Prostaglandin EP2 receptor explained

Prostaglandin E₂ receptor 2, 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 lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors).^[1] EP has been implicated in various physiological and pathological responses.^[2]

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).^[3]

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 cerebral cortex, brain striatum, brain hippocampus, 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.^{[4] [5]}

EP₂ expression in fibroblasts from the lungs of mice with bleomycin-induced pulmonary fibrosis and humans with Idiopathic pulmonary fibrosis is greatly reduced. In both instances, this reduced expression was associated with hypermethylation of CpG dinucleotide sites located in the first 420 base pairs upstream of the PTGER2 gene transcription start site of these fibroblasts. This suggests that EP₂ expression is regulated by this methylation.^[6]

Ligands

Activating ligands

The following standard prostaglandins have the following relative efficacies in binding to and activating EP₂: PGE₂>PGF2alpha>=PGI2>PGD2.^[4] The receptor binding affinity Dissociation constant K_d (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.^{[7] [8]} 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 K_i inhibitory binding values (see Biochemistry#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.^[8]

Inhibiting ligands

PF-04418948 (K_i=16 nM), TG4-155 (K_i=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.^[8]

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 any other of its agonists, it mobilizes G proteins containing the Gs alpha subunit (i.e. Gα_s)-G beta-gamma complexes (i.e. G_βγ). The Gα_s- G_βγ complexes dissociate into their Gα_s and G_βγ subunits which in turn regulate cell signaling pathways. In particular, Gα_s stimulates adenylyl 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 different types of functional responses depending on cell type.^{[2] [9]} EP₂ also activates the a) GSK-3 pathway which regulates cell migratory responses and innate immune responses including pro-inflammatory cytokine and interleukin production and b) Beta-catenin pathway which regulates not only cell–cell adhesion but also activates the Wnt signaling pathway which, in turn, stimulates the transcription of genes responsible for regulating cell migration and proliferation.^[2] In many of these respects, EP₂ actions resemble those of another type of relaxant prostanoid receptor, EP₄ but differs from the contractile prostanoid receptors, EP₁ and EP₃ receptors which mobilize G proteins containing the Gα_q-Gβγ complex. EP₂ also differs from all the other prostaglandin receptors in that it fails to undergo homologous desensitization. That is, following agonist-induced activation, the other prostaglandin (as well as most types of G protein coupled receptors) quickly become desensitized, often internalized, and whether or not internalized, incapable of activating their G protein targets. This effect limits the duration and extent to which agonists can stimulate cells. EP₂, by failing to become desensitized, is able to function over prolong periods and later time points than other prostaglandin receptors and therefore potentially able to contribute to more delayed and chronic phases of cellular and tissue responses.^[6]

Functions

Studies using animals genetically engineered to lack EP₂ 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 various functions.

Eye

When applied topically into the eyes of rodents, cats, rhesus monkeys, and humans PGE2 acts, apparently acting at least in part through EP₂, decreases intraocular pressure by stimulating increases in the drainage of aqueous humor through the uveoskceral pathway, the principal aqueous humor outflow pathway in the eye.^[10]

Reproduction

Female mice engineered to lack a functional Pgter2 gene show a modest reduction in ovulation and more severely impaired capacity for Fertilisation. Studies suggest that this impaired fertilization reflects the loss of EP₂ functions in stimulating cumulus cells clusters which surround oocytes to: a) form the CCL7 chemokine which serves as a chemoattractant that guides sperm cells to oocytes and b) disassemble the extracellular matrix which in turn allows sperm cells to penetrate to the oocyte. These data allow that an EP2 receptor antagonist may be a suitable candidate as a contraceptive for women.^[11]

Inflammation and allergy

Activation of EP₂ contributes to regulating B cell immunoglobulin class switching, maturation of T lymphocyte CD4−CD8− cells to CD4+CD8+ cells, and the function of Antigen-presenting cells, particularly Dendritic cells. EP thereby contributes to the development of inflammation in rodent models of certain types of experimentally-induced joint and paw inflammation and the neurotoxic effects of endotoxin. However, EP₂ activation also has anti-inflammatory actions on pro-inflammatory cells (e.g. neutrophils, monocytes, macrophages, dendritic cells, NK cells, TH1 cells, TH2 cells, and fibroblasts in various tissues and on microglia cells in the central nervous system). These actions suppress certain forms of inflammation such NMDA receptor-related neurotoxicity and the rodent model of Bleomycin-induced pulmonary fibrosis.^{[2] [12]} EP₂ activation also inhibits the phagocytosis and killing of pathogens by alveolar macrophages; these effects may serve an anti-inflammatory role but reduce host defense against these pathogens.^[6]

