Prostaglandin EP3 receptor explained

Prostaglandin EP₃ receptor (EP₃, 53kDa), is a prostaglandin receptor for prostaglandin E2 (PGE₂) encoded by the human gene PTGER3;^[1] it is one of four identified EP receptors, the others being EP₁, EP₂, and EP₄, all of which bind with and mediate cellular responses to PGE₂ and also, but generally with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors).^[2] EP has been implicated in various physiological and pathological responses.^[3]

Gene

The PTGER3 gene is located on human chromosome 1 at position p31.1 (i.e. 1p31.1), contains 10 exons, and codes for a G protein coupled receptor (GPCR) of the rhodopsin-like receptor family, Subfamily A14 (see rhodopsin-like receptors#Subfamily A14). PTGER3 codes for at least 8 different isoforms in humans, i.e. PTGER3-1 to PGGER3-8 (i.e., EP₃-1, EP₃-2, EP₃-3, EP₃-4, EP₃-5, EP₃-6, EP₃-7, and EP₃-8), while Ptger3 codes for at least 3 isoforms in mice, Ptger1-Ptger3 (i.e. Ep₃-α, Ep₃-β, and Ep₃-γ). These isoforms are variants made by Alternative splicing conducted at the 5'-end of DNA to form proteins that vary at or near their C-terminus.^{[1] [4] [5]} Since these isoforms different in their tissue expressions as well as the signaling pathways which they activate, they may vary in the functions that they perform.^[6] Further studies are needed to examine functional differences among these isoforms.

Expression

EP₃ is widely distributed in humans. Its protein and/or mRNA is expressed in kidney (i.e. glomeruli, Tamm-Horsfall protein negative late distal convoluted tubules, connecting segments, cortical and medullary collecting ducts, media and endothelial cells of arteries and arterioles); stomach (vascular smooth muscle and gastric fundus mucosal cells); thalamus (anterior, ventromedial, laterodorsal, paraventricular and central medial nuclei); intestinal mucosal epithelia at the apex of crypts; myometrium (stromal cells, endothelial cells, and, in pregnancy, placenta, chorion, and amnion); mouth gingival fibroblasts; and eye (corneal endothelium and keratocytes, trabecular cells, ciliary epithelium, and conjunctival and iridal stroma cells, and retinal Müller cells).^[7]

Ligands

Activating ligands

Standard prostanoids have the following relative efficacies in binding to and activating EP₃: PGE₂>PGF2α=PGI2>PGD2=TXA2. Prostaglandin E1 (PGE₁), which has one less double bond than PGE₂, has the same binding affinity and potency for EP₃ as PGE₂.^[7] PGE₂ has extreme high affinity (dissociation constant Kd=0.3 nM) for EP₃. Several synthetic compounds, e.g. sulprostone, SC-46275, MB-28767, and ONO-AE-248, bind to and stimulate with high potency EP₃ but unlike PGE₂ have the advantage of being highly selective for this receptor over other EP receptors and are relatively resistant to being metabolically degraded. They are in development as drugs for the potential treatment of stomach ulcers in humans.

Inhibiting ligands

Numerous synthetic compounds have been found to be highly selective in binding to but not stimulating EP₃. These Receptor antagonist DG-O41, L798,106, and ONO-AE3-240, block EP₃ from responding to PGE₂ or other agonists of this receptor, including Sulprostone, ONO-AE-248 and TEI-3356. They are in development primarily as anti-thrombotics, i.e. drugs to treat pathological blood clotting in humans.

