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1
Cipollone, Francesco, and Donato Santovito. "EP Receptors and Coxibs." Circulation Research 113, no. 2 (2013): 91–93. http://dx.doi.org/10.1161/circresaha.113.301616.
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Sawyer, ST, SB Krantz, and K. Sawada. "Receptors for erythropoietin in mouse and human erythroid cells and placenta." Blood 74, no. 1 (1989): 103–9. http://dx.doi.org/10.1182/blood.v74.1.103.103.
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Abstract High and lower affinity receptors for erythropoietin (EP) were initially identified on a very pure population of EP-responsive erythroblasts obtained from the spleens of mice infected with anemia strain of Friend virus (FVA). The structure of the receptor for EP in these cells was determined to be proteins of 100 and 85 Kd by cross- linking 125I-EP. In this investigation, studies on the receptors for EP were extended to other mouse erythroid cells and human erythroid cells as well as to the placentas of mice and rats. Only lower affinity receptors for EP were detected on erythroblasts purified from the spleens of mice infected with the polycythemia strain of Friend virus and a murine erythroleukemia cell line, both of which are not responsive to EP in culture. Internalization of 125I-EP was observed in both groups of cells. The structure of the receptor determined by cross- linking 125I-EP was two equally labeled proteins of 100 Kd and 85 Kd molecular mass in all these mouse erythroid cells. The structure of the receptor was found to be very similar in human erythroid colony forming cells cultured from normal blood. These cells respond to EP with erythroid maturation and were previously shown to have high and lower affinity receptors. Placentas from mice and rats were found to have only lower affinity receptors for EP, and when placental membranes were cross-linked to 125I-EP, the same 100 Kd and 85 Kd bands were found as seen in mouse and human erythroid cells. The structure of the receptor was similar in cells that have high affinity receptors (FVA-infected and human erythroid colony-forming cells) and nonresponsive erythroid cells and placenta that have lower affinity receptors, but only the cells with the high affinity receptors respond to the addition of EP with erythroid maturation.
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Sawyer, ST, SB Krantz, and K. Sawada. "Receptors for erythropoietin in mouse and human erythroid cells and placenta." Blood 74, no. 1 (1989): 103–9. http://dx.doi.org/10.1182/blood.v74.1.103.bloodjournal741103.
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High and lower affinity receptors for erythropoietin (EP) were initially identified on a very pure population of EP-responsive erythroblasts obtained from the spleens of mice infected with anemia strain of Friend virus (FVA). The structure of the receptor for EP in these cells was determined to be proteins of 100 and 85 Kd by cross- linking 125I-EP. In this investigation, studies on the receptors for EP were extended to other mouse erythroid cells and human erythroid cells as well as to the placentas of mice and rats. Only lower affinity receptors for EP were detected on erythroblasts purified from the spleens of mice infected with the polycythemia strain of Friend virus and a murine erythroleukemia cell line, both of which are not responsive to EP in culture. Internalization of 125I-EP was observed in both groups of cells. The structure of the receptor determined by cross- linking 125I-EP was two equally labeled proteins of 100 Kd and 85 Kd molecular mass in all these mouse erythroid cells. The structure of the receptor was found to be very similar in human erythroid colony forming cells cultured from normal blood. These cells respond to EP with erythroid maturation and were previously shown to have high and lower affinity receptors. Placentas from mice and rats were found to have only lower affinity receptors for EP, and when placental membranes were cross-linked to 125I-EP, the same 100 Kd and 85 Kd bands were found as seen in mouse and human erythroid cells. The structure of the receptor was similar in cells that have high affinity receptors (FVA-infected and human erythroid colony-forming cells) and nonresponsive erythroid cells and placenta that have lower affinity receptors, but only the cells with the high affinity receptors respond to the addition of EP with erythroid maturation.
4
Broudy, VC, N. Lin, M. Brice, B. Nakamoto, and T. Papayannopoulou. "Erythropoietin receptor characteristics on primary human erythroid cells." Blood 77, no. 12 (1991): 2583–90. http://dx.doi.org/10.1182/blood.v77.12.2583.2583.
