GPR31

Description

The GPR31 (G protein-coupled receptor 31) is a protein-coding gene located on chromosome 6.

G-protein coupled receptor 31 also known as 12-(S)-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 is most closely related in amino acid sequence to the oxoeicosanoid receptor 1, a G-protein coupled receptor encoded by the GPR170 gene. Oxoeicosanoid receptor 1 is the receptor for a family of arachidonic acid metabolites made by 5-lipoxygenase viz., 5-Hydroxyicosatetraenoic acid (5-HETE), 5-oxoicosanoic acid (5-oxo-ETE) and other members of this family of broadly bioactive cell stimuli. The GPR31 receptor is a receptor for very different arachidonic acid metabolite, 12-hydroxyeicosatetraenoic acid (12-HETE), whose synthesis is catalyzed by 12-lipoxygenase; this conclusion is based on studies that cloned the receptor from the PC-3 prostate cancer cell line and found that the cloned receptor, when expressed in other cell types, bound with high affinity (Kd=5 nM) and mediated the actions of low concentrations of the S but not R stereoisomer of 12-HETE. In a [35S]GTPγS binding assay, which indirectly estimates a receptor's binding affinity with a ligand by measuring this ligand's ability to stimulate the receptor to bind [35S]GTPγS, 12(S)-HETE stimulated the cloned GPR31 receptor to bind [35S]GTPγS with an EC50 (effective concentration causing a 50% of maximal rise in [35S]GTPγS binding) was <0.3 nM; it was 42 nM for 15(S)-HETE, 390 nM for 5(S)-HETE, and undetectable for 12(R)-HETE. Importantly, however, we do not known if GPR31 interacts with structural analogs of 12(S)-HETE such as 12-oxo-ETE (a metabolite of 12(S)-HETE), various 5,12-diHETEs including LTB4, and an array of bioactive 12(S)-HETE and 12(R)-HETE metabolites, the hepoxilins. Further studies will be needed to determine if the GPR31 receptor is dedicated to binding and mediating the action of 12(S)-HETE more or less exclusively or, like the oxoeicosanoid receptor 1, binds and mediates the actions of a family of analogs. GPR31 receptor, like the oxoeicosanoid receptor, activates the MEK-ERK1/2 pathway of intercellular signaling but unlike the oxoeicoanaoid receptor does not trigger rises in the concentration of cytosolic Ca2+; it also activates NFκB. GPR31 receptor therefore exhibits the stereospecificity and some other features generally expected from a true GPR receptor. 12(S)-HETE also: a) binds to and activates the leukotriene B4 receptor-2 (BLT2), a G protein-coupled receptor for the 5-lipoxygenase-derived arachidonic acid metabolite, LTB4 and LTB4 metabolites; b) binds to, but rather than activating, inhibits the G protein-coupled receptor for the cyclooxygenase-derived arachidonic acid metabolites prostaglandin H2 and thromboxane A2; c) binds with high affinity to a 50 kilodalton (kDa) subunit of a 650 kDa cytosolic and nuclear protein complex; and d) binds with low affinity to and activates intracellular peroxisome proliferator-activated receptor gamma. These alternate binding and cell-activating sites complicate the determination of 12(S)-HETE's dependency on GPR31 in stimulating cells as well as the overall function of GPR31. The effects of GPR31 Gene knockout in animal models, a technique critical to defining the in vivo function of genes, will be critical to shedding light on these issues.

GPR31 is a high-affinity receptor for 12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-S-HETE), with much lower affinities for other HETE isomers. 12-S-HETE is an eicosanoid, a 12-lipoxygenase (ALOX12) metabolite of arachidonic acid, involved in many physiologic and pathologic processes. Binding of 12-S-HETE to GPR31 activates the ERK1/2 (MAPK3/MAPK1), MEK, and NF-kappa-B pathways, leading to cell growth. GPR31 plays a crucial role in the proliferation, survival, and macropinocytosis of KRAS-dependent cancer cells by mediating the translocation of KRAS from the endoplasmic reticulum to the plasma membrane (PM) and its association with the PM. It also contributes to enhanced immune responses by inducing dendrite protrusion of small intestinal CX3CR1(+) phagocytes for the uptake of luminal antigens. GPR31 acts as a key receptor for 12-(S)-HETE-mediated liver ischemia reperfusion injury.

GPR31 is also known as 12-HETER, HETER, HETER1.

Associated Diseases

WES Whole Exome Sequencing