Oxoeicosanoid receptor 1

Oxoeicosanoid receptor 1 (OXER1) also known as G-protein coupled receptor 170 (GPR170) is a is_associated_with::protein that in humans is encoded by the OXER1 is_associated_with::gene. This receptor has also been called hGPCR48, HGPCR48, or R527. OXER1 is a is_associated_with::G protein-coupled receptor (GPCR) for the is_associated_with::5-HETE family of is_associated_with::eicosanoids. It is structurally related to the hydroxy-carboxylic acid (HCA) family of G protein-coupled receptors whose three members are HCA1 (is_associated_with::GPR81), HCA2 (is_associated_with::Niacin receptor 1), and HCA3 (is_associated_with::Niacin receptor 2); OXER1 has 30.3%, 30.7%, and 30.7% amino acid sequnce identity with these GPCRs, respectively. It is similarly related (30.4% amino acid sequence identity) to the recently defined receptor for is_associated_with::12-HETE, is_associated_with::GPR31.

Species and tissue distribution
is_associated_with::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 carboxilic acid subfamilty, Niacin receptor 1, has been proposed to mediate the responses of mouse tissues to 5-oxo-ETE.

OXER1 is highly expressed by human is_associated_with::white blood cells, particularly is_associated_with::eosinophils and to a lesser extent is_associated_with::neutrophils, is_associated_with::basophils, and is_associated_with::monocytes; by bronchoalveolar is_associated_with::macrophages isolated from human is_associated_with::bronchoalveolar lavage washings; and by the human is_associated_with::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 type(s) bearing OXER1 in these tissues has not been defined.

Ligands
The OXER1 G protein-coupled receptor closely resembles, the hydroxy carboxilic 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, is_associated_with::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 is_associated_with::polyunsaturated fatty acids containing either an is_associated_with::hydroxyl (i.e. -OH) or oxo (i.e. =O, keto) residue removed by 5 carbons from each of these acid's is_associated_with::carboxy residue.

Agonists
OXER1 is known or presumed to bind and thereby be activated by the following endogenous is_associated_with::arachidonic acid metabolites; 5-oxo-ETE>5-oxo-15-hydroxy-ETE>5-hydroperoxyicosatetraenoic acid (5-HpETE)>is_associated_with::5-HETE>5,20-diHETE. OXER1 is also activated by metabolites of other is_associated_with::polyunsaturated fatty acids that therefore may be categorized as members of the 5-oxo-ETE family of agonists; these agonists include 5(S)-hydroxyl-6E,8Z,11Z-eicosatrienoic acid (a 5-LO metabolite of is_associated_with::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 acid and 5-oxo-6E,8Z,11Z,14Z,17Z-eicosapentaenoic acid (5-LO metabolites of the n-3 is_associated_with::polyunsaturated fatty acid, is_associated_with::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 that 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 is_associated_with::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 is_associated_with::MAPK/ERK, is_associated_with::p38 mitogen-activated protein kinases, cytosolic is_associated_with::Phospholipase A2, is_associated_with::PI3K/is_associated_with::Akt, and is_associated_with::protein kinase C beta (i.e. is_associated_with::PRKCB1, delta (i.e. is_associated_with::PRKCD), epsilon (i.e. is_associated_with::PRKCE), and zeta (i.e. is_associated_with::PRKCZ).

Function
OXER1 is activated by 5-oxo-ETE, 5-HETE, and other members of the is_associated_with::5-Hydroxyicosatetraenoic acid family of is_associated_with::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 wekk 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 an 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 antgonists will help address this issue.