|, 12-HETER, HETER, HETER1, G protein-coupled receptor 31|
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.
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 aciont 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 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 (HUVEC), human umbilical vein endothelial cells (HUVEC), human brain microvascular endothelial cells (HBMEC), and human pulmonary aortic endothelial cells (HPAC). 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 lymphocye 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).
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 and metastasis-promoting actions that 12(S)-HETE is proposed to have in human prostate cancer. 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; in PC3 cells, BLT2 receptors stimulate the NF-κB pathway to inhibit the apoptosis induced by cell detachment from surfaces (i.e. Anoikis; and, in BLT2-overexpressing PWR-1E non-malignant prostate cells, 12(S)-HETE diminished anoikis-associated apoptotic cell death. 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 (see 12-Hydroxyeicosatetraenoic acid) and any other ligands found to interact with this receptor will require studies similar those conducted on PC3 cells and mesenteric arteries 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-cell chronic lymphocytic leukemia, Diabetic neuropathy, and high grade astrocytoma.
- GRCh38: Ensembl release 89: ENSG00000120436 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000071311 - Ensembl, May 2017
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- Zingoni A, Rocchi M, Storlazzi CT, Bernardini G, Santoni A, Napolitano M (Jun 1997). "Isolation and chromosomal localization of GPR31, a human gene encoding a putative G protein-coupled receptor". Genomics. 42 (3): 519–23. doi:10.1006/geno.1997.4754. PMID 9205127.
- "Entrez Gene: GPR31 G protein-coupled receptor 31".
- Hosoi T, Koguchi Y, Sugikawa E, Chikada A, Ogawa K, Tsuda N, Suto N, Tsunoda S, Taniguchi T, Ohnuki T (Aug 2002). "Identification of a novel human eicosanoid receptor coupled to G(i/o)". The Journal of Biological Chemistry. 277 (35): 31459–65. doi:10.1074/jbc.M203194200. PMID 12065583.
- Jones CE, Holden S, Tenaillon L, Bhatia U, Seuwen K, Tranter P, Turner J, Kettle R, Bouhelal R, Charlton S, Nirmala NR, Jarai G, Finan P (Mar 2003). "Expression and characterization of a 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid receptor highly expressed on human eosinophils and neutrophils". Molecular Pharmacology. 63 (3): 471–7. doi:10.1124/mol.63.3.471. PMID 12606753.
- Guo Y, Zhang W, Giroux C, Cai Y, Ekambaram P, Dilly AK, Hsu A, Zhou S, Maddipati KR, Liu J, Joshi S, Tucker SC, Lee MJ, Honn KV (Sep 2011). "Identification of the orphan G protein-coupled receptor GPR31 as a receptor for 12-(S)-hydroxyeicosatetraenoic acid". The Journal of Biological Chemistry. 286 (39): 33832–40. doi:10.1074/jbc.M110.216564. PMC 3190773. PMID 21712392.
- Guo, Y; Zhang, W; Giroux, C; Cai, Y; Ekambaram, P; Dilly, A. K.; Hsu, A; Zhou, S; Maddipati, K. R.; Liu, J; Joshi, S; Tucker, S. C.; Lee, M. J.; Honn, K. V. (2011). "Identification of the orphan G protein-coupled receptor GPR31 as a receptor for 12-(S)-hydroxyeicosatetraenoic acid". Journal of Biological Chemistry. 286 (39): 33832–40. doi:10.1074/jbc.M110.216564. PMC 3190773. PMID 21712392.
- O'Flaherty JT, Cordes JF, Lee SL, Samuel M, Thomas MJ (Dec 1994). "Chemical and biological characterization of oxo-eicosatetraenoic acids". Biochimica et Biophysica Acta. 1201 (3): 505–15. doi:10.1016/0304-4165(94)90083-3. PMID 7803484.