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Abstract Erythropoietin (EP) exerts its effects on erythropoiesis by binding to a cell surface receptor. We examined EP receptor expression during normal human erythroid differentiation and maturation from the burst- forming unit-erythroid (BFU-E) to the reticulocyte level. In contrast to previous studies, we assessed EP receptor number and affinity in erythroid precursors immunologically purified from fresh bone marrow aspirates or fetal liver samples and in reticulocytes purified from peripheral blood. EP receptors were quantitated by equilibrium binding experiments with 125I EP. We found that purified primary erythroblasts from both adult and fetal sources exhibited a single high-affinity (kd 100 pmol/L) binding site for EP under our experimental conditions, and 135 or 250 receptors per cell, respectively. Reticulocytes were devoid of EP receptors. We compared these data to in vitro-derived BFU-E progeny at both early and late stages of maturation. Cultured BFU-E progeny also displayed a single class of receptors of slightly lower affinity (210 to 220 pmol/L). Preparations enriched in colony-forming units-erythroid (CFU-E) and proerythroblasts (day 9 BFU-E progeny) displayed approximately 1,100 receptors per cell, whereas populations containing mature erythroblasts (day 14 BFU-E progeny) exhibited approximately 300 receptors per cell. Furthermore, information from binding experiments was complemented by autoradiography in both enriched BFU-E preparations, cultured BFU-E progeny (days 9 and 14), and marrow mononuclear cells. These studies are consistent with a peak in EP receptor expression at the CFU-E/proerythroblast stage and a decrease with further maturation to undetectable levels at the reticulocyte stage. These data examining EP receptor characteristics on freshly isolated erythroid precursor cells complement previous data on EP receptor biology using culture-derived erythroblasts.
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Broudy, VC, N. Lin, M. Brice, B. Nakamoto, and T. Papayannopoulou. "Erythropoietin receptor characteristics on primary human erythroid cells." Blood 77, no. 12 (1991): 2583–90. http://dx.doi.org/10.1182/blood.v77.12.2583.bloodjournal77122583.
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Erythropoietin (EP) exerts its effects on erythropoiesis by binding to a cell surface receptor. We examined EP receptor expression during normal human erythroid differentiation and maturation from the burst- forming unit-erythroid (BFU-E) to the reticulocyte level. In contrast to previous studies, we assessed EP receptor number and affinity in erythroid precursors immunologically purified from fresh bone marrow aspirates or fetal liver samples and in reticulocytes purified from peripheral blood. EP receptors were quantitated by equilibrium binding experiments with 125I EP. We found that purified primary erythroblasts from both adult and fetal sources exhibited a single high-affinity (kd 100 pmol/L) binding site for EP under our experimental conditions, and 135 or 250 receptors per cell, respectively. Reticulocytes were devoid of EP receptors. We compared these data to in vitro-derived BFU-E progeny at both early and late stages of maturation. Cultured BFU-E progeny also displayed a single class of receptors of slightly lower affinity (210 to 220 pmol/L). Preparations enriched in colony-forming units-erythroid (CFU-E) and proerythroblasts (day 9 BFU-E progeny) displayed approximately 1,100 receptors per cell, whereas populations containing mature erythroblasts (day 14 BFU-E progeny) exhibited approximately 300 receptors per cell. Furthermore, information from binding experiments was complemented by autoradiography in both enriched BFU-E preparations, cultured BFU-E progeny (days 9 and 14), and marrow mononuclear cells. These studies are consistent with a peak in EP receptor expression at the CFU-E/proerythroblast stage and a decrease with further maturation to undetectable levels at the reticulocyte stage. These data examining EP receptor characteristics on freshly isolated erythroid precursor cells complement previous data on EP receptor biology using culture-derived erythroblasts.
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Fang, K. M., W. H. Shu, H. C. Chang, J. J. Wang, and O. T. Mak. "Study of prostaglandin receptors in mitochondria on apoptosis of human lung carcinoma cell line A549." Biochemical Society Transactions 32, no. 6 (2004): 1078–80. http://dx.doi.org/10.1042/bst0321078.
