Genomes and Genes
prostaglandin e receptors
Summary: Cell surface receptors which bind prostaglandins with a high affinity and trigger intracellular changes which influence the behavior of cells. Prostaglandin E receptors prefer prostaglandin E2 to other endogenous prostaglandins. They are subdivided into EP1, EP2, and EP3 types based on their effects and their pharmacology.
- Hori R, Nakagawa T, Sugimoto Y, Sakamoto T, Yamamoto N, Hamaguchi K, et al. Prostaglandin E receptor subtype EP4 agonist protects cochleae against noise-induced trauma. Neuroscience. 2009;160:813-9 pubmed publisher..These findings indicate that EP4 is involved in mechanisms for prostaglandin E(1) actions on the cochlea, and local EP4 agonist treatment could attenuate acute sensorineural hearing loss. ..
- Saleem S, Li R, Wei G, DORE S. Effects of EP1 receptor on cerebral blood flow in the middle cerebral artery occlusion model of stroke in mice. J Neurosci Res. 2007;85:2433-40 pubmed..These findings suggest that pharmacologic modulation of the EP1 receptor might be a means to improve CBF and neuronal survival during ischemic stroke. ..
- Kim H, Rhee S, Pothoulakis C, LaMont J. Inflammation and apoptosis in Clostridium difficile enteritis is mediated by PGE2 up-regulation of Fas ligand. Gastroenterology. 2007;133:875-86 pubmed..Toxin A enteritis involves release of PGE(2), which activates the Fas/FasL system, causing enterocyte apoptosis and inflammation. ..
- Sugimoto Y, Narumiya S. Prostaglandin E receptors. J Biol Chem. 2007;282:11613-7 pubmed..Here we review recent advances in PGE receptor research. ..
- Bijvelds M, Bot A, Escher J, de Jonge H. Activation of intestinal Cl- secretion by lubiprostone requires the cystic fibrosis transmembrane conductance regulator. Gastroenterology. 2009;137:976-85 pubmed publisher..Lubiprostone enhances intestinal Cl(-) and fluid secretion via prostanoid receptor signaling, triggering activation of CFTR. Therefore, it is of limited use for treatment of CF-related intestinal disease. ..
- George R, Sturmoski M, Anant S, Houchen C. EP4 mediates PGE2 dependent cell survival through the PI3 kinase/AKT pathway. Prostaglandins Other Lipid Mediat. 2007;83:112-20 pubmed..These findings have critical implications regarding the mechanism and potential application of PGE(2) receptor specific inhibition in cancer therapy. ..
- Kershaw Young C, Khalid M, McGowan M, Pitsillides A, Scaramuzzi R. The mRNA expression of prostaglandin E receptors EP2 and EP4 and the changes in glycosaminoglycans in the sheep cervix during the estrous cycle. Theriogenology. 2009;72:251-61 pubmed publisher..Prostaglandin E(2) acts via prostaglandin E receptors EP(1) to EP(4), and EP(2) and EP(4) stimulate smooth muscle relaxation and glycosaminoglycan synthesis...
- Wang X, Klein R. Prostaglandin E2 induces vascular endothelial growth factor secretion in prostate cancer cells through EP2 receptor-mediated cAMP pathway. Mol Carcinog. 2007;46:912-23 pubmed..We conclude that PGE2-induced VEGF secretion in prostate cancer cells is mediated through EP2-, and possibly EP4-, dependent cAMP signaling pathways. ..
- Zhou P, Qian L, Chou T, Iadecola C. Neuroprotection by PGE2 receptor EP1 inhibition involves the PTEN/AKT pathway. Neurobiol Dis. 2008;29:543-51 pubmed publisher..The findings provide evidence for a link between EP1 receptors and the PI3K/AKT survival pathway and shed light on the molecular mechanisms of the prosurvival effect of EP1 receptor inhibition. ..
- Carrasco E, Casper D, Werner P. PGE(2) receptor EP1 renders dopaminergic neurons selectively vulnerable to low-level oxidative stress and direct PGE(2) neurotoxicity. J Neurosci Res. 2007;85:3109-17 pubmed..Together, these results strongly implicate PGE(2) activation of EP1 receptors as a mediator of selective toxicity in this model of dopaminergic cell loss. ..