Mechanism of cell activation

EP₃ is classified as an inhibitory type of prostanoid receptor based on its ability, upon activation, to inhibit the activation of adenylyl cyclase stimulated by relaxant types of prostanoid receptors viz., prostaglandin DP, E2, and E4 receptors (see Prostaglandin receptors). When initially bound to PGE₂ or other of its agonists, it mobilizes G proteins containing various types of G proteins, depending upon the particular EP₃ isoform: EP_3α and EP_3β isoforms activate Gi alpha subunit (i.e. Gα_i)-G beta-gamma complexes (i.e. Gα_i)-G_βγ) complexes) as well as Gα₁₂-G_βγ complexes while the EP_3γ isoform activates in addition to and the Gα_i- G_βγ complexes Gα_i- G_βγ complexes.^[8] (G protein linkages for the other EP₃ isoforms have not been defined.) In consequence, complexes dissociate into Gα_i, Gα₁₂, G_s and G_βγ components which proceed to activate cell signaling pathways that lead functional responses viz., pathways that activate phospholipase C to convert cellular phospholipids to diacylglycerol which promotes the activation of certain isoforms of protein kinase C, pathways that elevated cellular cytosolic Ca²⁺ which thereby regulate Ca²⁺-sensitive cell signaling molecules, and pathways that inhibit adenylyl cyclase which thereby lowers cellular levels of cyclic adenosine monophosphate (cAMP) to reduce the activity of cAMP-dependent signaling molecules.

Functions

Studies using animals genetically engineered to lack EP₃ and supplemented by studies examining the actions of EP₃ receptor antagonists and agonists in animals as well as animal and human tissues indicate that this receptor serves various functions. However, an EP₃ receptor function found in these studies does not necessarily indicate that in does do in humans. For example, EP₃ receptor activation promotes duodenal secretion in mice; this function is mediated by EP₄ receptor activation in humans. EP receptor functions can vary with species and most of the functional studies cited here have not translated their animal and tissue models to humans.

Digestive system

The secretion of (bicarbonate anion) from Brunner's glands of the duodenum serves to neutralize the highly acidified digestive products released from the stomach and thereby prevents ulcerative damage to the small intestine. Activation of EP₃ and EP₄ receptors in mice stimulates this secretion but in humans activation of EP₄, not EP₃, appears responsible for this secretion. These two prostanoid receptors also stimulate intestinal mucous secretion, a function which may also act to reduce acidic damage to the duodenum.^[9]

Fever

EP₃-deficient mice as well as mice selectively deleted of EP₃ expression in the brain's median preoptic nucleus fail to develop fever in response to endotoxins (i.e. bacteria-derived lipopolysaccharide) or the host-derived regulator of body temperature, IL-1β. The ability of endotoxins and IL-1β but not that of PGE₂ to trigger fever is blocked by inhibitors of nitric oxide and PG₂. EP₃-deficient mice exhibit normal febrile responses to stress, interleukin-8, and macrophage inflammatory protein-1beta (MIP-1β). It is suggested that these findings indicate that a) activation of the EP₃ receptor suppresses the inhibitory tone that the preoptic hypothalamus has on thermogenic effector cells in the brain; b) endotoxin and IL-1β simulate the production of nitric oxide which in turn causes the production of PGE₂ and thereby the EP₃-dependent fever-producing; c) other factors such as stress, interleukin 8, and MIP-1β trigger fever independently of EP₃; and d) inhibition of the PGE₂-EP₃ pathway underlies the ability of aspirin and other Nonsteroidal anti-inflammatory drugs to reduce fever caused by inflammation in animals and, possibly, humans.^{[10] [11]}

Allergy

In a mouse model of ovalbumin-induced asthma, a selective EP₃ agonist reduced airway cellularity, mucus, and bronchoconstriction responses to methacholine. In this model, EP₃-deficient mice, upon ovalbumin challenge, exhibited worsened allergic inflammation as measured by increased airway eosinophils, neutrophils, lymphocytes, and pro-allergic cytokines (i.e. interleukin 4, interleukin 5, and interleukin 13) as compared to wild type mice.^{[3] [12]} EP₃ receptor-deficient mice and/or wild type mice treated with an EP₃ receptor agonist are similarly protected from allergic responses in models of allergic conjunctivitis and contact hypersensitivity.^[13] Thus, EP₃ appears to serve an important role in reducing allergic reactivity at least in mice.