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PGs (prostaglandins) are synthesized through the cyclo-oxygenase (COX-1 and -2) pathway in a variety of cells in response to various physiological stimuli. All cells require at least one pathway for apoptosis, and mitochondrial play a central role in regulation of apoptosis. In a previous study, incubation of A549 cells with NS-398 (a COX-2-specific inhibitor) induced apoptosis and inhibited cell proliferation, and the concentrations of different PGs between various cellular compartments were found to be changed. To determine whether PG receptors are involved in this regulation, Western-blot analyses were performed specific for PGE2 (EP receptors) and PGF2α (FP receptor) receptors, which were expressed in A549 cells. Western-blot analysis revealed that mitochondria that were isolated from A549 cells expressed EP receptors (EP2, EP3 and EP4), whereas FP receptors were undetectable. EP receptors (EP1, EP3 and EP4) and FP receptors were detected from A549 cell membrane. These results suggest that the change of PG production in A549-cells-induced cancer cell apoptosis might be related to the different expressions of EP and FP receptors in cell and mitochondrial membrane.
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Wognum, AW, PM Lansdorp, RK Humphries, and G. Krystal. "Detection and isolation of the erythropoietin receptor using biotinylated erythropoietin." Blood 76, no. 4 (1990): 697–705. http://dx.doi.org/10.1182/blood.v76.4.697.697.
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Abstract Procedures have been developed to label human erythropoietin (Ep) with biotin to detect and isolate the Ep-receptor. The labeling method used the abundant carbohydrate groups on Ep and resulted in biologically active biotin-Ep (b-Ep) containing 8 to 10 biotins per Ep molecule. Specific binding of b-Ep to cells from spleens of mice made anemic by phenylhydrazine injections was demonstrated using 125I-labeled streptavidin. B-Ep, together with fluorescently tagged streptavidin, was found to specifically detect Ep-receptor-bearing cells by flow cytometry. This was demonstrated in several ways. First, approximately 90% of nucleated spleen cells from phenylhydrazine-treated mice were clearly fluorescent after staining with b-Ep and streptavidin- phycoerythrin, whereas only background fluorescence was detected using spleen cells from untreated mice. In addition, Ep-receptors were detected on 5% to 10% of normal mouse bone marrow cells, and these cells could be identified as erythroid in nature by separating the cells into subpopulations based on light-scatter properties. Third, Ep- receptor expression was found to correlate positively with expression of transferrin receptors, confirming the erythroid nature of these cells. B-Ep was also used to isolate Ep-receptors from monkey COS cells transfected with the murine Ep-receptor cDNA. In these experiments a cell-surface-bound protein of approximately 65 Kd and an intracellular protein of approximately 60 Kd were isolated from these cells. The procedures described in this report for detecting Ep-receptor expressing cells and for isolating the Ep-receptor should be valuable for purifying erythroid cells from heterogeneous cell populations, for elucidating the structure of the Ep-receptor, and for studying the biological activities of Ep at the cellular and molecular level.
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Wognum, AW, PM Lansdorp, RK Humphries, and G. Krystal. "Detection and isolation of the erythropoietin receptor using biotinylated erythropoietin." Blood 76, no. 4 (1990): 697–705. http://dx.doi.org/10.1182/blood.v76.4.697.bloodjournal764697.
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Procedures have been developed to label human erythropoietin (Ep) with biotin to detect and isolate the Ep-receptor. The labeling method used the abundant carbohydrate groups on Ep and resulted in biologically active biotin-Ep (b-Ep) containing 8 to 10 biotins per Ep molecule. Specific binding of b-Ep to cells from spleens of mice made anemic by phenylhydrazine injections was demonstrated using 125I-labeled streptavidin. B-Ep, together with fluorescently tagged streptavidin, was found to specifically detect Ep-receptor-bearing cells by flow cytometry. This was demonstrated in several ways. First, approximately 90% of nucleated spleen cells from phenylhydrazine-treated mice were clearly fluorescent after staining with b-Ep and streptavidin- phycoerythrin, whereas only background fluorescence was detected using spleen cells from untreated mice. In addition, Ep-receptors were detected on 5% to 10% of normal mouse bone marrow cells, and these cells could be identified as erythroid in nature by separating the cells into subpopulations based on light-scatter properties. Third, Ep- receptor expression was found to correlate positively with expression of transferrin receptors, confirming the erythroid nature of these cells. B-Ep was also used to isolate Ep-receptors from monkey COS cells transfected with the murine Ep-receptor cDNA. In these experiments a cell-surface-bound protein of approximately 65 Kd and an intracellular protein of approximately 60 Kd were isolated from these cells. The procedures described in this report for detecting Ep-receptor expressing cells and for isolating the Ep-receptor should be valuable for purifying erythroid cells from heterogeneous cell populations, for elucidating the structure of the Ep-receptor, and for studying the biological activities of Ep at the cellular and molecular level.
