Prostaglandin EP2 receptor: Difference between revisions
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==Function== |
==Function== |
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Studies using animals genetically engineered to lack EP<sub2</sub> and supplemented by studies |
Studies using animals genetically engineered to lack EP<sub2</sub> and supplemented by studies examining the actions of EP<sub>2</sub> receptor antagonists and agonists in animals as well as animal and human tissues indicate that this receptor serves several functions. Relative to immune responses, agonist binding to EP<sub>2</sub>: '''1)''' promotes exudation and swelling at sites of nascent inflammation; '''2)''' contributes to the regulation of [[B cell]] [[immunoglobulin class switching]], the maturation of T lymphocyte CD4−CD8− cells to doubly positive [[T cell#Development in the thymus|CD4+CD8+ cells]], and the function of [[Antigen-presenting cell]]s; '''d)''' contributes to the development of inflammation in rodent models of joint and paw inflammation but also contributes to the suppression of inflammation in the central nervous system; and '''4)''' suppresses the development of fibrosis in a model of [[Bleomycin#side effects|Bleomycin-induced pulmonary fibrosis]].<ref name="pmid17767353">{{cite journal | vauthors = Matsuoka T, Narumiya S | title = Prostaglandin receptor signaling in disease | journal = TheScientificWorldJournal | volume = 7 | issue = | pages = 1329–47 | year = 2007 | pmid = 17767353 | doi = 10.1100/tsw.2007.182 | url = }}</ref> Activation of this receptor tends to suppress allergic inflammatory responses; its smooth muscle-relaxing activity extends to dilating airways (]]bronchodilation]]) contracted by the allergic mediator, [[histamine]]; it inhibits [[Immunoglobulin E]]-activated [[mast cell]]s from releasing histamine and making bronchoconstricting and otherwise pro-allergic [[leukotriene]]s, i.e. [[LTC4]], [[LTD4]], and [[LTE4]]; and it inhibits the release of the pro-allergic cytokines [[Interleukin 5]], [[Interleukin 4]], and [[interleukin 13]] from human blood mononuclear cells.<ref name="pmid25155136">{{cite journal | vauthors = Machado-Carvalho L, Roca-Ferrer J, Picado C | title = Prostaglandin E2 receptors in asthma and in chronic rhinosinusitis/nasal polyps with and without aspirin hypersensitivity | journal = Respiratory Research | volume = 15 | issue = | pages = 100 | year = 2014 | pmid = 25155136 | pmc = 4243732 | doi = 10.1186/s12931-014-0100-7 | url = }}</ref><ref name="pmid24768319">{{cite journal | vauthors = Torres R, Picado C, de Mora F | title = The PGE2-EP2-mast cell axis: an antiasthma mechanism | journal = Molecular Immunology | volume = 63 | issue = 1 | pages = 61–8 | year = 2015 | pmid = 24768319 | doi = 10.1016/j.molimm.2014.03.007 | url = }}</ref> |
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Revision as of 15:59, 20 January 2017
Prostaglandin E2 receptor 2 (53kDa), also known as EP2, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER2: it is one of four identified EP receptors, the others being EP1, EP3, and EP4, which bind with and mediate cellular responses to PGE2 and also, but with with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors).[5] EP has been implicated in various physiological and pathological responses.[6]
Gene
The PTGER2 gene is located on human chromosome 14 at position p22.1 (i.e. 14q22.1), 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).[7]
Expression
EP2 is widely distributed in humans. Its protein is expressed in human small intestine, lung, media of arteries and arterioles of the kidney, thymus, uterus, brain, corneal epithelium, corneal choriocapillaries, Myometriuml cells, eosinophiles, sclera of the eye, articular cartilage, the corpus cavernosum of the penis, and airway smooth muscle cells; its mRNA is expressed in gingival fibroblasts, monocyte-derived dendritic cells, aorta, corpus cavernosum of the penis, articular cartilage, airway smooth muscle, and airway epithelial cells. In rats, the receptor protein and/or mRNA has been found in lung, spleen, intestine, skin, kidney, liver, long bones, and rather extensively throughout the brain and other parts of the central nervous system.[8]
Ligands
Activating ligands
The following standard prostaglandins have the following relative efficacies in binding to and activating EP2: PGE2>PGF2alpha>=PGI2>PGD2.[9] The receptor binding affinity Dissociation constant Kd (i.e. ligand concentration needed to bind with 50% of available EP1 receptors) is ~13 nM for PGE2 and ~10 nM for PGE1 with the human receptor and ~12 nM for PGE2 with the mouse receptor.[10][11] 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 EP2-selective activators are useful for the study of this receptor's function and could be clinically useful for the treatment of certain diseases. There are several such agonists including butaprost free acid and ONO-AE1-259-01 which have Ki inhibitory binding values (see Biochemis try#Receptor/ligand binding affinity) of 32 and 1.8 NM, respectively, and therefore are respectively ~2.5-fold less and 7-fold more potent than PGE2.[11]
