EP1 Receptor (ep1 + receptor)

Distribution by Scientific Domains


Selected Abstracts


EP1 and EP4 Receptors Mediate Exocytosis Evoked by Prostaglandin E2 in Guinea-Pig Antral Mucous Cells

EXPERIMENTAL PHYSIOLOGY, Issue 4 2001
Atsuko Ohnishi
Effects of prostaglandin E2 (PGE2) on exocytosis of mucin were studied in mucous cells isolated from guinea-pig antrum using video-microscopy. Stimulation with PGE2 elicited a sustained increase in the frequency of exocytotic events in a dose-dependent manner, which was under regulation by both Ca2+ and cAMP. Stimulation with a selective prostanoid EP4 receptor agonist (ONO-AEI-329, 10 ,M), which activates cAMP signals, elicited a sustained increase in the frequency of exocytotic events (30% of that evoked by 1 ,M PGE2). Stimulation with an EP1 agonist (17-P-T-PGE2, 1 ,M), which activates Ca2+ signals, increased the frequency of exocytotic events to a lesser extent (5% of that evoked by 1 ,M PGE2), while addition of an EP1 antagonist (ONO-8713, 10 ,M) decreased the frequency of exocytotic events (approximately 40% of that evoked by 1 ,M PGE2). However, addition of the EP1 agonist potentiated the frequency of exocytotic events evoked by the EP4 agonist or forskolin (which elevates cAMP levels) and increased the sensitivity of the exocytotic events to forskolin. These results suggest that the Ca2+ signal activated via the EP1 receptor potentiates the cAMP-regulated exocytotic events activated via the EP4 receptor during PGE2 stimulation, by increasing the sensitivity of the exocytotic response to cAMP. In conclusion, exocytotic events in PGE2 -stimulated antral mucous cells were regulated by interactions between EP1 and EP4 receptors. [source]


PGE2 receptor EP1 renders dopaminergic neurons selectively vulnerable to low-level oxidative stress and direct PGE2 neurotoxicity

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 14 2007
Emilce Carrasco
Abstract Oxidative stress and increased cyclooxygenase-2 (COX-2) activity are both implicated in the loss of dopaminergic neurons from the substantia nigra (SN) in idiopathic Parkinson's disease (PD). Prostaglandin E2 (PGE2) is one of the key products of COX-2 activity and PGE2 production is increased in PD. However, little is known about its role in the selective death of dopaminergic neurons. Previously, we showed that oxidative stress evoked by low concentrations of 6-hydroxydopamine (6-OHDA) was selective for dopaminergic neurons in culture and fully dependent on COX-2 activity. We postulated that this loss was mediated by PGE2 acting through its receptors, EP1, EP2, EP3, and EP4. Using double-label immunohistochemistry for specific EP receptors and tyrosine hydroxylase (TH), we identified EP1 and EP2 receptors on dopaminergic neurons in rat SN. EP2 receptors were also found in non-dopaminergic neurons of this nucleus, as were EP3 receptors, whereas the EP4 receptor was absent. PGE2, 16-phenyl tetranor PGE2 (a stable synthetic analogue), and 17-phenyl trinor PGE2 (an EP1 receptor,selective agonist) were significantly toxic to dopaminergic cells at nanomolar concentrations; EP2- and EP3-selective agonists were not. We challenged dopaminergic neurons in embryonic rat mesencephalic primary neuronal cultures and tested whether these receptors mediate selective 6-OHDA toxicity. The nonselective EP1,3 receptor antagonist AH-6809 and two selective EP1 antagonists, SC-19220 and SC-51089, completely prevented the 40%,50% loss of dopaminergic neurons caused by exposure to 5 ,M 6-OHDA. Together, these results strongly implicate PGE2 activation of EP1 receptors as a mediator of selective toxicity in this model of dopaminergic cell loss. © 2007 Wiley-Liss, Inc. [source]


Effects of EP1 receptor on cerebral blood flow in the middle cerebral artery occlusion model of stroke in mice