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Audoly, Laurent P., Stephen L. Tilley, Jennifer Goulet, et al. "Identification of specific EP receptors responsible for the hemodynamic effects of PGE2." American Journal of Physiology-Heart and Circulatory Physiology 277, no. 3 (1999): H924—H930. http://dx.doi.org/10.1152/ajpheart.1999.277.3.h924.
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To identify the E-prostanoid (EP) receptors that mediate the hemodynamic actions of PGE2, we studied acute vascular responses to infusions of PGE2using lines of mice in which each of four EP receptors (EP1 through EP4) have been disrupted by gene targeting. In mixed groups of males and females, vasodepressor responses after infusions of PGE2were significantly diminished in the EP2 −/− and EP4 −/− lines but not in the EP1 −/− or EP3 −/− lines. Because the actions of other hormonal systems that regulate blood pressure differ between sexes, we compared the roles of individual EP receptors in males and females. We found that the relative contribution of each EP-receptor subclass was strikingly different in males from that in females. In females, the EP2 and EP4 receptors, which signal by stimulating adenylate cyclase, mediate the major portion of the vasodepressor response to PGE2. In males, the EP2 receptor has a modest effect, but most of the vasodepressor effect is mediated by the phospholipase C-coupled EP1receptor. Finally, in male mice, the EP3 receptor actively opposes the vasodepressor actions of PGE2. Thus the hemodynamic actions of PGE2 are mediated through complex interactions of several EP-receptor subtypes, and the role of individual EP receptors differs dramatically in males from that in females. These differences may contribute to sexual dimorphism of blood pressure regulation.
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Kim, Soon Ok, Siabhon M. Harris, and Diane M. Duffy. "Prostaglandin E2 (EP) Receptors Mediate PGE2-Specific Events in Ovulation and Luteinization Within Primate Ovarian Follicles." Endocrinology 155, no. 4 (2014): 1466–75. http://dx.doi.org/10.1210/en.2013-2096.
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Prostaglandin E2 (PGE2) is a key mediator of ovulation. All 4 PGE2 receptors (EP receptors) are expressed in the primate follicle, but the specific role of each EP receptor in ovulatory events is poorly understood. To examine the ovulatory events mediated via these EP receptors, preovulatory monkey follicles were injected with vehicle, the PG synthesis inhibitor indomethacin, or indomethacin plus PGE2. An ovulatory dose of human chorionic gonadotropin was administered; the injected ovary was collected 48 hours later and serially sectioned. Vehicle-injected follicles showed normal ovulatory events, including follicle rupture, absence of an oocyte, and thickening of the granulosa cell layer. Indomethacin-injected follicles did not rupture and contained oocytes surrounded by unexpanded cumulus; granulosa cell hypertrophy did not occur. Follicles injected with indomethacin plus PGE2 were similar to vehicle-injected ovaries, indicating that PGE2 restored the ovulatory changes inhibited by indomethacin. Additional follicles were injected with indomethacin plus an agonist for each EP receptor. EP1, EP2, and EP4 agonists each promoted aspects of follicle rupture, but no single EP agonist recapitulated normal follicle rupture as seen in follicles injected with either vehicle or indomethacin plus PGE2. Although EP4 agonist-injected follicles contained oocytes in unexpanded cumulus, the absence of oocytes in EP1 agonist- and EP2 agonist-injected follicles suggests that these EP receptors promote cumulus expansion. Surprisingly, the EP3 agonist did not stimulate any of these ovulatory changes, despite the high level of EP3 receptor expression in the monkey follicle. Therefore, agonists and antagonists selective for EP1 and EP2 receptors hold the most promise for control of ovulatory events in women.