Cough

Studies with mice, guinea pig, and human tissues and in guinea pigs indicate that PGE₂ operates through EP₃ to trigger cough responses. Its mechanism of action involves activation and/or sensitization of TRPV1 (as well as TRPA1) receptors, presumably by an indirect mechanism. Genetic polymorphism in the EP3 receptor (rs11209716^[14]), has been associated with ACE inhibitor-induce cough in humans.^{[15] [16]} The use of EP₃ receptor antagonists may warrant study for the treatment of chronic cough in humans.^[17]

Blood pressure

Activation of EP₃ receptors contracts vascular beds including rat mesentery artery, rat tail artery, guinea-pig aorta, rodent and human pulmonary artery, and murine renal and brain vasculature. Mice depleted of EP₃ are partially protected from brain injury consequential to experimentally induced cerebral ischemia. Furthermore, rodent studies indicate that agonist-induced activation of EP₃ in the brain by intra-cerebroventricular injection of PGE₂ or selective EP₃ agonist cause hypertension; a highly selective EP₃ receptor antagonist blocked this PGE2-induced response. These studies, which examine a sympatho-excitatory response (i.e. responses wherein brain excitation such as stroke raises blood pressure) suggest that certain hypertension responses in humans are mediated, at least in part, by EP₃.^[18]

Vascular permeability

Model studies indicate that PG₂ (but not specific antigens or IgE cross-linkage) stimulates mouse and human mast cells to release histamine by an EP₃-dependent mechanism. Furthermore, EP₃-deficient mice fail to develop increased capillary permeability and tissue swelling in response to EP₃ receptor agonists and the metabolic precursor to PGE₂, arachidonic acid. It is suggested, based on these and other less direct studies, that PGE₂-EP₃ signaling may be responsible for the skin swelling and edema provoked by topical 5-aminolaevulinic acid photodynamic therapy, contact with chemical irritants, infection with pathogens, and various skin disorders in humans.^{[19] [20]}

Blood clotting

Activation of EP₃ receptors on the blood platelets of mice, monkeys, and humans enhances their aggregation, degranulation, and blood clot-promoting responsiveness to a wide array of physiological (e.g. thrombin) and pathological (e.g. atheromatous plaques. (In contrast, activation of either the EP₂ or EP₃ receptor inhibits platelet activation) Inhibition of EP₃ with the selective EP₃ receptor antagonist, DG-041, has been shown to prevent blood clotting but not to alter hemostasis or blood loss in mice and in inhibit platelet activation responses in human whole blood while not prolonging bleeding times when given to human volunteers. The drug has been proposed to be of potential clinical use for the prevention of blood clotting while causing little or no bleeding tendencies.^{[21] [22]}

Pain

EP₃ deficient mice exhibit significant reductions in: hyperalgesic writhing (i.e. squirming) responses to acetic acid administration; acute but not chronic Herpes simplex infection-induced pain; and HIV-1 Envelope glycoprotein GP120 intrathecal injection-induced tactile allodynia. Furthermore, a selective EP₃ agonist, ONO-AE-248, induces hyperalgesia pain in wild type but not EP₃-deficient mice.^{[23] [24] [25]} While pain perception is a complex phenomenon involving multiple causes and multiple receptors including EP₂, EP₁, LTB₄, bradykinin, nerve growth factor, and other receptors, these studies indicate that EP₃ receptors contribute to the perception of at least certain types of pain in mice and may also do so in humans.

Cancer

Studies of the direct effects of EP₃ receptor activation on cancer in animal and tissue models give contradictory results suggesting that this receptor does not play an important role in Carcinogenesis. However, some studies suggest an indirect pro-carcinogenic function for the EP₃ receptor: The growth and metastasis of implanted Lewis lung carcinoma cells, a mouse lung cancer cell line, is suppressed in EP₃ receptor deficient mice. This effect was associated with a reduction in the levels of Vascular endothelial growth factor and matrix metalloproteinase-9 expression in the tumor's stroma; expression of the pro-lymphangiogenic growth factor VEGF-C and its receptor, VEGFR3; and a tumor-associated angiogenesis and lymphangiogenesis.^[26]