Inhibiting ligands
PF-04418948 (Ki=16 nM), TG4-155 (Ki=9.9 nM), TG8-4, and TG6-129 are selective competitive antagonists for EP2 that have been used for studies in animal models of human diseases. Many of the earlier EP2 receptor antagonists used for such studies exhibited poor receptor selectivity, inhibiting, for example, other EP receptors.[11]
Mechanism of cell activation
EP2 is classified as a relaxant type of prostanoid receptor based on its ability, upon activation, to relax certain types of smooth muscle (see Prostaglandin receptors. When initially bound to PGE2 or other agonist, it mobilizes G proteins containing the Gs alpha subunit (i.e. Gαs)-G beta-gamma complexes [i.e. Gβγ]). The Gαs- Gβγ complexes dissociate into their Gαs and Gβγ subunits which in turn regulate cell signaling pathways. In particular, Gαs stimulates adenyl cyclase to raise cellular levels of cAMP thereby activating PKA; PKA activates various types of signaling molecules such as the transcription factor CREB which lead to various functional responses depending on cell type.[6] EP2 also activates the GSK-3 pathway which regulates cell migratory responses and innate immune responses including pro-inflammatory cytokine and interleukin production and the Beta-catenin pathway which regulates cell–cell adhesion and by activating the Wnt signaling pathway the transcription of genes that regulate cell migration and proliferation. In these respects, EP2 resembles another type of relaxant prostanoid receptor, EP2, while differing from the contractile prostanoid receptors, EP1 and EP3 receptors which mobilize G proteins containing the Gαq-Gβγ complex.
Function
Studies using animals genetically engineered to lack EP<sub2 and supplemented by studies examining the actions of EP2 receptor antagonists and agonists in animals as well as animal and human tissues indicate that this receptor serves several functions. Relative to immune responses, agonist binding to EP2: 1) promotes exudation and swelling at sites of nascent inflammation; 2) contributes to the regulation of B cell immunoglobulin class switching, the maturation of T lymphocyte CD4−CD8− cells to doubly positive CD4+CD8+ cells, and the function of Antigen-presenting cells; d) contributes to the development of inflammation in rodent models of joint and paw inflammation but also contributes to the suppression of inflammation in the central nervous system; and 4) suppresses the development of fibrosis in a model of Bleomycin-induced pulmonary fibrosis.[12] Activation of this receptor tends to suppress allergic inflammatory responses; its smooth muscle-relaxing activity extends to dilating airways (]]bronchodilation]]) contracted by the allergic mediator, histamine; it inhibits Immunoglobulin E-activated mast cells from releasing histamine and making bronchoconstricting and otherwise pro-allergic leukotrienes, i.e. LTC4, LTD4, and LTE4; and it inhibits the release of the pro-allergic cytokines Interleukin 5, Interleukin 4, and interleukin 13 from human blood mononuclear cells.[13][14]
See also
- Prostanoid receptors
- Prostaglandin receptors
- Prostaglandin E2 receptor 1 (EP1)
- Prostaglandin E2 receptor 3 (EP3)
- Prostaglandin E2 receptor 4 (EP4)
- Eicosanoid receptor
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000125384 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000037759 – 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".
- ^ a b Woodward DF, Jones RL, Narumiya S (2011). "International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress". Pharmacological Reviews. 63 (3): 471–538. doi:10.1124/pr.110.003517. PMID 21752876.
- ^ https://www.ncbi.nlm.nih.gov/gene/5732
- ^ http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=341
- ^ http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=341
- ^ Narumiya S, Sugimoto Y, Ushikubi F (1999). "Prostanoid receptors: structures, properties, and functions". Physiological Reviews. 79 (4): 1193–226. PMID 10508233.
- ^ a b c Markovič T, Jakopin Ž, Dolenc MS, Mlinarič-Raščan I (2017). "Structural features of subtype-selective EP receptor modulators". Drug Discovery Today. 22 (1): 57–71. doi:10.1016/j.drudis.2016.08.003. PMID 27506873.
- ^ Matsuoka T, Narumiya S (2007). "Prostaglandin receptor signaling in disease". TheScientificWorldJournal. 7: 1329–47. doi:10.1100/tsw.2007.182. PMID 17767353.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Machado-Carvalho L, Roca-Ferrer J, Picado C (2014). "Prostaglandin E2 receptors in asthma and in chronic rhinosinusitis/nasal polyps with and without aspirin hypersensitivity". Respiratory Research. 15: 100. doi:10.1186/s12931-014-0100-7. PMC 4243732. PMID 25155136.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Torres R, Picado C, de Mora F (2015). "The PGE2-EP2-mast cell axis: an antiasthma mechanism". Molecular Immunology. 63 (1): 61–8. doi:10.1016/j.molimm.2014.03.007. PMID 24768319.
External links
- "Prostanoid Receptor: EP2". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
Further reading
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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