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Ye, Yao, Peng Lin, Junyan Zhu, Udo Jeschke, and Viktoria von Schönfeldt. "Multiple Roles of Prostaglandin E2 Receptors in Female Reproduction." Endocrines 1, no. 1 (2020): 22–34. http://dx.doi.org/10.3390/endocrines1010003.
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Among prostaglandins, Prostaglandin E2 (PGE2) (PGE2) is considered especially important for decidualization, ovulation, implantation and pregnancy. Four major PGE2 receptor subtypes, EP1, EP2, EP3, EP4, as well as peroxisome proliferator-activated receptors (PPARs), mediate various PGE2 effects via their coupling to distinct signaling pathways. This review summarizes up-to-date literatures on the role of prostaglandin E2 receptors in female reproduction, which could provide a broad perspective to guide further research in this field. PGE2 plays an indispensable role in decidualization, ovulation, implantation and pregnancy. However, the precise mechanism of Prostaglandin E2 (EP) receptors in the female reproductive system is still limited. More investigations should be performed on the mechanism of EP receptors in the pathological states, and the possibility of EP agonists or antagonists clinically used in improving reproductive disorders.
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Taniguchi, Shuichi, Chun-Hua Dai, James O. Price та Sanford B. Krantz. "Interferon γ Downregulates Stem Cell Factor and Erythropoietin Receptors But Not Insulin-Like Growth Factor-I Receptors in Human Erythroid Colony-Forming Cells". Blood 90, № 6 (1997): 2244–52. http://dx.doi.org/10.1182/blood.v90.6.2244.
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Abstract Interferon γ (IFNγ) has been shown to inhibit proliferation and differentiation of erythroid progenitor cells and to produce apoptosis of erythroid cells, whereas stem cell factor (SCF ), erythropoietin (EP), and insulin-like growth factor-I (IGF-I) have distinct roles in enhancing erythroid cell production and preventing apoptosis. The mechanism by which IFNγ exerts an inhibitory effect on the positive roles of these growth factors is unknown. Although some inhibitory cytokines including IFNγ have been shown to downregulate growth factor receptors, the effect of IFNγ on SCF, EP, and IGF-I receptors of human erythroid progenitor cells has not been defined. We obtained highly purified day-5 or day-6 erythroid colony-forming cells (ECFCs) from human blood in sufficient quantity and purity for radiolabeled cytokine binding studies and analysis of mRNA. When day-5 ECFCs were incubated with increasing concentrations of recombinant human (rh) IFNγ for 24 hours at 37°C, specific binding of 125I-rhSCF to SCF receptors was significantly decreased by 25% to 40% in a dose-dependent fashion, with the maximum effect at 2,500 to 5,000 U/mL of IFNγ. The decrease was apparent by 12 hours of incubation and was only slightly lower by 24 hours. The numbers of SCF and EP receptors, but not of IGF-I receptors, per ECFC, calculated by Scatchard analysis, were significantly decreased by 30% and 23% to 25%, respectively, after incubation with 2,500 U/mL rhIFNγ for 24 hours at 37°C, whereas the binding affinities were not affected. This decrease in SCF receptors was confirmed by flow cytometry using an anti–c-kit mouse monoclonal antibody. Northern blot analysis showed that the mRNAs for the SCF and EP receptors, but not for the IGF-I receptors, were decreased by 50% to 60% after 3 hours of incubation at 37°C with 2,500 U/mL of rhIFNγ. This persisted for 24 hours without alteration of the stability of the SCF and EP receptor mRNAs. These observations suggest that one means by which IFNγ inhibits erythroid cell proliferation and differentiation and produces apoptosis may be through the reduction of the number of target receptors for SCF and EP and that this occurs through transcriptional inhibition of the corresponding mRNAs.
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Taniguchi, Shuichi, Chun-Hua Dai, James O. Price та Sanford B. Krantz. "Interferon γ Downregulates Stem Cell Factor and Erythropoietin Receptors But Not Insulin-Like Growth Factor-I Receptors in Human Erythroid Colony-Forming Cells". Blood 90, № 6 (1997): 2244–52. http://dx.doi.org/10.1182/blood.v90.6.2244.2244_2244_2252.
