Prostaglandin EP1 receptor
| PTGER1 | |||
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| Identifiers | |||
Gene ontology | |||
| Molecular function | |||
| Cellular component | |||
| Biological process |
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| Sources:Amigo / QuickGO | |||
Ensembl | |||||||||
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| UniProt | |||||||||
| RefSeq (mRNA) | |||||||||
| RefSeq (protein) | |||||||||
| Location (UCSC) | Chr 19: 14.47 – 14.48 Mb | Chr 8: 84.39 – 84.4 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
Prostaglandin E2 receptor 1 (EP1) is a 42kDa
Prostaglandin 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]
Gene
The PTGER1 gene is located on human chromosome 19 at position p13.12 (i.e. 19p13.12), contains 2
exons, and codes for a G protein-coupled receptor (GPCR) of the rhodopsin-like receptor family, Subfamily A14 (see rhodopsin-like receptors#Subfamily A14).[7]
Expression
Studies in mice, rats, and guinea pigs have found EP1
dorsal root ganglia neurons as well as several central nervous system sites.[8] 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.[6][9]
Ligands
Activating ligands
The following standard prostaglandins have the following relative potencies in binding to and activating EP1: PGE2≥
binding affinity Dissociation 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 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 Ki 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.[9]
Inhibiting ligands
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 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).[9]
Mechanism of cell activation
When initially bound to PGE2 or other stimulating ligand, EP1 mobilizes
heterologous desensitization). These desensitizations limit further EP1 receptor activation within the cell.[6][10][11] 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.[12]
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
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.[9]
See also
- Prostaglandin receptors
- Prostanoid receptors
- Prostaglandin E2 receptor 2 (EP2)
- Prostaglandin E2 receptor 3 (EP3)
- Prostaglandin E2 receptor 4 (EP4)
- Eicosanoid receptor
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000160951 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000019464 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: PTGER1 prostaglandin E receptor 1 (subtype EP1), 42kDa".
- ^ PMID 21752876.
- ^ "PTGER1 prostaglandin E receptor 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
- PMID 21508345.
- ^ PMID 27506873.
- ^ S2CID 7766467.
- PMID 25343148.
- ^ S2CID 1513449.
- S2CID 207058745.
- PMID 17767353.
- S2CID 33649705.
- S2CID 36191106.
- )
- PMID 25426930.
Further reading
- 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. PMID 7938166.
- Lee TY, Watanabe Y (May 1975). "A nonlinear regression model as applied to the comparison of axis-angles of electrocardiographic systems". Japanese Heart Journal. 16 (3): 243–56. PMID 1160156.
- 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. PMID 7759114.
- Funk CD, Furci L, FitzGerald GA, Grygorczyk R, Rochette C, Bayne MA, Abramovitz M, Adam M, Metters KM (December 1993). "Cloning and expression of a cDNA for the human prostaglandin E receptor EP1 subtype". The Journal of Biological Chemistry. 268 (35): 26767–72. PMID 8253813.
- 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. S2CID 21908528.
- 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. PMID 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 (April 2003). "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. PMID 12642666.
- Richards JA, Brueggemeier RW (June 2003). "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. PMID 12788892.
- Kitamura T, Itoh M, Noda T, Tani K, Kobayashi M, Maruyama T, Kobayashi K, Ohuchida S, Sugimura T, Wakabayashi K (July 2003). "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. S2CID 9202306.
- 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. S2CID 5845483.
- 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. S2CID 8510719.
- Wu T, Wu H, Wang J, Wang J (March 2011). "Expression and cellular localization of cyclooxygenases and prostaglandin E synthases in the hemorrhagic brain". Journal of Neuroinflammation. 8: 22. PMID 21385433.
- Han C, Wu T (June 2005). "Cyclooxygenase-2-derived prostaglandin E2 promotes human cholangiocarcinoma cell growth and invasion through EP1 receptor-mediated activation of the epidermal growth factor receptor and Akt". The Journal of Biological Chemistry. 280 (25): 24053–63. PMID 15855163.
- Nicola C, Timoshenko AV, Dixon SJ, Lala PK, Chakraborty C (August 2005). "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. PMID 15886234.
- 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 (January 2006). "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. PMID 16393343.
- Zhao X, Wu T, Chang CF, Wu H, Han X, Li Q, Gao Y, Li Q, Hou Z, Maruyama T, Zhang J, Wang J (May 2015). "Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice". Brain, Behavior, and Immunity. 46: 293–310. PMID 25697396.
- McGraw DW, Mihlbachler KA, Schwarb MR, Rahman FF, Small KM, Almoosa KF, Liggett SB (May 2006). "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. PMID 16670773.
- Horita H, Kuroda E, Hachisuga T, Kashimura M, Yamashita U (July 2007). "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. PMID 17525067.
External links
- "Prostanoid Receptors: EP1". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2008-12-09.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.