Prostaglandin EP₃ receptor

Prostaglandin EP₃ receptor (53kDa), also known as EP₃, is a prostaglandin receptor for prostaglandin E2 (PGE₂) encoded by the human gene PTGER3;^[5] 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).^[6] EP has been implicated in various physiological and pathological responses.^[7]

PTGER3
Identifiers
Aliases	PTGER3, EP3, EP3-I, EP3-II, EP3-III, EP3-IV, EP3e, PGE2-R, EP3-VI, Prostaglandin E receptor 3, lnc003875
External IDs	OMIM: 176806 MGI: 97795 HomoloGene: 105703 GeneCards: PTGER3
Gene location (Human) Chr. Chromosome 1 (human)^[1] Band 1p31.1 Start 70,852,353 bp^[1] End 71,047,816 bp^[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)^[2] Band 3 H4|3 81.32 cM Start 157,272,529 bp^[2] End 157,351,525 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in kidney tubule kidney renal medulla myometrium vena cava adipose tissue abdominal fat subcutaneous adipose tissue smooth muscle tissue lower lobe of lung Top expressed in barrel cortex brown adipose tissue white adipose tissue subcutaneous adipose tissue seminal vesicula intercostal muscle kidney uterus stria vascularis mammary gland More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled receptor activity prostaglandin receptor activity signal transducer activity prostaglandin E receptor activity protein binding Cellular component nuclear envelope membrane plasma membrane integral component of plasma membrane integral component of membrane Biological process G protein-coupled receptor signaling pathway positive regulation of fever generation cell death signal transduction negative regulation of gastric acid secretion phospholipase C-activating G protein-coupled receptor signaling pathway intestine smooth muscle contraction inflammatory response adenylate cyclase-activating G protein-coupled receptor signaling pathway positive regulation of cytosolic calcium ion concentration Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5733 19218 Ensembl ENSG00000050628 ENSMUSG00000040016 UniProt P43115 P30557 RefSeq (mRNA) NM_000957 NM_001126044 NM_198712 NM_198713 NM_198714 NM_198715 NM_198716 NM_198717 NM_198718 NM_198719 NM_198720 NM_011196 NM_001359745 RefSeq (protein) NP_001119516 NP_942007 NP_942008 NP_942009 NP_942010 NP_942011 NP_942012 n/a Location (UCSC) Chr 1: 70.85 – 71.05 Mb Chr 3: 157.27 – 157.35 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[5][8][9] 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.^[10] 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).^[11]

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.^[11] 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.^[12]

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.^[12]

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.^[13] (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.^[13]

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.^[13] 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 HCO⁻
₃ (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.^[13] These two prostanoid receptors also stimulate intestinal mucous secretion, a function which may also act to reduce acidic damage to the duodenum.^[14]

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.^[15][16]

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.^[7][17] 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.^[18] 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^[19]), has been associated with ACE inhibitor-induce cough in humans.^[20][21] The use of EP₃ receptor antagonists may warrant study for the treatment of chronic cough in humans.^[22]

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.^[23]

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.^[24][25]

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.^[26][27]

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.^[28][29][30] 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.^[31]

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^[13] 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.^[32]

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,^[13] was found in a prospective multicenter randomized controlled trial conducted in Japan to significantly improve the effects of cimetidine in treating gastric ulcer.^[33] It is considered to be an efficient and safe treatment for gastric and duodenal ulcers.^[34]
• 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.^[35]
• DG-041, a highly selective EP₃ antagonist, has been proposed to warrant further study as anti-thrombosis agent.^[26][27]
• 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.^[12]

Genomic studies

The single nucleotide polymorphism (SNP) in the PTGER3, rs977214 A/G variant^[36] 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.^[37][38]