Clinical significance

Therapeutics

Many drugs that act on EP₃ and, often, other prostaglandin receptors, are in clinical use. A partial list of these includes:

• Misoprostol, an EP₃ and EP₄ receptor agonist, is in clinical use to prevent ulcers, to induce labor in pregnancy, medical abortion, and late miscarriage, and to prevent and treat postpartum bleeding (see Misoprostol).
• Sulprostone, relatively selective EP₃ receptor agonist with a weak ability to stimulate the EP₁ receptor is in clinical use for inducing medical abortion and ending pregnancy after fetal death (see Sulprostone).
• Iloprost activates EP₂, EP₃, and EP₄ receptors; it is in clinical use to treat diseases involving pathological constriction of blood vessels such as pulmonary hypertension, Raynauds disease, and scleroderma. Presumably, Iloprost works by stimulating EP₂, and EP₄ receptors which have vasodilation actions.^[27]

Other drugs are in various stages of clinical development or have been proposed to be tested for clinical development. A sampling of these includes:

• Enprostil, which binds to and activates primarily the EP₃ receptor, was found in a prospective multicenter randomized controlled trial conducted in Japan to significantly improve the effects of cimetidine in treating gastric ulcer.^[28] It is considered to be an efficient and safe treatment for gastric and duodenal ulcers.^[29]
• ONO-9054 (Sepetoprost), a dual an EP₃/Prostaglandin F receptor agonist, is in phase 1 clinical trial studies for the treatment of ocular hypertension and open-angle glaucoma.^[30]
• DG-041, a highly selective EP₃ antagonist, has been proposed to warrant further study as anti-thrombosis agent.^{[21] [22]}
• GR 63799X, MB-28767, ONO-AE-248, and TEI-3356 are putative EP₃ receptor-selective agonists that have been proposed to warrant further study to treat and/or prevent various types of cardiovascular diseases.^[31]

Genomic studies

The single nucleotide polymorphism (SNP) in the PTGER3, rs977214 A/G variant^[32] has been associated with an increase in pre-term births in two populations of European ancestry; the SNP variant -1709T>A in PTGER3 has been associated with aspirin-exacerbated respiratory disease in a Korean population; and 6 SNP variants have been associated with development of the Steven Johnson syndrome and its more severe form, toxic epidermal necrolysis, in a Japanese population.^{[33] [34]}

See also

• Eicosanoid receptor
• Prostaglandin E2 receptor 1 (EP1)
• Prostaglandin E2 receptor 2 (EP2)
• Prostaglandin E2 receptor 4 (EP4)