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 11 2007
Sofiyan Saleem
Abstract The lipid mediator prostaglandin E2 (PGE2) exhibits diverse biologic activity in a variety of tissues. Four PGE2 receptor subtypes (EP1,4) are involved in various physiologic and pathophysiologic conditions, but differ in tissue distribution, ligand-binding affinity, and coupling to intracellular signaling pathways. To characterize the role of the EP1 receptor, physiologic parameters (mean arterial blood pressure, pH, blood gases PaO2 and PaCO2, and body temperature), cerebral blood flow (CBF), and neuronal cell death were studied in a middle cerebral artery occlusion model of ischemic stroke in wild-type (WT) and EP1 knockout (EP1,/,) mice. The right middle cerebral artery was occluded for 60 min, and absolute CBF was measured by [14C] iodoantipyrine autoradiography. The effect of EP1 receptor on oxidative stress in neuronal cultures was investigated. Although no differences were observed in the physiologic parameters, CBF was significantly (P < 0.01) higher in EP1,/, mice than in WT mice, suggesting a role for this receptor in physiologic and pathophysiologic control of vascular tone. Similarly, neuronal cultures derived from EP1,/, mice were more resistant (90.6 ± 5.8% viability) to tert -butyl hydroperoxide-induced oxidative stress than neurons from WT mice (39.6 ± 17.2% viability). The EP1 receptor antagonist SC-51089 and calcium channel blocker verapamil each attenuated the neuronal cell death induced by PGE2. Thus, the prostanoid EP1 receptor plays a significant role in regulating CBF and neuronal cell death. These findings suggest that pharmacologic modulation of the EP1 receptor might be a means to improve CBF and neuronal survival during ischemic stroke. © 2007 Wiley-Liss, Inc. [source]


PGE2 receptor EP1 renders dopaminergic neurons selectively vulnerable to low-level oxidative stress and direct PGE2 neurotoxicity

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 14 2007
Emilce Carrasco
Abstract Oxidative stress and increased cyclooxygenase-2 (COX-2) activity are both implicated in the loss of dopaminergic neurons from the substantia nigra (SN) in idiopathic Parkinson's disease (PD). Prostaglandin E2 (PGE2) is one of the key products of COX-2 activity and PGE2 production is increased in PD. However, little is known about its role in the selective death of dopaminergic neurons. Previously, we showed that oxidative stress evoked by low concentrations of 6-hydroxydopamine (6-OHDA) was selective for dopaminergic neurons in culture and fully dependent on COX-2 activity. We postulated that this loss was mediated by PGE2 acting through its receptors, EP1, EP2, EP3, and EP4. Using double-label immunohistochemistry for specific EP receptors and tyrosine hydroxylase (TH), we identified EP1 and EP2 receptors on dopaminergic neurons in rat SN. EP2 receptors were also found in non-dopaminergic neurons of this nucleus, as were EP3 receptors, whereas the EP4 receptor was absent. PGE2, 16-phenyl tetranor PGE2 (a stable synthetic analogue), and 17-phenyl trinor PGE2 (an EP1 receptor,selective agonist) were significantly toxic to dopaminergic cells at nanomolar concentrations; EP2- and EP3-selective agonists were not. We challenged dopaminergic neurons in embryonic rat mesencephalic primary neuronal cultures and tested whether these receptors mediate selective 6-OHDA toxicity. The nonselective EP1,3 receptor antagonist AH-6809 and two selective EP1 antagonists, SC-19220 and SC-51089, completely prevented the 40%,50% loss of dopaminergic neurons caused by exposure to 5 ,M 6-OHDA. Together, these results strongly implicate PGE2 activation of EP1 receptors as a mediator of selective toxicity in this model of dopaminergic cell loss. © 2007 Wiley-Liss, Inc. [source]


