Cellular distribution of prostanoid EP receptors mRNA in the rat gastrointestinal tract

Northey, Angela; Denis, Danielle; Cirino, Maria; Metters, Kathleen M.; Nantel, F.

doi:10.1016/s0090-6980(00)00058-7

Cited by 40 publications

(23 citation statements)

References 27 publications

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“…Also of interest is our current observation that EP4 agonist treatment preserves not only epithelial but also goblet cells, which are largely depleted in vehicle-treated mice. It has been reported that goblet cells from both human and experimental animals robustly express EP4, and its expression was further enhanced in colon mucosa during IBD (Northey et al, 2000;Takafuji et al, 2000;Nitta et al, 2002). Also known is that mucus secretion from goblet cells increases upon activation of EP4 but that it is inhibited by NSAIDs (Ohnishi et al, 2001;Shimamoto et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…EP1 and EP3 primarily contribute to inflammatory responses, whereas EP4 promotes both cell survival and growth by activating antiapoptotic and proliferative cellular signaling pathways (Fujino et al, 2003;Hase et al, 2003;Hoshino et al, 2003;Goulet et al, 2004;Joseph et al, 2005). Moreover, EP4 is constitutively expressed in the colonic epithelium and further induced during IBD, along with PGE 2 (WiercinskaDrapalo et al, 1999;Northey et al, 2000;Takafuji et al, 2000;Nitta et al, 2002). Recently, EP4 antagonists have been reported to impair epithelial proliferation in the colon (Kabashima et al, 2002).…”

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confidence: 99%

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The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

Jiang¹,

Nieves²,

Im³

et al. 2006

J Pharmacol Exp Ther

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Inflammatory bowel disease (IBD) is often triggered and/or exacerbated by nonsteroidal anti-inflammatory drugs (NSAIDs). Among various prostanoids affected by NSAIDs, prostaglandin E 2 (PGE 2 ), in particular, seems to play critical roles in IBD via the EP4 receptor, one of the four PGE 2 receptor subtypes (EP1-4). An EP4 agonist, [[3-[[(1R,2S,3R)(ONO-AE1-329), for example, when topically applied, has been reported to ameliorate typical colitis symptoms by suppressing the production of cytotoxic cytokines in the dextran sodium sulfate (DSS)-induced colitis model. EP4 agonists are also known, however, for their ability to protect epithelial cells from apoptosis in vitro, which may contribute to the protection of mucosal barrier functions. To investigate this potential application, we have tested another EP4-selective agonist in the DSS-indomethacin mouse colitis model. 7-[2-(3-Hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid methyl ester, C 23 H 33 NO 4 (AGN205203), an analog from the 8-azapiperidinone series of EP4 agonists, is metabolically and chemically more stable than the ONO agonist, because of its lack of oxidizable sulfur atoms in the ␣-chain and of 11-OH group, a potential source of ␤-elimination reaction. Treatment of mice subcutaneously with AGN205203 at 3 mg/kg/day minimized colitis symptoms, such as weight loss, diarrhea, and colonic bleeding. Further histological examination of colons revealed healthy surface columnar epithelial cells free of erosion and ulceration compared with those without the drug treatment. At cellular level, the drug treatment decreased colon epithelial apoptosis, prevented goblet cell depletion, and promoted epithelial regeneration. AGN205203 may be unique among known EP4 agonists for its metabolic and chemical stability, and it is amenable to systemic applications for the prevention and recovery of IBD.Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), affect approximately 1.4 million United States patients with 15,000 to 30,000 new cases annually at a mean age between 30s and early 40s. IBD patients suffer from body weight loss, diarrhea, fecal blood, and pain. Such symptoms could last for 15 to 25 years, frequently alternating between exacerbation and remission, thus severely affecting the quality of patient life and retarding the growth of young patients (Loftus, 2004;Isaacs et al., 2005). General consensus in the field is that IBD may arise from compromised colonic mucosal barrier functions that allow colonic antigens access to submucosal monocytes, which, upon activation, initiate innate immune responses and trigger cytotoxic cytokine production. Prevention and recovery of IBD thus largely depend on the integrity and maintenance of colonic mucosal barrier functions, which are compromised by inflammations along the entire bowel wall in CD and at the mucosal surface in UC.Current therapies primarily aim at the symptomatic remission by anti-inflammatory agents such as aminosalicylates and/or immunosuppres...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