Further reading

• Kotani M, Tanaka I, Ogawa Y, Usui T, Mori K, Ichikawa A, Narumiya S, Yoshimi T, Nakao K . Molecular cloning and expression of multiple isoforms of human prostaglandin E receptor EP3 subtype generated by alternative messenger RNA splicing: multiple second messenger systems and tissue-specific distributions . Molecular Pharmacology . 48 . 5 . 869–79 . November 1995 . 7476918 .
• Han X, Lan X, Li Q, Gao Y, Zhu W, Cheng T, Maruyama T, Wang J . Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury . Journal of Cerebral Blood Flow and Metabolism . 36 . 6 . 1059–74 . June 2016 . 26661165 . 10.1177/0271678X15606462 . 4908617 .
• 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 .
• Schmid A, Thierauch KH, Schleuning WD, Dinter H . Splice variants of the human EP3 receptor for prostaglandin E2 . European Journal of Biochemistry . 228 . 1 . 23–30 . February 1995 . 7883006 . 10.1111/j.1432-1033.1995.tb20223.x .
• An S, Yang J, So SW, Zeng L, Goetzl EJ . Isoforms of the EP3 subtype of human prostaglandin E2 receptor transduce both intracellular calcium and cAMP signals . Biochemistry . 33 . 48 . 14496–502 . December 1994 . 7981210 . 10.1021/bi00252a016 .
• Regan JW, Bailey TJ, Donello JE, Pierce KL, Pepperl DJ, Zhang D, Kedzie KM, Fairbairn CE, Bogardus AM, Woodward DF . Molecular cloning and expression of human EP3 receptors: evidence of three variants with differing carboxyl termini . British Journal of Pharmacology . 112 . 2 . 377–85 . June 1994 . 8075855 . 1910333 . 10.1111/j.1476-5381.1994.tb13082.x .
• Yang J, Xia M, Goetzl EJ, An S . Cloning and expression of the EP3-subtype of human receptors for prostaglandin E2 . Biochemical and Biophysical Research Communications . 198 . 3 . 999–1006 . February 1994 . 8117308 . 10.1006/bbrc.1994.1142 .
• Kunapuli SP, Fen Mao G, Bastepe M, Liu-Chen LY, Li S, Cheung PP, DeRiel JK, Ashby B . Cloning and expression of a prostaglandin E receptor EP3 subtype from human erythroleukaemia cells . The Biochemical Journal . 298 . 2 . 263–7 . March 1994 . 8135729 . 1137934 . 10.1042/bj2980263.
• Adam M, Boie Y, Rushmore TH, Müller G, Bastien L, McKee KT, Metters KM, Abramovitz M . Cloning and expression of three isoforms of the human EP3 prostanoid receptor . FEBS Letters . 338 . 2 . 170–4 . January 1994 . 8307176 . 10.1016/0014-5793(94)80358-7 . 36055482 .
• Chang C, Negishi M, Nishigaki N, Ichikawa A . Functional interaction of the carboxylic acid group of agonists and the arginine residue of the seventh transmembrane domain of prostaglandin E receptor EP3 subtype . The Biochemical Journal . 322 . 2 . 597–601 . March 1997 . 9065782 . 1218231 . 10.1042/bj3220597.
• Kotani M, Tanaka I, Ogawa Y, Usui T, Tamura N, Mori K, Narumiya S, Yoshimi T, Nakao K . Structural organization of the human prostaglandin EP3 receptor subtype gene (PTGER3) . Genomics . 40 . 3 . 425–34 . March 1997 . 9073510 . 10.1006/geno.1996.4585 .
• Ushikubi F, Segi E, Sugimoto Y, Murata T, Matsuoka T, Kobayashi T, Hizaki H, Tuboi K, Katsuyama M, Ichikawa A, Tanaka T, Yoshida N, Narumiya S . Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3 . Nature . 395 . 6699 . 281–4 . September 1998 . 9751056 . 10.1038/26233 . 1998Natur.395..281U . 4420632 .
• Bhattacharya M, Peri K, Ribeiro-da-Silva A, Almazan G, Shichi H, Hou X, Varma DR, Chemtob S . Localization of functional prostaglandin E2 receptors EP3 and EP4 in the nuclear envelope . The Journal of Biological Chemistry . 274 . 22 . 15719–24 . May 1999 . 10336471 . 10.1074/jbc.274.22.15719 . free .
• Liu J, Akahoshi T, Jiang S, Namai R, Kitasato H, Endo H, Kameya T, Kondo H . Induction of neutrophil death resembling neither apoptosis nor necrosis by ONO-AE-248, a selective agonist for PGE2 receptor subtype 3 . Journal of Leukocyte Biology . 68 . 2 . 187–93 . August 2000 . 10.1189/jlb.68.2.187 . 10947062 . 35606750 .
• 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 .
• 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 .
• Wing DA, Goharkhay N, Hanna M, Naidu YM, Kovacs BW, Felix JC . EP3-2 receptor mRNA expression is reduced and EP3-6 receptor mRNA expression is increased in gravid human myometrium . Journal of the Society for Gynecologic Investigation . 10 . 3 . 124–9 . April 2003 . 12699873 . 10.1016/S1071-5576(03)00007-8 . 210868931 .
• 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 .
• 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 .

External links

• Web site: Prostanoid Receptors: EP₃ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology .