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Interferon γ (IFNγ) has been shown to inhibit proliferation and differentiation of erythroid progenitor cells and to produce apoptosis of erythroid cells, whereas stem cell factor (SCF ), erythropoietin (EP), and insulin-like growth factor-I (IGF-I) have distinct roles in enhancing erythroid cell production and preventing apoptosis. The mechanism by which IFNγ exerts an inhibitory effect on the positive roles of these growth factors is unknown. Although some inhibitory cytokines including IFNγ have been shown to downregulate growth factor receptors, the effect of IFNγ on SCF, EP, and IGF-I receptors of human erythroid progenitor cells has not been defined. We obtained highly purified day-5 or day-6 erythroid colony-forming cells (ECFCs) from human blood in sufficient quantity and purity for radiolabeled cytokine binding studies and analysis of mRNA. When day-5 ECFCs were incubated with increasing concentrations of recombinant human (rh) IFNγ for 24 hours at 37°C, specific binding of 125I-rhSCF to SCF receptors was significantly decreased by 25% to 40% in a dose-dependent fashion, with the maximum effect at 2,500 to 5,000 U/mL of IFNγ. The decrease was apparent by 12 hours of incubation and was only slightly lower by 24 hours. The numbers of SCF and EP receptors, but not of IGF-I receptors, per ECFC, calculated by Scatchard analysis, were significantly decreased by 30% and 23% to 25%, respectively, after incubation with 2,500 U/mL rhIFNγ for 24 hours at 37°C, whereas the binding affinities were not affected. This decrease in SCF receptors was confirmed by flow cytometry using an anti–c-kit mouse monoclonal antibody. Northern blot analysis showed that the mRNAs for the SCF and EP receptors, but not for the IGF-I receptors, were decreased by 50% to 60% after 3 hours of incubation at 37°C with 2,500 U/mL of rhIFNγ. This persisted for 24 hours without alteration of the stability of the SCF and EP receptor mRNAs. These observations suggest that one means by which IFNγ inhibits erythroid cell proliferation and differentiation and produces apoptosis may be through the reduction of the number of target receptors for SCF and EP and that this occurs through transcriptional inhibition of the corresponding mRNAs.
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Breyer, M. D., H. R. Jacobson, and R. M. Breyer. "Functional and molecular aspects of renal prostaglandin receptors." Journal of the American Society of Nephrology 7, no. 1 (1996): 8–17. http://dx.doi.org/10.1681/asn.v718.
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The diverse intrarenal effects of the prostaglandins (PG) are mediated by distinct guanine nucleotide regulatory protein (G-protein)-coupled receptors. The cDNA for these receptors have been cloned, their signal transduction mechanisms determined, and their intrarenal distribution mapped. PGE2, the major intrarenal prostaglandin, interacts with at least three distinct E-prostanoid (EP) receptors that are highly expressed in specific regions of the kidney. Each EP receptor not only selectively binds PGE2, but also preferentially couples to different signal transduction pathways, including: stimulation of cAMP generation, via Gq (EP2 and EP4 receptors); inhibition of cAMP generation, via Gi (EP3 receptors); and activation of phosphatidylinositol hydrolysis (EP1 receptor), via one of the Gq family members. Activation of each these EP receptors is responsible for a distinct renal effect of PGE2, including its well-described renal hemodynamic and transport effects along the nephron. Other intrarenal prostanoid receptors include the PGF2 alpha receptor (FP), the thromboxane A2 receptor (TP) and the prostacyclin receptor (IP). Knowledge about localization of these receptors and their affinities for receptor-selective agonists and antagonists should aid in the understanding of renal disease and the development of therapeutic strategies for the use of these prostaglandin analogs in select renal diseases.
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Breyer, M. D., L. Davis, H. R. Jacobson, and R. M. Breyer. "Differential localization of prostaglandin E receptor subtypes in human kidney." American Journal of Physiology-Renal Physiology 270, no. 5 (1996): F912—F918. http://dx.doi.org/10.1152/ajprenal.1996.270.5.f912.