Activation of EP₂ also influences allergic inflammatory reactions. It dilates airways (bronchodilation) contracted by the allergic mediator, histamine; inhibits Immunoglobulin E-activated mast cells from releasing histamine and leukotrienes (viz., LTC4, LTD4, and LTE4), all of which have bronchoconstricting and otherwise pro-allergic actions; inhibits pro-allergic eosinophil apoptosis, chemotaxis, and release of pro-allergic granule contents; and reduces release of the pro-allergic cytokines Interleukin 5, Interleukin 4, and interleukin 13 from human blood mononuclear cells.^{[13] [14]}

Cardiovascular

EP₂ receptor-deficient mice develop mild systolic and/or systemic hypertension which is worsened by high dietary intake of salt. These effects are thought to be due to the loss of EP₂'s vasodilation effects and/or ability to increase the urinary excretion of salt.^{[2] [15] [16]}

Bone

EP₂-deficient mice exhibit impaired generation of osteoclasts (cells that break down bone tissue) due to a loss in the capacity of osteoblastic cells to stimulate osteoclast formation. These mice have weakened bones compared with the wild type animals. When administered locally or systemically to animals, EP₂-selective agonists stimulate the local or systemic formation of bone, augment bone mass, and accelerate the healing of fractures and other bone defects in animal models.^[17]

Nervous system

EP₂ deficient mice exhibit reduced Oxidative stress and beta amyloid formation. Activation of this receptor also has neuroprotective effects in models of Alzheimer's disease, Amyotrophic lateral sclerosis, multiple sclerosis, and stroke while its inhibition reduces Epileptic seizure. EP2 signaling can also increase stroke injury via neurons in a mice model according to a PNAS paper.^[18] EP₂ receptors on either nerve or Neuroglia cells of the peripheral and central nervous system act to promote pain perception, which are caused by inflammation, muscle stretch, temperature, and physical stimuli (see allodynia) in mice.^{[5] [12]} A 2021 study found that inhibition of myeloid cell EP2 signalling can reverse or prevent an inflammation element of brain-ageing in mice.^{[19] [20]}

Malignancy

The EP₂ receptor can act as a tumor promoter. EP₂ gene knockout mice have less lung, breast, skin, and colon cancers following exposure to carcinogens. Knockout of this gene in mice with the adenomatous polyposis coli mutation also causes a decrease in the size and number of pre-cancerous intestinal polyps that the animals develop. These effects are commonly ascribed to the loss of EP₂-mediated: Vascular endothelial growth factor production and thereby of tumor vascularization; regulation of endothelial cell motility and survival; interference with transforming growth factor-β's anti-cell proliferation activity; and, more recently, regulation of host anti-tumor immune responses.^[21]

Clinical significance

Therapeutics

Preclinical studies, as outlined above, indicate that EP₂ may be a target for treating and/or preventing particular human disorders involving: allergic diseases such as asthma and rhinitis, particularly aspirin-exacerbated respiratory disease (AERD); glaucoma;^[10] various diseases of the nervous system;^[5] fractures, osteoporosis, and other bone abnormalities;^[17] pulmonary fibrosis;^[12] certain forms of malignant disease such as colon cancer including those that arise from Adenomatous polyposis coli mutations;^[21] and salt-sensitive forms of hypertension;^[16] This receptor has also been suggested to be a target for contraception.^[11] To date, however, there has been little translational research to determine the possible beneficial effects of EP₂ antagonists or agonists in humans. The following drugs that act on EP₂ but also other prostaglandin receptors are in clinical use:

• Iloprost activates EP₂, EP₃, and EP₄ receptors to treat diseases involving pathological constriction of blood vessels such as pulmonary hypertension, Raynauds disease, and scleroderma. Presumably, it works by stimulating EP₂, and EP₄ receptors which have vasodilation actions.
• Misoprostol, an EP₃ and EP₄ receptor agonist, to prevent ulcers; to induce labor in pregnancy, medical abortion, and late miscarriage; and to prevent and treat postpartum bleeding.