See also

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

References

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14. Takeuchi K, Kato S, Amagase K (2010). "Prostaglandin EP receptors involved in modulating gastrointestinal mucosal integrity". Journal of Pharmacological Sciences. 114 (3): 248–61. doi:10.1254/jphs.10r06cr. PMID 21041985.
15. Furuyashiki T, Narumiya S (February 2009). "Roles of prostaglandin E receptors in stress responses". Current Opinion in Pharmacology. 9 (1): 31–8. doi:10.1016/j.coph.2008.12.010. PMID 19157987.
16. Narumiya S, Sugimoto Y, Ushikubi F (1999). "Prostanoid receptors: structures, properties, and functions". Physiological Reviews. 79 (4): 1193–226. doi:10.1152/physrev.1999.79.4.1193. PMID 10508233. S2CID 7766467.
17. Claar D, Hartert TV, Peebles RS (February 2015). "The role of prostaglandins in allergic lung inflammation and asthma". Expert Review of Respiratory Medicine. 9 (1): 55–72. doi:10.1586/17476348.2015.992783. PMC 4380345. PMID 25541289.
18. Ueta M (November 2012). "Epistatic interactions associated with Stevens-Johnson syndrome". Cornea. 31 (Suppl 1): S57-62. doi:10.1097/ICO.0b013e31826a7f41. PMID 23038037. S2CID 2468341.
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21. Grilo A, Sáez-Rosas MP, Santos-Morano J, Sánchez E, Moreno-Rey C, Real LM, Ramírez-Lorca R, Sáez ME (January 2011). "Identification of genetic factors associated with susceptibility to angiotensin-converting enzyme inhibitors-induced cough". Pharmacogenetics and Genomics. 21 (1): 10–7. doi:10.1097/FPC.0b013e328341041c. PMID 21052031. S2CID 22282464.
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23. Yang T, Du Y (October 2012). "Distinct roles of central and peripheral prostaglandin E2 and EP subtypes in blood pressure regulation". American Journal of Hypertension. 25 (10): 1042–9. doi:10.1038/ajh.2012.67. PMC 3578476. PMID 22695507.
24. Hohjoh H, Inazumi T, Tsuchiya S, Sugimoto Y (December 2014). "Prostanoid receptors and acute inflammation in skin". Biochimie. 107 Pt A: 78–81. doi:10.1016/j.biochi.2014.08.010. PMID 25179301.
25. Kawahara K, Hohjoh H, Inazumi T, Tsuchiya S, Sugimoto Y (April 2015). "Prostaglandin E2-induced inflammation: Relevance of prostaglandin E receptors". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1851 (4): 414–21. doi:10.1016/j.bbalip.2014.07.008. PMID 25038274.
26. Mawhin MA, Tilly P, Fabre JE (September 2015). "The receptor EP3 to PGE2: A rational target to prevent atherothrombosis without inducing bleeding". Prostaglandins & Other Lipid Mediators. 121 (Pt A): 4–16. doi:10.1016/j.prostaglandins.2015.10.001. PMID 26463849.
27. Friedman EA, Ogletree ML, Haddad EV, Boutaud O (September 2015). "Understanding the role of prostaglandin E2 in regulating human platelet activity in health and disease". Thrombosis Research. 136 (3): 493–503. doi:10.1016/j.thromres.2015.05.027. PMC 4553088. PMID 26077962.
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29. Minami T, Matsumura S, Mabuchi T, Kobayashi T, Sugimoto Y, Ushikubi F, Ichikawa A, Narumiya S, Ito S (July 2003). "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. doi:10.1016/s0028-3908(03)00133-3. PMID 12814662. S2CID 40071244.
30. Takasaki I, Nojima H, Shiraki K, Sugimoto Y, Ichikawa A, Ushikubi F, Narumiya S, Kuraishi Y (September 2005). "Involvement of cyclooxygenase-2 and EP3 prostaglandin receptor in acute herpetic but not postherpetic pain in mice". Neuropharmacology. 49 (3): 283–92. doi:10.1016/j.neuropharm.2004.12.025. PMID 15925391. S2CID 7011364.
31. O'Callaghan G, Houston A (November 2015). "Prostaglandin E2 and the EP receptors in malignancy: possible therapeutic targets?". British Journal of Pharmacology. 172 (22): 5239–50. doi:10.1111/bph.13331. PMC 5341220. PMID 26377664.
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33. 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 (2005). "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. PMID 16334808.
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Further reading

• Kotani M, Tanaka I, Ogawa Y, Usui T, Mori K, Ichikawa A, Narumiya S, Yoshimi T, Nakao K (November 1995). "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. PMID 7476918.
• Han X, Lan X, Li Q, Gao Y, Zhu W, Cheng T, Maruyama T, Wang J (June 2016). "Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury". Journal of Cerebral Blood Flow and Metabolism. 36 (6): 1059–74. doi:10.1177/0271678X15606462. PMC 4908617. PMID 26661165.
• 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. doi:10.1016/0888-7543(95)80022-E. PMID 7759114.
• Schmid A, Thierauch KH, Schleuning WD, Dinter H (February 1995). "Splice variants of the human EP3 receptor for prostaglandin E2". European Journal of Biochemistry. 228 (1): 23–30. doi:10.1111/j.1432-1033.1995.tb20223.x. PMID 7883006.
• An S, Yang J, So SW, Zeng L, Goetzl EJ (December 1994). "Isoforms of the EP3 subtype of human prostaglandin E2 receptor transduce both intracellular calcium and cAMP signals". Biochemistry. 33 (48): 14496–502. doi:10.1021/bi00252a016. PMID 7981210.
• Regan JW, Bailey TJ, Donello JE, Pierce KL, Pepperl DJ, Zhang D, Kedzie KM, Fairbairn CE, Bogardus AM, Woodward DF (June 1994). "Molecular cloning and expression of human EP3 receptors: evidence of three variants with differing carboxyl termini". British Journal of Pharmacology. 112 (2): 377–85. doi:10.1111/j.1476-5381.1994.tb13082.x. PMC 1910333. PMID 8075855.
• Yang J, Xia M, Goetzl EJ, An S (February 1994). "Cloning and expression of the EP3-subtype of human receptors for prostaglandin E2". Biochemical and Biophysical Research Communications. 198 (3): 999–1006. doi:10.1006/bbrc.1994.1142. PMID 8117308.
• Kunapuli SP, Fen Mao G, Bastepe M, Liu-Chen LY, Li S, Cheung PP, DeRiel JK, Ashby B (March 1994). "Cloning and expression of a prostaglandin E receptor EP3 subtype from human erythroleukaemia cells". The Biochemical Journal. 298 (2): 263–7. doi:10.1042/bj2980263. PMC 1137934. PMID 8135729.
• Adam M, Boie Y, Rushmore TH, Müller G, Bastien L, McKee KT, Metters KM, Abramovitz M (January 1994). "Cloning and expression of three isoforms of the human EP3 prostanoid receptor". FEBS Letters. 338 (2): 170–4. doi:10.1016/0014-5793(94)80358-7. PMID 8307176. S2CID 36055482.
• Chang C, Negishi M, Nishigaki N, Ichikawa A (March 1997). "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. doi:10.1042/bj3220597. PMC 1218231. PMID 9065782.
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External links

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

This article incorporates text from the United States National Library of Medicine, which is in the public domain.