- Donnini S, Finetti F, Solito R, Terzuoli E, Sacchetti A, Morbidelli L, et al. EP2 prostanoid receptor promotes squamous cell carcinoma growth through epidermal growth factor receptor transactivation and iNOS and ERK1/2 pathways. FASEB J. 2007;21:2418-30 pubmed..Silencing of iNOS also impaired EGFR-induced ERK1/2 phosphorylation. These results indicate that iNOS/GC signaling is a downstream player in the control of EP2/EGFR-mediated tumor cell proliferation and invasion. ..
- Ma X, Kundu N, Rifat S, Walser T, Fulton A. Prostaglandin E receptor EP4 antagonism inhibits breast cancer metastasis. Cancer Res. 2006;66:2923-7 pubmed..These studies support the hypothesis that EP receptor antagonists may be an alternative approach to the use of COX inhibitors to prevent tumor metastasis. ..
- Kay L, Yeo W, Peachell P. Prostaglandin E2 activates EP2 receptors to inhibit human lung mast cell degranulation. Br J Pharmacol. 2006;147:707-13 pubmed..Collectively, these data suggest that PGE2 mediates effects on human lung mast cells by interacting with EP2 receptors. ..
- Legler D, Krause P, Scandella E, Singer E, Groettrup M. Prostaglandin E2 is generally required for human dendritic cell migration and exerts its effect via EP2 and EP4 receptors. J Immunol. 2006;176:966-73 pubmed..Our results provide clear evidence that PGE2 is a general and mandatory factor for the development of a migratory phenotype of human MoDCs as well as for peripheral blood myeloid DCs. ..
- Hawcroft G, Ko C, Hull M. Prostaglandin E2-EP4 receptor signalling promotes tumorigenic behaviour of HT-29 human colorectal cancer cells. Oncogene. 2007;26:3006-19 pubmed..Inhibition of protumorigenic PGE2-EP4 receptor signalling represents a potential strategy for anti-CRC therapy that may avoid the toxicity associated with systemic COX inhibition. ..
- Chell S, Witherden I, Dobson R, Moorghen M, Herman A, Qualtrough D, et al. Increased EP4 receptor expression in colorectal cancer progression promotes cell growth and anchorage independence. Cancer Res. 2006;66:3106-13 pubmed
- Yang L, Huang Y, Porta R, Yanagisawa K, Gonzalez A, Segi E, et al. Host and direct antitumor effects and profound reduction in tumor metastasis with selective EP4 receptor antagonism. Cancer Res. 2006;66:9665-72 pubmed..Selective antagonism of the EP4 receptor may thus represent a novel therapeutic approach for the treatment of cancer and especially its propensity to metastasize. ..
- Hösl K, Reinold H, Harvey R, Müller U, Narumiya S, Zeilhofer H. Spinal prostaglandin E receptors of the EP2 subtype and the glycine receptor alpha3 subunit, which mediate central inflammatory hyperalgesia, do not contribute to pain after peripheral nerve injury or formalin injection. Pain. 2006;126:46-53 pubmed..We have recently identified spinal prostaglandin E receptors of the EP2 subtype (EP2 receptors) and the glycine receptor alpha3 subunit (GlyR alpha3) as signal ..
- Ahmad A, Ahmad M, de Brum Fernandes A, DORE S. Prostaglandin EP4 receptor agonist protects against acute neurotoxicity. Brain Res. 2005;1066:71-7 pubmed..This is the first study revealing the protective effect of ONO-AE1-329 in an acute model of excitotoxicity in brain, and it suggests that preferential stimulation of EP4 receptors attenuates excitotoxic brain injury. ..
- Chell S, Kaidi A, Kadi A, Williams A, Paraskeva C. Mediators of PGE2 synthesis and signalling downstream of COX-2 represent potential targets for the prevention/treatment of colorectal cancer. Biochim Biophys Acta. 2006;1766:104-19 pubmed..Furthermore, as COX-2 is found to be overexpressed in cancers such as breast, gastric, lung and pancreatic, these investigations may also have broad implications for the prevention/treatment of a number of other malignancies. ..