- Kim HJ, Kim DK, Kim H, Koh JY, Kim KM, Noh MS, Lee S, Kim S, Park SH, Kim JJ, Kim SY, Lee CH (Jul 2008). "Involvement of the BLT2 receptor in the itch-associated scratching induced by 12-(S)-lipoxygenase products in ICR mice". British Journal of Pharmacology. 154 (5): 1073–8. doi:10.1038/bjp.2008.220. PMC 2451041. PMID 18536755.
- Yokomizo T, Kato K, Hagiya H, Izumi T, Shimizu T (Apr 2001). "Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor, BLT2". The Journal of Biological Chemistry. 276 (15): 12454–9. doi:10.1074/jbc.M011361200. PMID 11278893.
- Fonlupt P, Croset M, Lagarde M (Jul 1991). "12-HETE inhibits the binding of PGH2/TXA2 receptor ligands in human platelets". Thrombosis Research. 63 (2): 239–48. doi:10.1016/0049-3848(91)90287-7. PMID 1837628.
- Herbertsson H, Kühme T, Hammarström S (Jul 1999). "The 650-kDa 12(S)-hydroxyeicosatetraenoic acid binding complex: occurrence in human platelets, identification of hsp90 as a constituent, and binding properties of its 50-kDa subunit". Archives of Biochemistry and Biophysics. 367 (1): 33–8. doi:10.1006/abbi.1999.1233. PMID 10375396.
- Li Q, Cheon YP, Kannan A, Shanker S, Bagchi IC, Bagchi MK (Mar 2004). "A novel pathway involving progesterone receptor, 12/15-lipoxygenase-derived eicosanoids, and peroxisome proliferator-activated receptor gamma regulates implantation in mice". The Journal of Biological Chemistry. 279 (12): 11570–81. doi:10.1074/jbc.M311773200. PMID 14688261.
- Siangjong, L; Gauthier, K. M.; Pfister, S. L.; Smyth, E. M.; Campbell, W. B. (2013). "Endothelial 12(S)-HETE vasorelaxation is mediated by thromboxane receptor inhibition in mouse mesenteric arteries". AJP: Heart and Circulatory Physiology. 304 (3): H382–92. doi:10.1152/ajpheart.00690.2012. PMC 3774504. PMID 23203967.
- Nie D, Krishnamoorthy S, Jin R, Tang K, Chen Y, Qiao Y, Zacharek A, Guo Y, Milanini J, Pages G, Honn KV (Jul 2006). "Mechanisms regulating tumor angiogenesis by 12-lipoxygenase in prostate cancer cells". The Journal of Biological Chemistry. 281 (27): 18601–9. doi:10.1074/jbc.M601887200. PMID 16638750.
- Yang P, Cartwright CA, Li J, Wen S, Prokhorova IN, Shureiqi I, Troncoso P, Navone NM, Newman RA, Kim J (Oct 2012). "Arachidonic acid metabolism in human prostate cancer". International Journal of Oncology. 41 (4): 1495–503. doi:10.3892/ijo.2012.1588. PMC 3982713. PMID 22895552.
- Porro B, Songia P, Squellerio I, Tremoli E, Cavalca V (Aug 2014). "Analysis, physiological and clinical significance of 12-HETE: a neglected platelet-derived 12-lipoxygenase product". Journal of Chromatography B. 964: 26–40. doi:10.1016/j.jchromb.2014.03.015. PMID 24685839.
- Lee, J. W.; Kim, G. Y.; Kim, J. H. (2012). "Androgen receptor is up-regulated by a BLT2-linked pathway to contribute to prostate cancer progression". Biochemical and Biophysical Research Communications. 420 (2): 428–33. doi:10.1016/j.bbrc.2012.03.012. PMID 22426480.
- Lee, J. W.; Kim, J. H. (2013). "Activation of the leukotriene B4 receptor 2-reactive oxygen species (BLT2-ROS) cascade following detachment confers anoikis resistance in prostate cancer cells". Journal of Biological Chemistry. 288 (42): 30054–63. doi:10.1074/jbc.M113.481283. PMC 3798474. PMID 23986446.