The following drugs are in development or proposed to be candidates for development as highly selective EP₂ agonists for the indicated conditions:^[8]

• Butaprost for the treatment of pulmonary fibrosis and certain neurological diseases
• CP533,536 for the stimulation of bone formation
• Taprenepag isopropyl (PF-04217329) for the treatment of glaucoma and various neurological diseases (see above section on Nervous system)

Genomic studies

The single-nucleotide polymorphism (SNP) variant rs17197^[22] in the 3' untranslated region of PTGER2 has been associated with an increased incidence of essential hypertension in a population of Japanese men. SNP variant rs1254598^[23] in a Spanish population; SNP variant uS5 located in a STAT-binding consensus sequence of the regulatory region of PTGER2 with reduced transcription activity in a Japanese population; and two PTGER2 SNP variants (-616C>G and -166G>A) in a Korean population have been associated with an increased incidence of Aspirin-induced asthma.^[24]

See also

• Prostanoid receptors
• Prostaglandin receptors
• Prostaglandin E2 receptor 1 (EP1)
• Prostaglandin E2 receptor 3 (EP3)
• Prostaglandin E2 receptor 4 (EP4)
• Eicosanoid receptor

Further reading

• 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 .
• Wu H, Wu T, Hua W, Dong X, Gao Y, Zhao X, Chen W, Cao W, Yang Q, Qi J, Zhou J, Wang J . PGE2 receptor agonist misoprostol protects brain against intracerebral hemorrhage in mice . Neurobiology of Aging . 36 . 3 . 1439–50 . March 2015 . 25623334 . 10.1016/j.neurobiolaging.2014.12.029 . 4417504.
• Regan JW, Bailey TJ, Pepperl DJ, Pierce KL, Bogardus AM, Donello JE, Fairbairn CE, Kedzie KM, Woodward DF, Gil DW . Cloning of a novel human prostaglandin receptor with characteristics of the pharmacologically defined EP2 subtype . Molecular Pharmacology . 46 . 2 . 213–20 . August 1994 . 8078484 .
• Wu H, Wu T, Han X, Wan J, Jiang C, Chen W, Lu H, Yang Q, Wang J . Cerebroprotection by the neuronal PGE2 receptor EP2 after intracerebral hemorrhage in middle-aged mice . Journal of Cerebral Blood Flow and Metabolism . 37 . 1 . 39–51 . January 2017 . 26746866 . 10.1177/0271678X15625351 . 5363749 .
• Bastien L, Sawyer N, Grygorczyk R, Metters KM, Adam M . Cloning, functional expression, and characterization of the human prostaglandin E2 receptor EP2 subtype . The Journal of Biological Chemistry . 269 . 16 . 11873–7 . April 1994 . 10.1016/S0021-9258(17)32654-6 . 8163486 . free .
• An S, Yang J, Xia M, Goetzl EJ . Cloning and expression of the EP2 subtype of human receptors for prostaglandin E2 . Biochemical and Biophysical Research Communications . 197 . 1 . 263–70 . November 1993 . 8250933 . 10.1006/bbrc.1993.2470 .
• Stillman BA, Breyer MD, Breyer RM . Importance of the extracellular domain for prostaglandin EP(2) receptor function . Molecular Pharmacology . 56 . 3 . 545–51 . September 1999 . 10462542 . 10.1124/mol.56.3.545.
• Smock SL, Pan LC, Castleberry TA, Lu B, Mather RJ, Owen TA . Cloning, structural characterization, and chromosomal localization of the gene encoding the human prostaglandin E(2) receptor EP2 subtype . Gene . 237 . 2 . 393–402 . September 1999 . 10521663 . 10.1016/S0378-1119(99)00323-6 .