- Ahmad A, Zhuang H, Echeverria V, DORE S. Stimulation of prostaglandin EP2 receptors prevents NMDA-induced excitotoxicity. J Neurotrauma. 2006;23:1895-903 pubmed..Development and testing of specific PGE(2) receptor mimetics could lead to a decrease in side effects associated with anti-inflammatory drugs and could help to fight acute and/or chronic neurologic disorders. ..
- DORE S. GPCR antagonists as an alternative to COX-2 inhibitors: a case for the PGE2 EP1 receptor. Trends Pharmacol Sci. 2006;27:458-60 pubmed..Drugs that offer the beneficial anti-inflammatory and neuroprotective effects of PGs but that limit the negative effects of COX-2 inhibition could provide the next generation of treatment for acute neuronal damage. ..
- Kawano T, Anrather J, Zhou P, Park L, Wang G, Frys K, et al. Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat Med. 2006;12:225-9 pubmed..An EP1 receptor inhibitor reduces brain injury when administered 6 hours after MCA occlusion, suggesting that EP1 receptor inhibition may be a viable therapeutic option in ischemic stroke. ..
- Fulton A, Ma X, Kundu N. Targeting prostaglandin E EP receptors to inhibit metastasis. Cancer Res. 2006;66:9794-7 pubmed..These initial results indicate that selective targeting of individual EP receptors should be investigated as an approach to exploit the high COX-2 activity in many epithelial malignancies. ..
- Matlhagela K, Taub M. Involvement of EP1 and EP2 receptors in the regulation of the Na,K-ATPase by prostaglandins in MDCK cells. Prostaglandins Other Lipid Mediat. 2006;79:101-13 pubmed
- Grasa L, Arruebo M, Plaza M, Murillo M. PGE(2) receptors and their intracellular mechanisms in rabbit small intestine. Prostaglandins Other Lipid Mediat. 2006;79:206-17 pubmed..This study did not detect EP(4) receptor. PGE(2)-induced contractions would be mediated through EP(1) and EP(3) receptors, and voltage-dependent Ca(2+) channels, protein kinase C, and cAMP would be implicated in these responses. ..
- Miyata Y, Kanda S, Maruta S, Matsuo T, Sakai H, Hayashi T, et al. Relationship between prostaglandin E2 receptors and clinicopathologic features in human prostate cancer tissue. Urology. 2006;68:1360-5 pubmed..In particular, the EP1R seems to play an important role in malignant aggressiveness and tumor development in patients with prostate cancer. ..
- Rask K, Zhu Y, Wang W, Hedin L, Sundfeldt K. Ovarian epithelial cancer: a role for PGE2-synthesis and signalling in malignant transformation and progression. Mol Cancer. 2006;5:62 pubmed..The observed augmentations of COX-1, COX-2 and mPGES-1 have implications for future therapeutic strategies. ..
- Cameron K, Lefker B, Chu Moyer M, Crawford D, Jardine P, DeNinno S, et al. Discovery of highly selective EP4 receptor agonists that stimulate new bone formation and restore bone mass in ovariectomized rats. Bioorg Med Chem Lett. 2006;16:1799-802 pubmed..Lead optimization led to the identification of lactams with a 30-fold increase in EP4 potency in vitro. Compounds demonstrated robust bone anabolic effects when administered in vivo in rat models of osteoporosis. ..
- Li R, Mouillesseaux K, Montoya D, Cruz D, Gharavi N, Dun M, et al. Identification of prostaglandin E2 receptor subtype 2 as a receptor activated by OxPAPC. Circ Res. 2006;98:642-50 pubmed..These results suggest that EP2 functions as a receptor for OxPAPC and PEIPC, either as the phospholipid ester or the released fatty acid, in both endothelial cells and macrophages. ..
