The roles of prostaglandin E receptor subtypes in the cytoprotective action of prostaglandin E<sub>2</sub> in rat stomach

Araki, Hideo; Ukawa, Hideki; Sugawa, Y.; Yagi, Koji; Suzuki, K.; Takeuchi, Koji

doi:10.1046/j.1365-2036.2000.014s1116.x

Cited by 79 publications

(88 citation statements)

References 25 publications

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“…On the other hand, results of this study suggest that antagonists for either the EP 2 or EP 4 receptors, or more importantly antagonists for both EP 2 and EP 4 receptors, will be effective for the treatment and prevention of AD through inhibiting the production of A␤. EP 1 and EP 3 receptors were reported to be involved in PGE 2 -mediated protection of gastrointestinal mucosa through stimulating the production of bicarbonate and gastric mucosal blood flow, respectively (74,75). Therefore, antagonists specific for both EP 2 and EP 4 would be safer for gastrointestinal mucosa than NSAIDs.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Prostaglandin E2 in Production of Amyloid-β Peptides Both in Vitro and in Vivo

Hoshino

Nakaya

Homan

et al. 2007

Journal of Biological Chemistry

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Amyloid-␤ peptides (A␤), generated by proteolysis of the ␤-amyloid precursor protein (APP) by ␤-and ␥-secretases, play an important role in the pathogenesis of Alzheimer disease (AD). Inflammation is also believed to be integral to the pathogenesis of AD. Here we show that prostaglandin E 2 (PGE 2 ), a strong inducer of inflammation, stimulates the production of A␤ in cultured human embryonic kidney (HEK) 293 or human neuroblastoma (SH-SY5Y) cells, both of which express a mutant type of APP. We have demonstrated using subtype-specific agonists that, of the four

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Section: Discussionmentioning

confidence: 99%

Involvement of Prostaglandin E2 in Production of Amyloid-β Peptides Both in Vitro and in Vivo

Hoshino

Nakaya

Homan

et al. 2007

Journal of Biological Chemistry

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“…It has been reported that the EP 1 receptor is mainly responsible for the gastro-protective effect of PGE 2 in vivo through the inhibition of gastric motility (37,42). In these reports, the authors examined an acute phase of gastric lesions (1 h after administration of high doses of gastric irritants), suggesting that they damaged gastric mucosal cells mainly through necrosis (not apoptosis).…”

Section: Fig 3 Effect Of Pge 2 On Ethanol-induced Release Of Cytochmentioning

confidence: 99%

Prostaglandin E2 Protects Gastric Mucosal Cells from Apoptosis via EP2 and EP4 Receptor Activation

Hoshino

Tsutsumi

Tomisato

et al. 2003

Journal of Biological Chemistry

135

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Prostaglandin E 2 (PGE 2 ) has a strong protective effect on the gastric mucosa in vivo; however, the molecular mechanism of a direct cytoprotective effect of PGE 2 on gastric mucosal cells has yet to be elucidated. Although we reported previously that PGE 2 inhibited gastric irritant-induced apoptotic DNA fragmentation in primary cultures of guinea pig gastric mucosal cells, we show here that PGE 2 inhibits the ethanol-dependent release of cytochrome c from mitochondria. Of the four main subtypes of PGE 2 receptors, we also demonstrated, using subtype-specific agonists, that EP 2 and EP 4 receptors are involved in the PGE 2 -mediated protection of gastric mucosal cells from ethanol-induced apoptosis. Activation of EP 2 and EP 4 receptors is coupled with an increase in cAMP, for which a cAMP analogue was found here to inhibit the ethanol-induced apoptosis. The increase in cAMP is known to activate both protein kinase A (PKA) and phosphatidylinositol 3-kinase pathways. An inhibitor of PKA but not of phosphatidylinositol 3-kinase blocked the PGE 2 -mediated protection of cells from ethanol-induced apoptosis, suggesting that a PKA pathway is mainly responsible for the PGE 2 -mediated inhibition of apoptosis. Based on these results, we considered that PGE 2 inhibited gastric irritant-induced apoptosis in gastric mucosal cells via induction of an increase in cAMP and activation of PKA, and that this effect was involved in the PGE 2 -mediated protection of the gastric mucosa from gastric irritants in vivo.

