Prostaglandin EP1 receptor explained

Prostaglandin E₂ receptor 1 (EP₁) is a 42kDa prostaglandin receptor encoded by the PTGER1 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 other prostanoids (see Prostaglandin receptors).^[1] 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.^[2]

Gene

The PTGER₁ gene is located on human chromosome 19 at position p13.12 (i.e. 19p13.12), contains 2 introns and 3 exons, and codes for a G protein-coupled receptor (GPCR) of the rhodopsin-like receptor family, Subfamily A14 (see rhodopsin-like receptors#Subfamily A14).^[3]

Expression

Studies in mice, rats, and guinea pigs have found EP₁ Messenger RNA and protein to be expressed in the papillary collecting ducts of the kidney, in the kidney, lung, stomach, thalamus, and in the dorsal root ganglia neurons as well as several central nervous system sites.^[4] However, the expression of EP₁ In humans, its expression appears to be more limited: EP₁ receptors have been detected in human mast cells, pulmonary veins, keratinocytes, myometrium, and colon smooth muscle.^{[2] [5]}

Ligands

Activating ligands

The following standard prostaglandins have the following relative potencies in binding to and activating EP₁: PGE₂≥PGE1>PGF2alpha>PGD2. The receptor binding affinity Dissociation constant K_d (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.^[6]

Because PGE₂ activates multiple prostanoid receptors and has a short half-life in vivo due to its rapidly metabolism in cells by omega 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 K_i inhibitory binding value (see Biochemistry#Receptor/ligand binding affinity) of 150 nM compared to that of 25 nM for PGE₂ and is therefore ~5 times weaker than PGE₂.

Inhibiting ligands

SC51322 (K_i=13.8 nM), GW-848687 (K_i=8.6 nM), ONO-8711, SC-19220, SC-51089, and several other synthetic compounds given in next cited reference are selective competitive 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).

Mechanism of cell activation

When initially bound to PGE₂ or other stimulating ligand, EP₁ mobilizes G proteins containing the Gq alpha subunit (Gαq/11)-G beta-gamma complex. These two subunits in turn stimulate the Phosphoinositide 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 certain protein kinase C isoforms.^[2] 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 (see homologous desensitization but may also desensitize other types of prostanoid and non-prostanoid receptors (see heterologous desensitization). These desensitizations limit further EP₁ receptor activation within the cell.^{[2] [6] [7]} Concurrently with the mobilization of these pathways, ligand-activated EP₁ stimulates ERK, p38 mitogen-activated protein kinases, and CREB pathways that lead to cellular functional responses.^[8]

Function

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 mediates hyperalgesia due to EP1₁ receptors located in the central nervous system but suppresses pain perception due to E₁ located on dorsal root ganglia neurons in rats. Thus, PGE₂ causes increased pain perception when administered into the central nervous system but inhibits pain perception when administered systemically; 2) It promotes colon cancer development in Azoxymethane-induced and APC gene 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 of Dopamine receptor D1 and Dopamine receptor D2 signaling. 5) It enhances the differentiation of uncommitted T cell lymphocytes to the Th1 cell phenotype 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 of Sodium-glucose transport proteins in the apical membrane or cells of the intestinal mucosa in rodents.^{[2] [8] [9] [10]} 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 as ischemic stroke,^[11] epileptic seizure,^[12] surgically induced brain injury^[13] and traumatic brain injury.^[14]

Clinical studies

EP1 receptor antagonists have been studied clinically primarily to treat hyperalgesia. 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.^[5]

See also

• Prostaglandin receptors
• Prostanoid receptors
• Prostaglandin E2 receptor 2 (EP2)
• Prostaglandin E2 receptor 3 (EP3)
• Prostaglandin E2 receptor 4 (EP4)
• Eicosanoid receptor