- Feng C, Beller E, Bagga S, Boyce J. Human mast cells express multiple EP receptors for prostaglandin E2 that differentially modulate activation responses. Blood. 2006;107:3243-50 pubmed..These functions explain the potency of PGE2 as a suppressor of early- and late-phase allergic responses. ..
- Zhang L, Jiang L, Sun Q, Peng T, Lou K, Liu N, et al. Prostaglandin E2 enhances mitogen-activated protein kinase/Erk pathway in human cholangiocarcinoma cells: involvement of EP1 receptor, calcium and EGF receptors signaling. Mol Cell Biochem. 2007;305:19-26 pubmed
- Woodward D, Nilsson S, Toris C, Kharlamb A, Nieves A, Krauss A. Prostanoid EP4 receptor stimulation produces ocular hypotension by a mechanism that does not appear to involve uveoscleral outflow. Invest Ophthalmol Vis Sci. 2009;50:3320-8 pubmed publisher..It has no effect on uveoscleral outflow but does increase total outflow facility, which accounts for a substantial proportion of the ocular hypotensive activity. ..
- Herrerias A, Torres R, Serra M, Marco A, Roca Ferrer J, Picado C, et al. Subcutaneous prostaglandin E(2) restrains airway mast cell activity in vivo and reduces lung eosinophilia and Th(2) cytokine overproduction in house dust mite-sensitive mice. Int Arch Allergy Immunol. 2009;149:323-32 pubmed publisher..Finally, the effect of PGE(2) is linked to reduced upregulation of airway Th(2) cytokines. ..
- Ji H, Dailey T, Long V, Chien E. Prostaglandin E2-regulated cervical ripening: analysis of proteoglycan expression in the rat cervix. Am J Obstet Gynecol. 2008;198:536.e1-7 pubmed publisher..The decrease in sulfated GAG could decrease electrostatic interactions that would weaken interfibrillar interactions. These findings would be consistent with a decline in cervical resistance. ..
- Jimenez P, García A, Santander S, Piazuelo E. Prevention of cancer in the upper gastrointestinal tract with COX-inhibition. Still an option?. Curr Pharm Des. 2007;13:2261-73 pubmed..Taken together, these data indicate that a re-evaluation of potential chemoprevention strategies for cancers of the upper gastrointestinal tract needs to be considered. ..
- Lee R, Goodwin T, Yang W, Li A, Wilson M, Mullin P, et al. Quantitative detection of EP3-II, III and VI messenger RNA in gravid and non-gravid human myometrium using real-time RT-PCR. J Matern Fetal Neonatal Med. 2009;22:59-64 pubmed publisher..This may reflect differential relaxation of the lower segment of the uterus allowing dilatation and descent of the fetus. ..
- Sanchez Alavez M, Klein I, Brownell S, Tabarean I, Davis C, Conti B, et al. Night eating and obesity in the EP3R-deficient mouse. Proc Natl Acad Sci U S A. 2007;104:3009-14 pubmed..The findings add to the growing literature on links between inflammatory signaling and obesity. ..
- Matlhagela K, Taub M. Prostaglandins regulate transcription by means of prostaglandin response elements located in the promoters of mammalian Na,K-ATPase beta 1 subunit genes. Ann N Y Acad Sci. 2006;1091:233-43 pubmed..Two alternative PGREs were subsequently identified. The sequence of the one of these PGREs (TGACCTTC, -445 to -438) was conserved throughout all species examined, suggesting its physiologic significance. ..
- Amano H, Ito Y, Suzuki T, Kato S, Matsui Y, Ogawa F, et al. Roles of a prostaglandin E-type receptor, EP3, in upregulation of matrix metalloproteinase-9 and vascular endothelial growth factor during enhancement of tumor metastasis. Cancer Sci. 2009;100:2318-24 pubmed publisher..An EP3 receptor antagonist may be useful to protect against tumor metastasis. ..
- Aguirre S, Huang W, Prasanna G, Jessen B. Corneal neovascularization and ocular irritancy responses in dogs following topical ocular administration of an EP4-prostaglandin E2 agonist. Toxicol Pathol. 2009;37:911-20 pubmed publisher..A resolving acute to subacute inflammation in the iris/ciliary body was observed after the four-week recovery period. ..