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Four prostaglandin E2 (PGE2) receptors designated EP1, EP2, EP3, and EP4 have been pharmacologically identified, cloned, and sequenced. The present studies determined the intrarenal distribution of these EP-receptor subtypes in human kidney using in situ hybridization with riboprobes for the human EP receptors. mRNA for the phosphatidylinositol hydrolysis-coupled EP receptor was highly expressed in cortical, outer medullary, and inner medullary collecting duct. RNA for the Gi-coupled EP3 receptor was primarily expressed in the cortical and outer medullary collecting duct, as well as in the medullary thick ascending limb; however, it was absent from the inner medullary collecting duct. Expression of mRNA for EP1 and EP3 in connecting segment could not be excluded. There was no expression of the GS-coupled EP2 receptor mRNA detected in human kidney by in situ hybridization; however, mRNA for the GS-coupled EP4 receptor was highly expressed in the glomerulus. These studies demonstrate distinct regions of intrarenal expression for the different EP receptors and suggest that each receptor subtype may modulate different aspects of renal function in humans.
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Nasrallah, Rania, Ramzi Hassouneh, and Richard L. Hébert. "Chronic kidney disease: targeting prostaglandin E2 receptors." American Journal of Physiology-Renal Physiology 307, no. 3 (2014): F243—F250. http://dx.doi.org/10.1152/ajprenal.00224.2014.
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Chronic kidney disease is a leading cause of morbidity and mortality in the world. A better understanding of disease mechanisms has been gained in recent years, but the current management strategies are ineffective at preventing disease progression. A widespread focus of research is placed on elucidating the specific processes implicated to find more effective therapeutic options. PGE2, acting on its four EP receptors, regulates many renal disease processes; thus EP receptors could prove to be important targets for kidney disease intervention strategies. This review summarizes the major pathogenic mechanisms contributing to initiation and progression of chronic kidney disease, emphasizing the role of hyperglycemia, hypertension, inflammation, and oxidative stress. We have long recognized the multifaceted role of PGs in both the initiation and progression of chronic kidney disease, yet studies are only now seriously contemplating specific EP receptors as targets for therapy. Given the plethora of renal complications attributed to PG involvement in the kidney, this review highlights these pathogenic events and emphasizes the PGE2 receptor targets as options available to complement current therapeutic strategies.
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Coskun, Tamer, Libbey S. O’Farrell, Samreen K. Syed, et al. "Activation of Prostaglandin E Receptor 4 Triggers Secretion of Gut Hormone Peptides GLP-1, GLP-2, and PYY." Endocrinology 154, no. 1 (2013): 45–53. http://dx.doi.org/10.1210/en.2012-1446.
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Prostaglandins E1 and E2 are synthesized in the intestine and mediate a range of gastrointestinal functions via activation of the prostanoid E type (EP) family of receptors. We examined the potential role of EP receptors in the regulation of gut hormone secretion from L cells. Analysis of mRNA expression in mouse enteroendocrine GLUTag cells demonstrated the abundant expression of EP4 receptor, whereas expression of other EP receptors was much lower. Prostaglandin E1 and E2, nonselective agonists for all EP receptor subtypes, triggered glucagon like peptide 1 (GLP-1) secretion from GLUTag cells, as did the EP4-selective agonists CAY10580 and TCS2510. The effect of EP4 agonists on GLP-1 secretion was blocked by incubation of cells with the EP4-selective antagonist L161,982 or by down-regulating EP4 expression with specific small interfering RNA. Regulation of gut hormone secretion with EP4 agonists was further studied in mice. Administration of EP4 agonists to mice produced a significant elevation of plasma levels of GLP-1, glucagon like peptide 2 (GLP-2) and peptide YY (PYY), whereas gastric inhibitory peptide (GIP) levels were not increased. Thus, our data demonstrate that activation of the EP4 receptor in enteroendocrine L cells triggers secretion of gut hormones.
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Tilley, Stephen L., John M. Hartney, Christopher J. Erikson, et al. "Receptors and pathways mediating the effects of prostaglandin E2 on airway tone." American Journal of Physiology-Lung Cellular and Molecular Physiology 284, no. 4 (2003): L599—L606. http://dx.doi.org/10.1152/ajplung.00324.2002.
