Prostaglandin E2 receptor 1 (EP1) is a 42kDaprostaglandin receptor encoded by thePTGER1 gene. EP1 is one of four identified EP receptors, EP1, EP2, EP3, and EP4 which bind with and mediate cellular responses principally to prostaglandin E2) (PGE2) and also but generally with lesser affinity and responsiveness to certain otherprostanoids (seeProstaglandin receptors).[5] Animal model studies have implicated EP1 in various physiological and pathological responses. However, key differences in the distribution of EP1 between these test animals and humans as well as other complicating issues make it difficult to establish the function(s) of this receptor in human health and disease.[6]
The following standard prostaglandins have the following relative potencies in binding to and activating EP1: PGE2≥PGE1>PGF2alpha>PGD2. The receptorbinding affinityDissociation constant Kd (i.e. ligand concentration needed to bind with 50% of available EP1 receptors) is ~20 nM and that of PGE1 ~40 for the mouse receptor and ~25 nM for PGE2 with the human receptor.[9][10]
Because PGE2 activates multiple prostanoid receptors and has a short half-life in vivo due to its rapidly metabolism in cells byomega oxidation and beta oxidation], metabolically resistant EP1-selective activators are useful for the study of EP1's function and could be clinically useful for the treatment of certain diseases. Only one such agonist that is highly selective in stimulating EP1 has been synthesized and identified, ONO-D1-OO4. This compound has a Ki inhibitory binding value (seeBiochemistry#Receptor/ligand binding affinity) of 150 nM compared to that of 25 nM for PGE2 and is therefore ~5 times weaker than PGE2.[9]
SC51322 (Ki=13.8 nM), GW-848687 (Ki=8.6 nM), ONO-8711, SC-19220, SC-51089, and several other synthetic compounds given in next cited reference are selectivecompetitive antagonists for EP1 that have been used for studies in animal models of human diseases. Carbacylin, 17-phenyltrinor PGE1, and several other tested compounds are dual EP1/EP3 antagonists (most marketed prostanoid receptor antagonists exhibit poor receptor selectivity).[9]
When initially bound to PGE2 or other stimulating ligand, EP1 mobilizesG proteins containing theGq alpha subunit (Gαq/11)-G beta-gamma complex. These two subunits in turn stimulate thePhosphoinositide 3-kinase pathway that raises cellular cytosolic Ca2+ levels thereby regulating Ca2+-sensitive cell signal pathways which include, among several others, those that promote the activation of certainprotein kinase C isoforms.[6] Since, this rise in cytosolic Ca2+ can also contract muscle cells, EP1 has been classified as a contractile type of prostanoid receptor. The activation of protein kinases C feeds back to phosphorylate and thereby desensitizes the activated EP1 receptor (seehomologous desensitization but may also desensitize other types of prostanoid and non-prostanoid receptors (seeheterologous desensitization). These desensitizations limit further EP1 receptor activation within the cell.[6][10][11] Concurrently with the mobilization of these pathways, ligand-activated EP1 stimulatesERK,p38 mitogen-activated protein kinases, and CREB pathways that lead to cellular functional responses.[12]
Studies using animals genetically engineered to lack EP1 and supplemented by studies using treatment with EP1 receptor antagonists and agonists indicate that this receptor serves several functions.1) It mediateshyperalgesia due to EP11 receptors located in the central nervous system but suppresses pain perception due to E1 located ondorsal root ganglianeurons in rats. Thus, PGE2 causes increased pain perception when administered into the central nervous system but inhibits pain perception when administered systemically[citation needed];2) It promotes colon cancer development inAzoxymethane-induced andAPCgene knockout mice.3) It promotes hypertension in diabetic mice and spontaneously hypertensive rats.4) It suppresses stress-induced impulsive behavior and social dysfunction in mice by suppressing the activation ofDopamine receptor D1 andDopamine receptor D2 signaling.5) It enhances the differentiation of uncommittedT cell lymphocytes to theTh1 cellphenotype and may thereby favor the development of inflammatory rather than allergic responses to immune stimulation in rodents. Studies with human cells indicate that EP1 serves a similar function on T cells.6) It may reduce expression ofSodium-glucose transport proteins in the apical membrane or cells of the intestinal mucosa in rodents.[6][12][13][14]7) It may be differentially involved in etiology of acute brain injuries. Pharmacological inhibition or genetic deletion of EP1 receptor produce either beneficial or deleterious effects in rodent models of neurological disorders such asischemic stroke,[15]epileptic seizure,[16] surgically induced brain injury[17] andtraumatic brain injury.[18]
EP1 receptor antagonists have been studied clinically primarily to treathyperalgesia. Numerous EP antagonists have been developed including SC51332, GW-848687X, a benzofuran-containing drug that have had some efficacy in treating various hyperalgesic syndromes in animal models. None have as yet been reported to be useful in humans.[9]
^abMoreno JJ (December 2016). "Eicosanoid receptors: Targets for the treatment of disrupted intestinal epithelial homeostasis".European Journal of Pharmacology.796:7–19.doi:10.1016/j.ejphar.2016.12.004.PMID27940058.S2CID1513449.