• Desai S, April H, Nwaneshiudu C, Ashby B . Comparison of agonist-induced internalization of the human EP2 and EP4 prostaglandin receptors: role of the carboxyl terminus in EP4 receptor sequestration . Molecular Pharmacology . 58 . 6 . 1279–86 . December 2000 . 11093764 . 10.1124/mol.58.6.1279.
• Duckworth N, Marshall K, Clayton JK . An investigation of the effect of the prostaglandin EP2 receptor agonist, butaprost, on the human isolated myometrium from pregnant and non-pregnant women . The Journal of Endocrinology . 172 . 2 . 263–9 . February 2002 . 11834444 . 10.1677/joe.0.1720263 . free .
• 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 .
• Takafuji VA, Evans A, Lynch KR, Roche JK . PGE(2) receptors and synthesis in human gastric mucosa: perturbation in cancer . Prostaglandins, Leukotrienes, and Essential Fatty Acids . 66 . 1 . 71–81 . January 2002 . 12051958 . 10.1054/plef.2001.0299 .
• Scandella E, Men Y, Gillessen S, Förster R, Groettrup M . Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells . Blood . 100 . 4 . 1354–61 . August 2002 . 12149218 . 10.1182/blood-2001-11-0017 .
• Okuyama T, Ishihara S, Sato H, Rumi MA, Kawashima K, Miyaoka Y, Suetsugu H, Kazumori H, Cava CF, Kadowaki Y, Fukuda R, Kinoshita Y . Activation of prostaglandin E2-receptor EP2 and EP4 pathways induces growth inhibition in human gastric carcinoma cell lines . The Journal of Laboratory and Clinical Medicine . 140 . 2 . 92–102 . August 2002 . 12228765 . 10.1016/s0022-2143(02)00023-9 .
• Konger RL, Scott GA, Landt Y, Ladenson JH, Pentland AP . Loss of the EP2 prostaglandin E2 receptor in immortalized human keratinocytes results in increased invasiveness and decreased paxillin expression . The American Journal of Pathology . 161 . 6 . 2065–78 . December 2002 . 12466123 . 1850902 . 10.1016/S0002-9440(10)64485-9 .
• Abulencia JP, Gaspard R, Healy ZR, Gaarde WA, Quackenbush J, Konstantopoulos K . Shear-induced cyclooxygenase-2 via a JNK2/c-Jun-dependent pathway regulates prostaglandin receptor expression in chondrocytic cells . The Journal of Biological Chemistry . 278 . 31 . 28388–94 . August 2003 . 12743126 . 10.1074/jbc.M301378200 . 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 .
• Sun HS, Hsiao KY, Hsu CC, Wu MH, Tsai SJ . Transactivation of steroidogenic acute regulatory protein in human endometriotic stromalcells is mediated by the prostaglandin EP2 receptor . Endocrinology . 144 . 9 . 3934–42 . September 2003 . 12933667 . 10.1210/en.2003-0289 . free .
• Bradbury DA, Newton R, Zhu YM, El-Haroun H, Corbett L, Knox AJ . Cyclooxygenase-2 induction by bradykinin in human pulmonary artery smooth muscle cells is mediated by the cyclic AMP response element through a novel autocrine loop involving endogenous prostaglandin E2, E-prostanoid 2 (EP2), and EP4 receptors . The Journal of Biological Chemistry . 278 . 50 . 49954–64 . December 2003 . 14517215 . 10.1074/jbc.M307964200 . free .
• 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 .
• Sugimoto Y, Nakato T, Kita A, Takahashi Y, Hatae N, Tabata H, Tanaka S, Ichikawa A . A cluster of aromatic amino acids in the i2 loop plays a key role for Gs coupling in prostaglandin EP2 and EP3 receptors . The Journal of Biological Chemistry . 279 . 12 . 11016–26 . March 2004 . 14699136 . 10.1074/jbc.M307404200 . free .

External links

• Web site: Prostanoid Receptor: EP₂ . 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/20160303195929/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2418 . dead .