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“…Effect of capsaicin pretreatment on responses induced by PGE 2 , sulprostone, and ONO-AE1-329. It is believed that the acid-induced HCO 3 Ϫ secretion is mediated via an axonal reflex pathway in addition to endogenous PGs (10,19).…”

Section: Effects Of Verapamil and Ibmx On Duodenal Hcomentioning

confidence: 99%

“…The present study was designed using the selective EP4 agonist and antagonist to clarify the involvement of EP4 receptors in duodenal HCO 3 Ϫ secretion induced by PGE 2 or mucosal acidification in rats in addition to the role of EP3 receptors. We also investigated the cooperative effect of stimuli sent through EP3 and EP4 receptors on this secretion, including the intracellular signaling pathway of HCO 3 Ϫ secretion mediated by these receptors.…”

mentioning

confidence: 99%

Participation of prostaglandin E receptor EP4 subtype in duodenal bicarbonate secretion in rats

Aoi

Aihara

Nakashima

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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We examined, by using a specific PGE receptor subtype EP4 agonist and antagonist, the involvement of EP4 receptors in duodenal HCO 3 Ϫ secretion induced by PGE2 and mucosal acidification in rats. Mucosal acidification was achieved by exposing a duodenal loop to 10 mM HCl for 10 min, and various EP agonists were given intravenously 10 min before the acidification. Secretion of HCO 3 Ϫ was dose-dependently stimulated by AE1-329 (EP4 agonist), the maximal response being equivalent to that induced by sulprostone (EP1/EP3 agonist) or PGE2. The stimulatory action of AE1-329 and PGE2 but not sulprostone was attenuated by AE3-208, a specific EP4 antagonist. This antagonist also significantly mitigated the acidinduced HCO 3 Ϫ secretion. Coadministration of sulprostone and AE1-329 caused a greater secretory response than either agent alone. IBMX potentiated the stimulatory action of both sulprostone and AE1-329, whereas verapamil mitigated the effect of sulprostone but not AE1-329. Chemical ablation of capsaicin-sensitive afferent neurons did not affect the response to any of the EP agonists used. We conclude that EP4 receptors are involved in the duodenal HCO 3 Ϫ response induced by PGE2 or acidification in addition to EP3 receptors. The process by which HCO 3 Ϫ is secreted through these receptors differs regarding secondmessenger coupling. Stimulation through EP4 receptors is mediated by cAMP, whereas that through EP3 receptors is regulated by both cAMP and Ca 2ϩ ; yet there is cooperation between the actions mediated by these two receptors. The neuronal reflex pathway is not involved in stimulatory actions of these prostanoids. prostaglandin E2; EP receptor subtype; EP4 receptor SECRETION OF HCO 3 Ϫ FROM surface epithelial cells is one of the mucosal defensive mechanisms and plays an important role in protecting the duodenal mucosa against acid injury (6,4,18). Although the physiological regulation of this secretion involves several factors such as PGs, peptides, and neuronal factors (4,10,19,20), endogenous PGs are particularly important in the local control of the process. We (23) previously investigated the relationship between PGE receptor (EP) subtypes and HCO 3 Ϫ secretion, using specific EP1, EP2, and EP3 agonists, and found that the secretion was stimulated by EP agonists having a potent affinity for EP3 receptors. Using EP3 receptor knockout mice, we (21) also demonstrated the involvement of EP3 receptors in the acid-induced secretion of HCO 3 Ϫ in the duodenum. At that time, however, the possibility remained that the stimulatory action of PGE 2 is mediated by EP4 receptors, because specific EP4 agonists and antagonists were not available. It is now known that the increase in duodenal HCO 3 Ϫ secretion is mediated by the stimulation of adenylate cyclase (AC) activity and an elevation in intracellular cAMP levels (8,16,20) and that the activation of EP4 receptors results in an increase of intracellular cAMP via G s protein (3). Thus it is possible that EP4 receptors play a role in the regulation of duodenal HCO...

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The roles of prostaglandin E receptor subtypes in the cytoprotective action of prostaglandin E₂ in rat stomach

Cited by 79 publications

References 25 publications

Involvement of Prostaglandin E2 in Production of Amyloid-β Peptides Both in Vitro and in Vivo

Involvement of Prostaglandin E2 in Production of Amyloid-β Peptides Both in Vitro and in Vivo

Prostaglandin E2 Protects Gastric Mucosal Cells from Apoptosis via EP2 and EP4 Receptor Activation

Participation of prostaglandin E receptor EP4 subtype in duodenal bicarbonate secretion in rats

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The roles of prostaglandin E receptor subtypes in the cytoprotective action of prostaglandin E2 in rat stomach

Cited by 79 publications

References 25 publications

Involvement of Prostaglandin E2 in Production of Amyloid-β Peptides Both in Vitro and in Vivo

Involvement of Prostaglandin E2 in Production of Amyloid-β Peptides Both in Vitro and in Vivo

Prostaglandin E2 Protects Gastric Mucosal Cells from Apoptosis via EP2 and EP4 Receptor Activation

Participation of prostaglandin E receptor EP4 subtype in duodenal bicarbonate secretion in rats

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The roles of prostaglandin E receptor subtypes in the cytoprotective action of prostaglandin E₂ in rat stomach