| GPR31 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | GPR31, 12-HETER, HETER, HETER1, G protein-coupled receptor 31 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:602043;MGI:1354372;HomoloGene:48337;GeneCards:GPR31;OMA:GPR31 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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G-protein coupled receptor 31 also known as12-(S)-HETE receptor is a protein that in humans is encoded by theGPR31gene. The human gene is located on chromosome 6q27 and encodes aG-protein coupled receptor protein composed of 319 amino acids.[5][6]
The GPR31 receptor shares a close amino acid sequence similarity with theoxoeicosanoid receptor 1, a G-protein coupled receptor encoded by the GPR170 gene.[7][8][9]
The oxoeicosanoid receptor 1 is the receptor for a group ofarachidonic acid metabolites produced by5-lipoxygenase, such as5-Hydroxyicosatetraenoic acid (5-HETE), 5-oxoicosanoic acid (5-oxo-ETE), and other members of this family, which are potent bioactive cell stimuli. In contrast, the GPR31 receptor binds to a different arachidonic acid metabolite,12-hydroxyeicosatetraenoic acid (12-HETE), synthesized by12-lipoxygenase. This conclusion is supported by studies that cloned the receptor from thePC-3 prostate cancer cell line. The cloned receptor, when expressed in other cell types, bound 12-HETE with high affinity (Kd = 5nM) and mediated the effects of low concentrations of theS but notRstereoisomer of 12-HETE.[9]
In a [35S]GTPγS binding assay, which estimates a receptor's binding affinity by measuring its stimulation of [35S]GTPγS binding, 12(S)-HETE activated GPR31 with anEC50 (effective concentration causing a 50% of maximal [35S]GTPγS binding) of less than 0.3 nM. In comparison, the EC50 was 42 nM for 15(S)-HETE, 390 nM for 5(S)-HETE, and undetectable for 12(R)-HETE.[10]
It is currently unknown whether GPR31 interacts with structural analogs of 12(S)-HETE, such as 12-oxo-ETE (a metabolite of 12(S)-HETE), various 5,12-diHETEs includingLTB4, or other bioactive metabolites like thehepoxilins. Further research is required to determine whether GPR31 exclusively binds and mediates the effects of 12(S)-HETE or, like the oxoeicosanoid receptor 1, interacts with a broader family of analogs.
Like the oxoeicosanoid receptor, GPR31 activates theMEK-ERK1/2 signaling pathway, but unlike oxoeicosanoid receptor 1, it does not cause an increase in cytosolicCa2+ concentration. It also activatesNFκB.[9] GPR31 exhibitsstereospecificity and other properties expected of a true G-protein coupled receptor (GPCR).
12(S)-HETE also: a) binds to and activates theleukotriene B4 receptor-2 (BLT2), a GPCR for the 5-lipoxygenase-derived metaboliteLTB4;[9][11] b) binds to, but inhibits, the GPCR forprostaglandin H2 andthromboxane A2, two arachidonic acid metabolites;[12] c) binds with high affinity to a 50kilodalton (kDa) subunit of a 650 kDa cytosolic and nuclear protein complex;[13] and d) binds with low affinity to and activates intracellularperoxisome proliferator-activated receptor gamma.[14]
These alternate binding sites complicate the determination of 12(S)-HETE's reliance on GPR31 for cell activation and the overall function of GPR31. Studies utilizing GPR31Gene knockout models will be crucial for understanding its role in vivo.
GPR31 receptor mRNA is highly expressed in the PC-3 prostate cancer cell line and to a lesser extent theDU145 prostate cancer cell line and tohuman umbilical vein endothelial cells (HUVEC),human umbilical vein endothelial cells (HUVEC), human brain microvascular endothelial cells (HBMEC), and human pulmonary aortic endothelial cells (HPAC).[9] Its mRNA is also express but at rather low levels in several other human cell lines including:K562 cells (human myelogenous leukemia cells);Jurkat cells (T lymphocyte cells); Hut78 cells (T cell lymphoma cells),HEK 293 cells (primary embryonic kidney cells),MCF-7 cells (mammary adenocarcinoma cellss), and EJ cells (bladder carcinoma cells).[5][6]
Mice express an ortholog to human GPR31 in their circulating bloodplatelets.[15]
The GPR31 receptor appears to mediate the responses of PC-3 prostate cancer cells to 12(S)-HETE in stimulating the MEK-ERK1/2 and NFκB pathways and therefore may contribute to the growth-promoting andmetastasis-promoting actions that 12(S)-HETE is proposed to have in human prostate cancer.[16][17][18] However, LNCaP and PC3 human prostate cancer cells also express BLT2 receptors; in LNCaP cells, BLT2 receptors stimulate the expression of the growth- and metastasis-promoting androgen receptor;[19] in PC3 cells, BLT2 receptors stimulate the NF-κB pathway to inhibit the apoptosis induced by cell detachment from surfaces (i.e.Anoikis;[20] and, in BLT2-overexpressing PWR-1E non-malignant prostate cells, 12(S)-HETE diminished anoikis-associated apoptotic cell death.[20] Thus, the roles of 12(S)-HETE in human prostate cancer, if any, may involve its activation of either or both GPR31 and BLT2 receptors.
The many other actions of 12(S)-HETE (see12-Hydroxyeicosatetraenoic acid) and any other ligands found to interact with this receptor will require studies similar those conducted on PC3 cells[10] and mesenteric arteries[15] to determine the extent to which they interact with BLT2, TXA2/PGH2, and PPARgamma receptors and thereby may contribute in part or whole to their activity. Clues implicating the GPR31, as opposed to the other receptors in the actions of 12(S)-HETE include findings that GPR31 receptors do not respond to 12(R)-HETE nor induce rises in cytosolic Ca2+ whereas the other receptors mediate one or both of these actions. These studies will be important because, in addition to prostate cancer, preliminary studies suggest that the GPR31 receptor is implicated in several other diseases such as malignant megakaryocytis (Acute megakaryoblastic leukemia), arthritis,Alzheimer's disease, progressive B-cellchronic lymphocytic leukemia,Diabetic neuropathy, and high gradeastrocytoma.[10]