Notes and References

1. Web site: PTGER3 prostaglandin e receptor 3 [Homo sapiens (human)] - Gene - NCBI.
2. Web site: Entrez Gene: PTGER1 prostaglandin E receptor 1 (subtype EP1), 42kDa.
3. 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 .
4. Web site: Ptger3 prostaglandin e receptor 3 (subtype EP3) [Mus musculus (house mouse)] - Gene - NCBI.
5. Web site: Gene symbol report | HUGO Gene Nomenclature Committee.
6. Kim SO, Dozier BL, Kerry JA, Duffy DM . EP3 receptor isoforms are differentially expressed in subpopulations of primate granulosa cells and couple to unique G-proteins . Reproduction . 146 . 6 . 625–35 . December 2013 . 24062570 . 3832896 . 10.1530/REP-13-0274 .
7. Web site: Norel X, Jones RL, Giembycz M, Narumiya S, Woodward DF, Coleman RA, Abramovitz M, Breyer RM, Hills R . Prostanoid receptors: EP3 receptor . 2016-09-05 . IUPHAR/BPS Guide to Pharmacology .
8. Moreno JJ . Eicosanoid receptors: Targets for the treatment of disrupted intestinal epithelial homeostasis . European Journal of Pharmacology . 796 . 7–19 . February 2017 . 27940058 . 10.1016/j.ejphar.2016.12.004 . 1513449 .
9. Takeuchi K, Kato S, Amagase K . Prostaglandin EP receptors involved in modulating gastrointestinal mucosal integrity . Journal of Pharmacological Sciences . 114 . 3 . 248–61 . 2010 . 21041985 . 10.1254/jphs.10r06cr. free .
10. Furuyashiki T, Narumiya S . Roles of prostaglandin E receptors in stress responses . Current Opinion in Pharmacology . 9 . 1 . 31–8 . February 2009 . 19157987 . 10.1016/j.coph.2008.12.010 .
11. Narumiya S, Sugimoto Y, Ushikubi F . Prostanoid receptors: structures, properties, and functions . Physiological Reviews . 79 . 4 . 1193–226 . 1999 . 10508233 . 10.1152/physrev.1999.79.4.1193. 7766467 .
12. Claar D, Hartert TV, Peebles RS . The role of prostaglandins in allergic lung inflammation and asthma . Expert Review of Respiratory Medicine . 9 . 1 . 55–72 . February 2015 . 25541289 . 4380345 . 10.1586/17476348.2015.992783 .
13. Ueta M . Epistatic interactions associated with Stevens-Johnson syndrome . Cornea . 31 . S57-62 . November 2012 . Suppl 1 . 23038037 . 10.1097/ICO.0b013e31826a7f41 . 2468341 .
14. Web site: Rs11209716 RefSNP Report - DBSNP - NCBI.
15. Maher SA, Dubuis ED, Belvisi MG . G-protein coupled receptors regulating cough . Current Opinion in Pharmacology . 11 . 3 . 248–53 . June 2011 . 21727026 . 10.1016/j.coph.2011.06.005 .
16. Grilo A, Sáez-Rosas MP, Santos-Morano J, Sánchez E, Moreno-Rey C, Real LM, Ramírez-Lorca R, Sáez ME . Identification of genetic factors associated with susceptibility to angiotensin-converting enzyme inhibitors-induced cough . Pharmacogenetics and Genomics . 21 . 1 . 10–7 . January 2011 . 21052031 . 10.1097/FPC.0b013e328341041c . 22282464 .
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18. 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 . October 2012 . 22695507 . 3578476 . 10.1038/ajh.2012.67 .
19. Hohjoh H, Inazumi T, Tsuchiya S, Sugimoto Y . Prostanoid receptors and acute inflammation in skin . Biochimie . 107 . Pt A . 78–81 . December 2014 . 25179301 . 10.1016/j.biochi.2014.08.010 .
20. Kawahara K, Hohjoh H, Inazumi T, Tsuchiya S, Sugimoto Y . Prostaglandin E2-induced inflammation: Relevance of prostaglandin E receptors . Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids . 1851 . 4 . 414–21 . April 2015 . 25038274 . 10.1016/j.bbalip.2014.07.008 .
