroxy-6E,8E,11Z,14Z-eicosatetraenoic acid, and a series of synthetic mimetics of 5-oxo-ETE structure (compounds 346, S-264, S-230, Gue154, and still to be named but considerably more potent drugs than these) block the activity of 5-oxo-ETE but not other stimuli in leukocytes and are presumed to be OXER1 antagonists.

Mechanisms of activating cells

OXE-R couples to the G protein complex Gαi-Gβγ; when bound to a 5-oxo-ETE family member, OXE-R triggers this G protein complex to dissociate into its Gαi and Gβγ components. Gβγ appears to be the component most responsible for activating many of the signal pathways that lead to cellular functional responses. Intracellular cell-activation pathways stimulated by OXER1 include those involving rises in cytosolic calcium ion levels, and along with others that lead to the activation of MAPK/ERK, p38 mitogen-activated protein kinases, cytosolic Phospholipase A2, PI3K/Akt, and protein kinase C beta (i.e. PRKCB1, delta (i.e. PRKCD), epsilon (i.e. PRKCE), and zeta (i.e. PRKCZ).

Function

OXER1 is activated by 5-oxo-ETE, 5-HETE, and other members of the 5-Hydroxyicosatetraenoic acid family of arachidonic acid metabolites and thereby mediates this family's stimulatory effects on cell types that are involved in mediating immunity-based inflammatory reactions such as neutrophils, monocytes, and macrophages) as well as allergic reactions such as eosinophils and basophils. It also mediates the in vitro proliferation and other pro-malignant responses of cultured prostate, breast, ovary, and kidney cancer cells to the 5-HETE family of agonists. These studies suggest that OXER1 may be involved in orchestrating inflammatory and allergic responses in humans and contribute to the growth and spread of human prostate, breast, ovary, and kidney cancers. OXER1 is responsible for steroid production response to 5-oxo-ETE by human steroidogenic cells in vitro and therefore could be involved in steroid production in humans.

To date, however, all studies have been pre-clinical; they use model systems that can suggest but not prove the contribution of OXER1 to human physiology and diseases. The most well-studied and promising area for OXER1 function is in allergic reactions. The recent development of OXER1 antagonists will help address this issue.

