GPR31
G-protein coupled receptor 31 also known as 12--HETE receptor is a protein that in humans is encoded by the GPR31 gene. The human gene is located on chromosome 6q27 and encodes a G-protein coupled receptor protein composed of 319 amino acids.
Function
The GPR31 receptor shares a close amino acid sequence similarity with the oxoeicosanoid receptor 1, a G-protein coupled receptor encoded by the GPR170 gene.Ligand binding and activation
The oxoeicosanoid receptor 1 is the receptor for a group of arachidonic acid metabolites produced by 5-lipoxygenase, such as 5-Hydroxyicosatetraenoic acid, 5-oxoicosanoic acid, 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, synthesized by 12-lipoxygenase. This conclusion is supported by studies that cloned the receptor from the PC-3 prostate cancer cell line. The cloned receptor, when expressed in other cell types, bound 12-HETE with high affinity and mediated the effects of low concentrations of the S but not R stereoisomer of 12-HETE.In a GTPγS binding assay, which estimates a receptor's binding affinity by measuring its stimulation of GTPγS binding, 12-HETE activated GPR31 with an EC50 of less than 0.3 nM. In comparison, the EC50 was 42 nM for 15-HETE, 390 nM for 5-HETE, and undetectable for 12-HETE.
It is currently unknown whether GPR31 interacts with structural analogs of 12-HETE, such as 12-oxo-ETE, various 5,12-diHETEs including LTB4, or other bioactive metabolites like the hepoxilins. Further research is required to determine whether GPR31 exclusively binds and mediates the effects of 12-HETE or, like the oxoeicosanoid receptor 1, interacts with a broader family of analogs.
Signaling pathways
Like the oxoeicosanoid receptor, GPR31 activates the MEK-ERK1/2 signaling pathway, but unlike oxoeicosanoid receptor 1, it does not cause an increase in cytosolic Ca2+ concentration. It also activates NFκB. GPR31 exhibits stereospecificity and other properties expected of a true G-protein coupled receptor.Additional receptors activated by 12(S)-HETE
12 binds to and activates the leukotriene B4 receptor-2 binds to, but inhibits, the GPCR for prostaglandin H2 and thromboxane A2, two arachidonic acid metabolites; c) binds with high affinity to a 50 kilodalton binds with low affinity to and activates intracellular peroxisome proliferator-activated receptor gamma.Complications in determining GPR31 function
These alternate binding sites complicate the determination of 12-HETE's reliance on GPR31 for cell activation and the overall function of GPR31. Studies utilizing GPR31 Gene knockout models will be crucial for understanding its role in vivo.Tissue distribution
GPR31 receptor mRNA is highly expressed in the PC-3 prostate cancer cell line and to a lesser extent the DU145 prostate cancer cell line and to human umbilical vein endothelial cells, human umbilical vein endothelial cells, human brain microvascular endothelial cells, and human pulmonary aortic endothelial cells. Its mRNA is also express but at rather low levels in several other human cell lines including: K562 cells ; Jurkat cells ; Hut78 cells, HEK 293 cells, MCF-7 cells, and EJ cells.Mice express an ortholog to human GPR31 in their circulating blood platelets.