21. Mawhin MA, Tilly P, Fabre JE . The receptor EP3 to PGE2: A rational target to prevent atherothrombosis without inducing bleeding . Prostaglandins & Other Lipid Mediators . 121 . Pt A . 4–16 . September 2015 . 26463849 . 10.1016/j.prostaglandins.2015.10.001 .
22. Friedman EA, Ogletree ML, Haddad EV, Boutaud O . Understanding the role of prostaglandin E2 in regulating human platelet activity in health and disease . Thrombosis Research . 136 . 3 . 493–503 . September 2015 . 26077962 . 4553088 . 10.1016/j.thromres.2015.05.027 .
23. Matsuoka T, Narumiya S . Prostaglandin receptor signaling in disease . TheScientificWorldJournal . 7 . 1329–47 . September 2007 . 17767353 . 5901339 . 10.1100/tsw.2007.182 . free .
24. Minami T, Matsumura S, Mabuchi T, Kobayashi T, Sugimoto Y, Ushikubi F, Ichikawa A, Narumiya S, Ito S . Functional evidence for interaction between prostaglandin EP3 and kappa-opioid receptor pathways in tactile pain induced by human immunodeficiency virus type-1 (HIV-1) glycoprotein gp120 . Neuropharmacology . 45 . 1 . 96–105 . July 2003 . 12814662 . 10.1016/s0028-3908(03)00133-3. 40071244 .
25. Takasaki I, Nojima H, Shiraki K, Sugimoto Y, Ichikawa A, Ushikubi F, Narumiya S, Kuraishi Y . Involvement of cyclooxygenase-2 and EP3 prostaglandin receptor in acute herpetic but not postherpetic pain in mice . Neuropharmacology . 49 . 3 . 283–92 . September 2005 . 15925391 . 10.1016/j.neuropharm.2004.12.025 . 7011364 .
26. 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.
27. 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 .
28. Murata H, Kawano S, Tsuji S, Tsujii M, Hori M, Kamada T, Matsuzawa Y, Katsu K, Inoue K, Kobayashi K, Mitsufuji S, Bamba T, Kawasaki H, Kajiyama G, Umegaki E, Inoue M, Saito I . Combination of enprostil and cimetidine is more effective than cimetidine alone in treating gastric ulcer: prospective multicenter randomized controlled trial . Hepato-Gastroenterology . 52 . 66 . 1925–9 . 2005 . 16334808 .
29. Web site: Drug Information Portal - U.S. National Library of Medicine - Quick Access to Quality Drug Information.
30. Harris A, Ward CL, Rowe-Rendleman CL, Ouchi T, Wood A, Fujii A, Serle JB . Ocular Hypotensive Effect of ONO-9054, an EP3/FP Receptor Agonist: Results of a Randomized, Placebo-controlled, Dose Escalation Study . Journal of Glaucoma . 25 . 10 . e826–e833 . October 2016 . 27300645 . 10.1097/IJG.0000000000000449 . 27501398 . 1805/11908 . free .
31. Markovič T, Jakopin Ž, Dolenc MS, Mlinarič-Raščan I . Structural features of subtype-selective EP receptor modulators . Drug Discovery Today . 22 . 1 . 57–71 . 2017 . 27506873 . 10.1016/j.drudis.2016.08.003 . free .
32. Web site: Rs977214 RefSNP Report - DBSNP - NCBI.
33. Ueta M, Sotozono C, Nakano M, Taniguchi T, Yagi T, Tokuda Y, Fuwa M, Inatomi T, Yokoi N, Tashiro K, Kinoshita S . Association between prostaglandin E receptor 3 polymorphisms and Stevens-Johnson syndrome identified by means of a genome-wide association study . The Journal of Allergy and Clinical Immunology . 126 . 6 . 1218–25.e10 . 2010 . 20947153 . 10.1016/j.jaci.2010.08.007 . free .
34. 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 .