References

References

1. (2002). "Identification of a novel human eicosanoid receptor coupled to G(i/o)". J. Biol. Chem..
2. (2004). "International Union of Pharmacology XLIV. Nomenclature for the oxoeicosanoid receptor". Pharmacol. Rev..
3. "Entrez Gene: OXER1 oxoeicosanoid (OXE) receptor 1".
4. (1998). "Receptors for the 5-oxo class of eicosanoids in neutrophils". J. Biol. Chem..
5. (2002). "Identification of a novel human eicosanoid receptor coupled to G(i/o)". J. Biol. Chem..
6. (2003). "Expression and characterization of a 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid receptor highly expressed on human eosinophils and neutrophils". Mol. Pharmacol..
7. (2005). "TG1019/OXE, a Galpha(i/o)-protein-coupled receptor, mediates 5-oxo-eicosatetraenoic acid-induced chemotaxis". Biochem. Biophys. Res. Commun..
8. (2013). "The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor". Prog. Lipid Res..
9. (2006). "5-Oxo-eicosatetraenoic acid-induced chemotaxis: identification of a responsible receptor hGPCR48 and negative regulation by G protein G(12/13)". J. Biochem..
10. (Jun 2011). "International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)". Pharmacological Reviews.
11. (Sep 2011). "Identification of the orphan G protein-coupled receptor GPR31 as a receptor for 12-(S)-hydroxyeicosatetraenoic acid". The Journal of Biological Chemistry.
12. (2013). "The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor". Prog. Lipid Res..
13. (2014). "Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid". Biochim. Biophys. Acta.
14. (2001). "Synthesis of 5-oxo-6,8,11,14-eicosatetraenoic acid and identification of novel omega-oxidized metabolites in the mouse macrophage". J. Pharmacol. Exp. Ther..
15. (2013). "Expression and function of OXE receptor, an eicosanoid receptor, in steroidogenic cells". Mol. Cell. Endocrinol..
16. (1998). "Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells". Proc. Natl. Acad. Sci. U.S.A..
17. (2014). "Serum levels of arachidonic acid metabolites change during prostate cancer progression". Prostate.
18. (2005). "5-Oxo-ETE analogs and the proliferation of cancer cells". Biochim. Biophys. Acta.
19. (2011). "Enhanced formation of 5-oxo-6,8,11,14-eicosatetraenoic acid by cancer cells in response to oxidative stress, docosahexaenoic acid and neutrophil-derived 5-hydroxy-6,8,11,14-eicosatetraenoic acid". Carcinogenesis.
20. (1996). "Growth control of lung cancer by interruption of 5-lipoxygenase-mediated growth factor signaling". J. Clin. Invest..
21. (2009). "HPLC quantification of 5-hydroxyeicosatetraenoic acid in human lung cancer tissues". Biomed. Chromatogr..
22. (2007). "Comparative analysis of peritoneum and tumor eicosanoids and pathways in advanced ovarian cancer". Clin. Cancer Res..
23. (1996). "Inhibition of tumour growth by lipoxygenase inhibitors". Br. J. Cancer.
24. (2003). "Multiple signal pathways are involved in the mitogenic effect of 5(S)-HETE in human pancreatic cancer". Oncology.
25. (1999). "Lipoxygenase inhibitors abolish proliferation of human pancreatic cancer cells". Biochem. Biophys. Res. Commun..
26. (Apr 2015). "Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids.
27. (Aug 2015). "Biosynthesis and actions of 5-oxoeicosatetraenoic acid (5-oxo-ETE) on feline granulocytes". Biochem Pharmacol.
28. (2009). "GPR109A, GPR109B and GPR81, a family of hydroxy-carboxylic acid receptors". Trends Pharmacol. Sci..
29. (2011). "International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)". Pharmacol. Rev..
30. (1998). "Receptors for the 5-oxo class of eicosanoids in neutrophils". J. Biol. Chem..
31. (1987). "5-Hydroxyeicosatetraenoate promotes Ca2+ and protein kinase C mobilization in neutrophils". Biochem. Biophys. Res. Commun..
32. (2003). "Expression and characterization of a 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid receptor highly expressed on human eosinophils and neutrophils". Mol. Pharmacol..
33. (2005). "TG1019/OXE, a Galpha(i/o)-protein-coupled receptor, mediates 5-oxo-eicosatetraenoic acid-induced chemotaxis". Biochem. Biophys. Res. Commun..
34. (2014). "Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7". Br. J. Pharmacol..
35. (2014). "A biased non-Gαi OXE-R antagonist demonstrates that Gαi protein subunit is not directly involved in neutrophil, eosinophil, and monocyte activation by 5-oxo-ETE". J. Immunol..
36. (1998). "Receptors for the 5-oxo class of eicosanoids in neutrophils". J. Biol. Chem..
37. (2014). "ICAM-1: isoforms and phenotypes". J. Immunol..
38. (1988). "Stereospecific bioactions of 5-hydroxyeicosatetraenoate". FEBS Lett..
39. (1993). "5-Oxo-eicosatetraenoate, a potent human neutrophil stimulus". Biochem. Biophys. Res. Commun..
40. (1995). "5-Lipoxygenase products modulate the activity of the 85-kDa phospholipase A2 in human neutrophils". J. Biol. Chem..
41. (2011). "Inhibition of 5-lipoxygenase triggers apoptosis in prostate cancer cells via down-regulation of protein kinase C-epsilon". Biochim. Biophys. Acta.
42. (2013). "OXER1, a G protein-coupled oxoeicosatetraenoid receptor, mediates the survival-promoting effects of arachidonate 5-lipoxygenase in prostate cancer cells". Cancer Lett..
43. (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..