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

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2000
H. Araki
Summary Aim: To investigate the EP receptor subtype involved in the gastroprotective action of prostaglandin (PG) E2 using various EP receptor agonists in rats, and using knockout mice lacking EP1 or EP3 receptors. Methods: Male SD rats and C57BL/6 mice were used after an 18-h fast. Gastric lesions were induced by oral administration of HCl/ethanol (150 m m HCl in 60% ethanol). Rats were given various EP agonists i.v. 10 min before HCl/ethanol: PGE2, sulprostone (EP1/EP3 agonist), butaprost (EP2 agonist), 17-phenyl-,-trinorPGE2 (17-phenylPGE2: EP1 agonist), ONO-NT012 (EP3 agonist) and 11-deoxyPGE1 (EP3/EP4 agonist). In a separate study, the effect of PGE2 on HCl/ethanol lesions was examined in EP1 - and EP3 -receptor knockout mice. Results: Gastric lesions induced by HCl/ethanol were dose dependently prevented by PGE2; this effect was mimicked by sulprostone and 17-phenylPGE2 and was significantly antagonized by ONO-AE-829, an EP1 antagonist. Neither butaprost, ONO-NT012 nor 11-deoxyPGE1 exhibited any protective activity against HCl/ethanol-induced gastric lesions. PGE2 caused an inhibition of gastric motility as well as an increase of mucosal blood flow and mucus secretion, the effects being mimicked by prostanoids activating EP1 receptors, EP2/EP3/EP4 receptors and EP4 receptors, respectively. On the other hand, although HCl/ethanol caused similar damage in both wild-type mice and knockout mice lacking EP1 or EP3 receptors, the cytoprotective action of PGE2 observed in wild-type and EP3 -receptor knockout mice totally disappeared in mice lacking EP1 receptors. Conclusion: The gastric cytoprotective action of PGE2 is mediated by activation of EP1 receptors. This effect may be functionally associated with inhibition of gastric motility but not with increased mucosal blood flow or mucus secretion. [source]


Intermolecular cross-talk between the prostaglandin E2 receptor (EP)3 subtype and thromboxane A2 receptor signalling in human erythroleukaemic cells

BRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2009
Helen M Reid
Background and purpose:, In previous studies investigating cross-talk of signalling between prostaglandin (PG)E2 receptor (EP) and the TP, and TP, isoforms of the human thromboxane (TX)A2 receptor (TP), 17-phenyl trinor PGE2 -induced desensitization of TP receptor signalling through activation of the AH6809 and SC19220-sensitive EP1 subtype of the EP receptor family, in a cell-specific manner. Here, we sought to further investigate that cross-talk in human erythroleukaemic (HEL) 92.1.7 cells. Experimental approach:, Specificity of 17-phenyl trinor PGE2 signalling and its possible cross-talk with signalling by TP,/TP, receptors endogenously expressed in HEL cells was examined through assessment of agonist-induced inositol 1,4,5-trisphosphate (IP)3 generation and intracellular calcium ([Ca2+]i) mobilization. Key results:, While 17-Phenyl trinor PGE2 led to activation of phospholipase (PL)C, to yield increases in IP3 generation and [Ca2+]i, it did not desensitize but rather augmented that signalling in response to subsequent stimulation with the TXA2 mimetic U46619. Furthermore, the augmentation was reciprocal. Signalling by 17-phenyl trinor PGE2 was found to occur through AH6809- and SC19920-insensitive, Pertussis toxin-sensitive, Gi/G,, -dependent activation of PLC,. Further pharmacological investigation using selective EP receptor subtype agonists and antagonists confirmed that 17-phenyl trinor PGE2 -mediated signalling and reciprocal cross-talk with the TP receptors occurred through the EP3, rather than the EP1, EP2 or EP4 receptor subtype in HEL cells. Conclusions and Implications:, The EP1 and EP3 subtypes of the EP receptor family mediated intermolecular cross-talk to differentially regulate TP receptor-mediated signalling whereby activation of EP1 receptors impaired or desensitized, while that of EP3 receptors augmented signalling through TP,/TP, receptors, in a cell type-specific manner. [source]