^Kawano T, Anrather J, Zhou P, Park L, Wang G, Frys KA, Kunz A, Cho S, Orio M, Iadecola C (February 2006). "Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity".Nature Medicine.12 (2):225–9.doi:10.1038/nm1362.PMID16432513.S2CID33649705.
^Fischborn SV, Soerensen J, Potschka H (September 2010). "Targeting the prostaglandin E2 EP1 receptor and cyclooxygenase-2 in the amygdala kindling model in mice".Epilepsy Research.91 (1):57–65.doi:10.1016/j.eplepsyres.2010.06.012.PMID20655707.S2CID36191106.
^Khatibi NH, Jadhav V, Matus B, Fathali N, Martin R, Applegate R, Tang J, Zhang JH (2011). "Prostaglandin E2 EP1 Receptor Inhibition Fails to Provide Neuroprotection in Surgically Induced Brain-Injured Mice".Intracerebral Hemorrhage Research. Acta Neurochirurgica Supplementum. Vol. 111. pp. 277–81.doi:10.1007/978-3-7091-0693-8_46.ISBN978-3-7091-0692-1.PMC3569069.PMID21725768.{{cite book}}:|journal= ignored (help)
Coleman RA, Smith WL, Narumiya S (June 1994). "International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes".Pharmacological Reviews.46 (2):205–29.PMID7938166.
Duncan AM, Anderson LL, Funk CD, Abramovitz M, Adam M (February 1995). "Chromosomal localization of the human prostanoid receptor gene family".Genomics.25 (3):740–2.doi:10.1016/0888-7543(95)80022-E.PMID7759114.
Kurihara Y, Endo H, Kondo H (January 2001). "Induction of IL-6 via the EP3 subtype of prostaglandin E receptor in rat adjuvant-arthritic synovial cells".Inflammation Research.50 (1):1–5.doi:10.1007/s000110050716.PMID11235015.S2CID21908528.
Kyveris A, Maruscak E, Senchyna M (March 2002). "Optimization of RNA isolation from human ocular tissues and analysis of prostanoid receptor mRNA expression using RT-PCR".Molecular Vision.8:51–8.PMID11951086.
Moreland RB, Kim N, Nehra A, Goldstein I, Traish A (October 2003). "Functional prostaglandin E (EP) receptors in human penile corpus cavernosum".International Journal of Impotence Research.15 (5):362–8.doi:10.1038/sj.ijir.3901042.PMID14562138.S2CID5845483.
Su JL, Shih JY, Yen ML, Jeng YM, Chang CC, Hsieh CY, Wei LH, Yang PC, Kuo ML (January 2004). "Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma".Cancer Research.64 (2):554–64.doi:10.1158/0008-5472.CAN-03-1301.PMID14744769.S2CID8510719.
"Prostanoid Receptors: EP1".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2016-03-03. Retrieved2008-12-09.