Notes and References

1. Web site: PTGER2 prostaglandin e receptor 2 [Homo sapiens (human)] - Gene - NCBI.
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: PTGER2 prostaglandin E receptor 2 (human) . Entrez Gene . National Center for Biotechnology Information, U.S. National Library of Medicine .
4. Web site: EP₂ receptor . IUPHAR/BPS Guide to Pharmacology .
5. Yagami T, Koma H, Yamamoto Y . Pathophysiological Roles of Cyclooxygenases and Prostaglandins in the Central Nervous System . Molecular Neurobiology . 53 . 7 . 4754–71 . 2016 . 26328537 . 10.1007/s12035-015-9355-3 . 11624385 .
6. Kalinski P . Regulation of immune responses by prostaglandin E2 . Journal of Immunology . 188 . 1 . 21–8 . 2012 . 22187483 . 3249979 . 10.4049/jimmunol.1101029 .
7. 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 .
8. 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 .
9. Moreno JJ . Eicosanoid receptors: Targets for the treatment of disrupted intestinal epithelial homeostasis . European Journal of Pharmacology . 796 . 7–19 . 2017 . 27940058 . 10.1016/j.ejphar.2016.12.004 . 1513449 .
10. Doucette LP, Walter MA . Prostaglandins in the eye: Function, expression, and roles in glaucoma . Ophthalmic Genetics . 38. 2. 1–9 . 2016 . 27070211 . 10.3109/13816810.2016.1164193 . 2395560 .
11. Sugimoto Y, Inazumi T, Tsuchiya S . Roles of prostaglandin receptors in female reproduction . Journal of Biochemistry . 157 . 2 . 73–80 . 2015 . 25480981 . 10.1093/jb/mvu081 . free .
12. Matsuoka T, Narumiya S . Prostaglandin receptor signaling in disease . TheScientificWorldJournal . 7 . 1329–47 . September 2007 . 17767353 . 5901339 . 10.1100/tsw.2007.182 . free .
13. Machado-Carvalho L, Roca-Ferrer J, Picado C . Prostaglandin E2 receptors in asthma and in chronic rhinosinusitis/nasal polyps with and without aspirin hypersensitivity . Respiratory Research . 15 . 100 . August 2014 . 1 . 25155136 . 4243732 . 10.1186/s12931-014-0100-7 . free .
14. Torres R, Picado C, de Mora F . The PGE2-EP2-mast cell axis: an antiasthma mechanism . Molecular Immunology . 63 . 1 . 61–8 . January 2015 . 24768319 . 10.1016/j.molimm.2014.03.007 .
15. Yang G, Chen L . An Update of Microsomal Prostaglandin E Synthase-1 and PGE2 Receptors in Cardiovascular Health and Diseases . Oxidative Medicine and Cellular Longevity . 2016 . 5249086 . 2016 . 27594972 . 4993943 . 10.1155/2016/5249086 . free .
16. Yang T, Du Y . Distinct roles of central and peripheral prostaglandin E2 and EP subtypes in blood pressure regulation . American Journal of Hypertension . 25 . 10 . 1042–9 . 2012 . 22695507 . 3578476 . 10.1038/ajh.2012.67 .
17. Li M, Thompson DD, Paralkar VM . Prostaglandin E(2) receptors in bone formation . International Orthopaedics . 31 . 6 . 767–72 . 2007 . 17593365 . 2266676 . 10.1007/s00264-007-0406-x .
18. Liu Q, Liang X, Wang Q, Wilson EN, Lam R. 3 . PGE2 signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia. Proc Natl Acad Sci USA. 116 . 20 . 10019–10024. May 2019 . 31036664 . 10.1073/pnas.1818544116. 6525498 . 2019PNAS..11610019L . free .
19. News: Study reveals immune driver of brain aging . 13 February 2021 . medicalxpress.com . en.
20. Minhas PS, Latif-Hernandez A, McReynolds MR, Durairaj AS, Wang Q, Rubin A, Joshi AU, He JQ, Gauba E, Liu L, Wang C, Linde M, Sugiura Y, Moon PK, Majeti R, Suematsu M, Mochly-Rosen D, Weissman IL, Longo FM, Rabinowitz JD, Andreasson KI . 6 . Restoring metabolism of myeloid cells reverses cognitive decline in ageing . Nature . 590 . 7844 . 122–128 . February 2021 . 33473210 . 10.1038/s41586-020-03160-0 . 2021Natur.590..122M . 8274816 .
21. O'Callaghan G, Houston A . Prostaglandin E2 and the EP receptors in malignancy: possible therapeutic targets? . British Journal of Pharmacology . 172 . 22 . 5239–50 . November 2015 . 26377664 . 10.1111/bph.13331 . 5341220.
22. Web site: Rs17197 RefSNP Report - DBSNP - NCBI.
23. Web site: Rs1254598 RefSNP Report - DBSNP - NCBI.
24. Cornejo-García JA, Perkins JR, Jurado-Escobar R, García-Martín E, Agúndez JA, Viguera E, Pérez-Sánchez N, Blanca-López N . Pharmacogenomics of Prostaglandin and Leukotriene Receptors . Frontiers in Pharmacology . 7 . 316 . 2016 . 27708579 . 5030812 . 10.3389/fphar.2016.00316 . free .