Jiang¹,

Nieves²,

Im³

et al. 2006

J Pharmacol Exp Ther

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“…The EP 3 receptor reduces adenylate cyclase activity by stimulating G α -i protein while activation of EP 2 and EP 4 receptor subtypes activate G α -s protein and thereby increase the intracellular level of cyclic-adenosime-monophosphate (cAMP). Lately, EP 4 stimulation may also be related to induction of the PI3-K signalling pathway [9][10][11][12][13] and to the G α -i pathway [14].Although all four receptor subtypes are expressed at the mRNA level in rodent colon [15][16][17], it remains to be shown which receptor subtypes inserted in the plasma membrane are actors in the various functions of the colon. Thus, for instance, Belley and Chadee could demonstrate that only the EP 4 receptor subtype is involved in mucin secretion in colon from man and rat [18].…”

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confidence: 99%

EP₄ and EP₂ Receptor Subtypes Involved in Colonic Secretion in Rat

Mosa

Hansen

Tilotta

et al. 2008

Basic Clin Pharma Tox

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Abstract:The study was designed to determine the prostaglandin EP receptor subtypes functionally involved in electrogenic ion secretion in rat colon. With 30 rats, measurements of short circuit current (SCC) and slope conductance were obtained by Ussing chamber technique. Prostaglandin E2 (PGE 2 ) and other EP receptor selective agonists were employed on stripped rat colon pre-treated with indomethacin and theophylline. Receptor-specific agonists were butaprost (EP 2 ), sulprostone (EP 1 and EP 3 ) and PGE 1 alcohol (OH-PGE 1 ) (EP 4 ). GW627368X was used as a specific EP 4 receptor antagonist. Forskolin-induced SCC was used as a control of tissue viability. The mean basal SCC was 24.5 ± 0.9 μ A/cm 2 (range 9.8-45.1), and mean basal slope conductance was 23.7 ± 6.1 mS/cm 2 (range 9.7-39.8). The basal SCC decreased after pre-treatment with indomethacin and increased after pre-treatment with theophylline. PGE 2 , butaprost and OH-PGE 1 stimulated maximal increase in SCC (55.8 ± 4.1, 43.9 ± 3.8 and 93.9 ± 2.7 μ A/cm 2 , respectively), while sulprostone had no apparent effects. GW627368X eliminated OH-PGE 1 -induced SCC and partially PGE 2 -induced SCC, leaving butaprostinduced SCC almost unperturbed. Bumetanide, 20 μ M, inhibited between 40% and 80% of the agonist-induced changes in SCC. In conclusion, compilation of the results on induced SCC by subtype specific receptor agonists for EP receptors and the pattern of induced SCCs inhibited by GW627368X indicate the EP 4 receptor subtype as the major mediator of PGE 2 -induced electrogenic ion secretion with a lesser induction through the EP 2 receptor subtype.Prostaglandins are locally acting paracrine-and autocrinesignalling molecules derived from the metabolism of arachidonic acid by cyclooxygenase enzymes COX-1 and COX-2 (prostaglandin endoperoxide H synthases). Prostaglandins play a significant role in the physiology and pathophysiology of the digestive system affecting water and electrolyte transport, mucus secretion, blood flow and motility [1,2]. Prostaglandin E (PGE) is synthesized in large amounts and widely distributed throughout the gastrointestinal tract [3]. It is also produced in the immune cells in the lamina propria , the submucosa, and to a lesser extent by the intestinal epithelial cells [4]. Prostaglandins, including PGE 2 , are released in colon by a host of primary messengers including signals as increased release of serotonin [5].Prostaglandin E 2 , PGE 2 , may interact with at least four cell surface prostaglandin type E receptors EP 1 , EP 2 , EP 3 and EP 4 which trigger a variety of intracellular responses depending on which G protein they are coupled to [6,7]. The PGE 2 receptors are transmembrane G protein-coupled receptors and it has been established that EP 1 signals are transmitted by increased intracellular Ca 2+ concentrations with activation of phosphorylated protein kinase C [8]. The EP 3 receptor reduces adenylate cyclase activity by stimulating G α -i protein while activation of EP 2 and EP 4 receptor subtypes activate G α -s prot...