Further reading

• Coleman RA, Smith WL, Narumiya S . International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes . Pharmacological Reviews . 46 . 2 . 205–29 . June 1994 . 7938166 .
• Lee TY, Watanabe Y . A nonlinear regression model as applied to the comparison of axis-angles of electrocardiographic systems . Japanese Heart Journal . 16 . 3 . 243–56 . May 1975 . 1160156 . 10.1536/ihj.16.243 . free .
• Duncan AM, Anderson LL, Funk CD, Abramovitz M, Adam M . Chromosomal localization of the human prostanoid receptor gene family . Genomics . 25 . 3 . 740–2 . February 1995 . 7759114 . 10.1016/0888-7543(95)80022-E .
• Funk CD, Furci L, FitzGerald GA, Grygorczyk R, Rochette C, Bayne MA, Abramovitz M, Adam M, Metters KM . Cloning and expression of a cDNA for the human prostaglandin E receptor EP1 subtype . The Journal of Biological Chemistry . 268 . 35 . 26767–72 . December 1993 . 10.1016/S0021-9258(19)74379-8 . 8253813 . free .
• Kurihara Y, Endo H, Kondo H . Induction of IL-6 via the EP3 subtype of prostaglandin E receptor in rat adjuvant-arthritic synovial cells . Inflammation Research . 50 . 1 . 1–5 . January 2001 . 11235015 . 10.1007/s000110050716 . 21908528 .
• Kyveris A, Maruscak E, Senchyna M . Optimization of RNA isolation from human ocular tissues and analysis of prostanoid receptor mRNA expression using RT-PCR . Molecular Vision . 8 . 51–8 . March 2002 . 11951086 .
• Matsuoka Y, Furuyashiki T, Bito H, Ushikubi F, Tanaka Y, Kobayashi T, Muro S, Satoh N, Kayahara T, Higashi M, Mizoguchi A, Shichi H, Fukuda Y, Nakao K, Narumiya S . Impaired adrenocorticotropic hormone response to bacterial endotoxin in mice deficient in prostaglandin E receptor EP1 and EP3 subtypes . Proceedings of the National Academy of Sciences of the United States of America . 100 . 7 . 4132–7 . April 2003 . 12642666 . 153060 . 10.1073/pnas.0633341100 . 2003PNAS..100.4132M . free .
• Richards JA, Brueggemeier RW . Prostaglandin E2 regulates aromatase activity and expression in human adipose stromal cells via two distinct receptor subtypes . The Journal of Clinical Endocrinology and Metabolism . 88 . 6 . 2810–6 . June 2003 . 12788892 . 10.1210/jc.2002-021475 . free .
• Kitamura T, Itoh M, Noda T, Tani K, Kobayashi M, Maruyama T, Kobayashi K, Ohuchida S, Sugimura T, Wakabayashi K . Combined effects of prostaglandin E receptor subtype EP1 and subtype EP4 antagonists on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice . Cancer Science . 94 . 7 . 618–21 . July 2003 . 12841871 . 10.1111/j.1349-7006.2003.tb01492.x . 9202306 . 11160211 .
• Moreland RB, Kim N, Nehra A, Goldstein I, Traish A . Functional prostaglandin E (EP) receptors in human penile corpus cavernosum . International Journal of Impotence Research . 15 . 5 . 362–8 . October 2003 . 14562138 . 10.1038/sj.ijir.3901042 . 5845483 .
• Su JL, Shih JY, Yen ML, Jeng YM, Chang CC, Hsieh CY, Wei LH, Yang PC, Kuo ML . 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 . January 2004 . 14744769 . 10.1158/0008-5472.CAN-03-1301 . 8510719 .
• Wu T, Wu H, Wang J, Wang J . Expression and cellular localization of cyclooxygenases and prostaglandin E synthases in the hemorrhagic brain . Journal of Neuroinflammation . 8 . 22 . March 2011 . 21385433 . 3062590 . 10.1186/1742-2094-8-22 . free .
• Nicola C, Timoshenko AV, Dixon SJ, Lala PK, Chakraborty C . EP1 receptor-mediated migration of the first trimester human extravillous trophoblast: the role of intracellular calcium and calpain . The Journal of Clinical Endocrinology and Metabolism . 90 . 8 . 4736–46 . August 2005 . 15886234 . 10.1210/jc.2005-0413 . free .
• Durrenberger PF, Facer P, Casula MA, Yiangou Y, Gray RA, Chessell IP, Day NC, Collins SD, Bingham S, Wilson AW, Elliot D, Birch R, Anand P . Prostanoid receptor EP1 and Cox-2 in injured human nerves and a rat model of nerve injury: a time-course study . BMC Neurology . 6 . 1 . January 2006 . 16393343 . 1361784 . 10.1186/1471-2377-6-1 . free .
• Zhao X, Wu T, Chang CF, Wu H, Han X, Li Q, Gao Y, Li Q, Hou Z, Maruyama T, Zhang J, Wang J . Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice . Brain, Behavior, and Immunity . 46 . 293–310 . May 2015 . 25697396 . 10.1016/j.bbi.2015.02.011 . 4422065.
• McGraw DW, Mihlbachler KA, Schwarb MR, Rahman FF, Small KM, Almoosa KF, Liggett SB . Airway smooth muscle prostaglandin-EP1 receptors directly modulate beta2-adrenergic receptors within a unique heterodimeric complex . The Journal of Clinical Investigation . 116 . 5 . 1400–9 . May 2006 . 16670773 . 1451203 . 10.1172/JCI25840 .
• Horita H, Kuroda E, Hachisuga T, Kashimura M, Yamashita U . Induction of prostaglandin E2 production by leukemia inhibitory factor promotes migration of first trimester extravillous trophoblast cell line, HTR-8/SVneo . Human Reproduction . 22 . 7 . 1801–9 . July 2007 . 17525067 . 10.1093/humrep/dem125 . free .