- Yung H, Chow K, Lai K, Wise H. Gi-coupled prostanoid receptors are the likely targets for COX-1-generated prostanoids in rat pheochromocytoma (PC12) cells. Prostaglandins Leukot Essent Fatty Acids. 2009;81:65-71 pubmed publisher..The functional role of NGF-stimulated COX-1 remains to be determined since we found no strong evidence of a role for EP3 receptors in the morphological changes induced by NGF during the early stages of differentiation of PC12 cells. ..
- Park B, Park S, Park J, Uh S, Choi J, Kim Y, et al. Association of PTGER gene family polymorphisms with aspirin intolerant asthma in Korean asthmatics. BMB Rep. 2010;43:445-9 pubmed..Our findings provide further evidence that polymorphisms in PTGER3 might play a significant role in aspirin hypersensitivity among Korean asthmatics. ..
- Tian L, Suzuki M, Nakajima T, Kubo R, Sekine Y, Shibuya K, et al. Clinical significance of aberrant methylation of prostaglandin E receptor 2 (PTGER2) in nonsmall cell lung cancer: association with prognosis, PTGER2 expression, and epidermal growth factor receptor mutation. Cancer. 2008;113:1396-403 pubmed publisher..0144). Aberrant methylation of the PTGER2 gene was observed frequently in NSCLC tissues and was associated with the presence of EGFR mutation and a better prognosis. ..
- Chuang Y, Yoshimura N, Huang C, Wu M, Chiang P, Chancellor M. Intravesical botulinum toxin A administration inhibits COX-2 and EP4 expression and suppresses bladder hyperactivity in cyclophosphamide-induced cystitis in rats. Eur Urol. 2009;56:159-66 pubmed publisher..These findings suggest a potential benefit of EP4-targeted pharmacotherapy and BoNT-A treatment for bladder inflammatory conditions. ..
- Black S, Palamakumbura A, Stan M, Trackman P. Tissue-specific mechanisms for CCN2/CTGF persistence in fibrotic gingiva: interactions between cAMP and MAPK signaling pathways, and prostaglandin E2-EP3 receptor mediated activation of the c-JUN N-terminal kinase. J Biol Chem. 2007;282:15416-29 pubmed
- Sugino Y, Misawa A, Inoue J, Kitagawa M, Hosoi H, Sugimoto T, et al. Epigenetic silencing of prostaglandin E receptor 2 (PTGER2) is associated with progression of neuroblastomas. Oncogene. 2007;26:7401-13 pubmed
- Jiang G, Im W, Donde Y, Wheeler L. EP4 agonist alleviates indomethacin-induced gastric lesions and promotes chronic gastric ulcer healing. World J Gastroenterol. 2009;15:5149-56 pubmed..EP4-selective agonist may prevent indomethacin-induced gastric lesions and promote healing of existing and indomethacin-aggravated gastric ulcers, via promoting proliferation and survival of mucous epithelial cells. ..
- Hall A, Brown S, Chowdhury A, Giblin G, Gibson M, Healy M, et al. Identification and optimization of novel 1,3,4-oxadiazole EP1 receptor antagonists. Bioorg Med Chem Lett. 2007;17:4450-5 pubmed..Optimization of the substitution patterns on the three aromatic rings led to the identification of high affinity EP1 receptor antagonists. The derivative with highest affinity displayed a binding IC50 of 2.5 nM (pIC50 8.6). ..
- Nishitani K, Ito H, Hiramitsu T, Tsutsumi R, Tanida S, Kitaori T, et al. PGE2 inhibits MMP expression by suppressing MKK4-JNK MAP kinase-c-JUN pathway via EP4 in human articular chondrocytes. J Cell Biochem. 2010;109:425-33 pubmed publisher..These results demonstrate that PGE2 inhibits IL-1beta-induced MMP-1 and MMP-13 productions via EP4 by suppressing MKK4-JNK MAP kinase-c-JUN pathway. ..