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“…By contrast, strong signals for EP1 transcripts were detected in cells of the muscularis mucosae layer, especially in the body of the stomach. Furthermore, it was reported that EP1 and EP3 receptor mRNA were detected in the smooth muscle and enteric ganglia of rat stomach (31). Localization of signals for EP1 transcripts suggested that the site of actions of PGE 2 and/or EP1 agonist may be the muscularis mucosa layer and/or enteric ganglia.…”

Section: Discussionmentioning

confidence: 98%

Roles of prostaglandin E₂-EP1 receptor signaling in regulation of gastric motor activity and emptying

Mizuguchi

Ohno²,

Hattori

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Majima M. Roles of prostaglandin E 2-EP1 receptor signaling in regulation of gastric motor activity and emptying. Am J Physiol Gastrointest Liver Physiol 299: G1078 -G1086, 2010. First published August 26, 2010 doi:10.1152/ajpgi.00524.2009.-It is widely accepted that the inhibition of gastric motor activity as well as the maintenance of gastric mucosal blood flow and mucous secretion are important for the homeostasis of the gastric mucosa. The present study was performed to ascertain whether or not endogenous PGs, which can protect the stomach from noxious stimuli, affect gastric motor activity and emptying. The myoelectrical activity of rat gastric smooth muscle was increased at intragastric pressures of over 2 cmH 2O. Replacement of intragastric physiological saline with 1 M NaCl solution significantly increased PGI 2 and PGE2 in stomach and suppressed the myoelectrical activity under a pressure of 2 cmH 2O by 70%. Indomethacin inhibited the suppression of myoelectrical activity by 1 M NaCl. The myoelectrical activity under a pressure of 2 cmH 2O was suppressed by continuous infusion of a selective EP1 agonist (ONO-DI-004, 3-100 nmol·kg Ϫ1 ·min Ϫ1 ) into the gastric artery in a dose-dependent manner, but not by that of the PGI receptor agonist beraprost sodium (100 nmol·kg Ϫ1 ·min Ϫ1 ). Suppression of myoelectrical activity with 1 M NaCl was inhibited by continuous infusion of a selective EP1 antagonist (ONO-8711, 100 nmol·kg Ϫ1 ·min Ϫ1 ) into the gastric artery. Furthermore, gastric emptying was tested in EP1 knockout mice and their wild-type counterparts. Gastric emptying was strongly suppressed with intragastric 1 M NaCl in wild-type mice, but this 1 M NaCl-induced suppression was not seen in EP1 knockout mice. These results suggest that PGE 2-EP1 signaling has crucial roles in suppression of myoelectrical activity of gastric smooth muscles and inhibition of gastric emptying and that EP1 is an obvious target for drugs that control gastric emptying. myoelectrical activity; gastric emptying; hyperosmolarity

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Cellular distribution of prostanoid EP receptors mRNA in the rat gastrointestinal tract

Cited by 40 publications

References 27 publications

The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

EP₄ and EP₂ Receptor Subtypes Involved in Colonic Secretion in Rat

Roles of prostaglandin E₂-EP1 receptor signaling in regulation of gastric motor activity and emptying

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Cellular distribution of prostanoid EP receptors mRNA in the rat gastrointestinal tract

Cited by 40 publications

References 27 publications

The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

EP4 and EP2 Receptor Subtypes Involved in Colonic Secretion in Rat

Roles of prostaglandin E2-EP1 receptor signaling in regulation of gastric motor activity and emptying

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EP₄ and EP₂ Receptor Subtypes Involved in Colonic Secretion in Rat

Roles of prostaglandin E₂-EP1 receptor signaling in regulation of gastric motor activity and emptying