External links

• Web site: Prostanoid Receptors: EP₁ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-12-09 . 2016-03-03 . https://web.archive.org/web/20160303192140/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2416 . dead .

Notes and References

1. Web site: Entrez Gene: PTGER1 prostaglandin E receptor 1 (subtype EP1), 42kDa.
2. Woodward DF, Jones RL, Narumiya S . International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress . Pharmacological Reviews . 63 . 3 . 471–538 . September 2011 . 21752876 . 10.1124/pr.110.003517 . free .
3. Web site: PTGER1 prostaglandin E receptor 1 [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov.
4. Ricciotti E, FitzGerald GA . Prostaglandins and inflammation . Arteriosclerosis, Thrombosis, and Vascular Biology . 31 . 5 . 986–1000 . May 2011 . 21508345 . 3081099 . 10.1161/ATVBAHA.110.207449 .
5. Markovič T, Jakopin Ž, Dolenc MS, Mlinarič-Raščan I . Structural features of subtype-selective EP receptor modulators . Drug Discovery Today . 22 . 1 . 57–71 . January 2017 . 27506873 . 10.1016/j.drudis.2016.08.003 . free .
6. Narumiya S, Sugimoto Y, Ushikubi F . Prostanoid receptors: structures, properties, and functions . Physiological Reviews . 79 . 4 . 1193–226 . October 1999 . 10508233 . 10.1152/physrev.1999.79.4.1193. 7766467 .
7. Korbecki J, Baranowska-Bosiacka I, Gutowska I, Chlubek D . Cyclooxygenase pathways . Acta Biochimica Polonica . 61 . 4 . 639–49 . 2014 . 25343148 . 10.18388/abp.2014_1825. free .
8. Moreno JJ . Eicosanoid receptors: Targets for the treatment of disrupted intestinal epithelial homeostasis . European Journal of Pharmacology . 796 . 7–19 . December 2016 . 27940058 . 10.1016/j.ejphar.2016.12.004 . 1513449 .
9. Matsuoka T, Narumiya S . The roles of prostanoids in infection and sickness behaviors . Journal of Infection and Chemotherapy . 14 . 4 . 270–8 . August 2008 . 18709530 . 10.1007/s10156-008-0622-3 . 207058745 .
10. Matsuoka T, Narumiya S . Prostaglandin receptor signaling in disease . TheScientificWorldJournal . 7 . 1329–47 . September 2007 . 17767353 . 10.1100/tsw.2007.182 . 5901339 . free .
11. Kawano T, Anrather J, Zhou P, Park L, Wang G, Frys KA, Kunz A, Cho S, Orio M, Iadecola C . Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity . Nature Medicine . 12 . 2 . 225–9 . February 2006 . 16432513 . 10.1038/nm1362 . 33649705 .
12. Fischborn SV, Soerensen J, Potschka H . Targeting the prostaglandin E2 EP1 receptor and cyclooxygenase-2 in the amygdala kindling model in mice . Epilepsy Research . 91 . 1 . 57–65 . September 2010 . 20655707 . 10.1016/j.eplepsyres.2010.06.012 . 36191106 .
13. Book: Khatibi NH, Jadhav V, Matus B, Fathali N, Martin R, Applegate R, Tang J, Zhang JH . Prostaglandin E2 EP1 Receptor Inhibition Fails to Provide Neuroprotection in Surgically Induced Brain-Injured Mice . Intracerebral Hemorrhage Research . Acta Neurochirurgica. Supplement . Acta Neurochirurgica Supplementum . 111 . 277–81 . 2011 . 21725768 . 3569069 . 10.1007/978-3-7091-0693-8_46 . 978-3-7091-0692-1 .
14. Glushakov AV, Fazal JA, Narumiya S, Doré S . Role of the prostaglandin E2 EP1 receptor in traumatic brain injury . PLOS ONE . 9 . 11 . e113689 . 2014 . 25426930 . 4245217 . 10.1371/journal.pone.0113689 . 2014PLoSO...9k3689G . free .