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Prostaglandin E2(PGE2) has complex effects on airway tone, and the existence of four PGE2 [E-prostanoid (EP)] receptors, each with distinct signaling characteristics, has provided a possible explanation for the seemingly contradictory actions of this lipid mediator. To identify the receptors mediating the actions of PGE2 on bronchomotor tone, we examined its effects on the airways of wild-type and EP receptor-deficient mice. In conscious mice the administration of PGE2 increased airway responsiveness primarily through the EP1 receptor, although on certain genetic backgrounds a contribution of the EP3 receptor was detected. These effects of PGE2 were eliminated by pretreatment with either atropine or bupivacaine and were undetectable in anesthetized mice or in denervated tracheal rings, where only EP2-mediated relaxation of airway smooth muscle was observed. Together, our findings are consistent with a model in which PGE2 modulates airway tone by activating multiple receptors expressed on various cell populations and in which the relative contribution of these receptors might depend on the expression of modifier alleles. PGE2/EP1/EP3-induced airway constriction occurs indirectly through activation of neural pathways, whereas PGE2-induced bronchodilation results from direct activation of EP2 receptors on airway smooth muscle. This segregation of EP receptor function within the airway suggests that PGE2 analogs that selectively activate the EP2 receptor without activating the EP1/EP3 receptors might prove useful in the treatment of asthma.
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Santilli, Francesca, Andrea Boccatonda, Giovanni Davì, and Francesco Cipollone. "The Coxib case: Are EP receptors really guilty?" Atherosclerosis 249 (June 2016): 164–73. http://dx.doi.org/10.1016/j.atherosclerosis.2016.04.004.
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Charles, C. J., E. A. Espiner, M. G. Nicholls, et al. "Clearance receptors and endopeptidase 24.11: equal role in natriuretic peptide metabolism in conscious sheep." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 271, no. 2 (1996): R373—R380. http://dx.doi.org/10.1152/ajpregu.1996.271.2.r373.
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Although many studies have examined the effects of administering natriuretic peptide receptor C (NPR-C) ligands and endopeptidase 24.11 (EP 24.11) inhibitors on clearance and bioactivity of atrial natriuretic peptide (ANP), none have systematically compared their effects on the endogenous levels of both ANP and brain natriuretic peptide (BNP) under physiological conditions. Accordingly, we examined the hemodynamic, hormonal, and renal actions of an EP 24.11 inhibitor, SCH-32615, and an NPR-C ligand, C-ANP-(4-23), both alone and in combination in eight normal conscious sheep. NPR-C blockade and EP 24.11 inhibition induce similar rises in plasma ANP, BNP, and guanosine 3',5'-cyclic monophosphate (cGMP). Synergistic increments in plasma ANP, BNP, and cGMP observed during combined administration are likely to be due to the reduced clearance of C-ANP-(4-23) in the setting of EP 24.11 inhibition, leading to increased inhibition of the receptor pathway. Combined administration was also associated with enhanced hemodynamic actions and diuretic and natriuretic effects. Our findings show that both enzymatic and receptor clearance pathways contribute equally to natriuretic peptide clearance and induce potentially important hemodynamic and renal effects in normal conscious sheep.
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Melis, Maria Rosaria, Salvatora Succu, Maria Sabrina Spano, Romano Deghenghi, and Antonio Argiolas. "EP 91073 prevents EP 80661-induced penile erection: new evidence for the existence of specific EP peptide receptors mediating penile erection." Neuropharmacology 41, no. 2 (2001): 254–62. http://dx.doi.org/10.1016/s0028-3908(01)00059-4.
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Schmitz, Thomas, Brian A. Levine, and Peter W. Nathanielsz. "Localization and steroid regulation of prostaglandin E2 receptor protein expression in ovine cervix." Reproduction 131, no. 4 (2006): 743–50. http://dx.doi.org/10.1530/rep.1.00767.
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Although prostaglandin E2(PGE2) has been identified as a central mediator of the cervical ripening process, the mechanisms responsible for PGE2ripening are still poorly understood, partly because of the lack of information concerning the precise cellular localization and regulation of PGE2(EP) receptors in the cervix. To provide new insights into the mechanisms of cervical ripening, we used indirect immunofluorescence to localize cervical EP receptor protein expression in ovariectomized ewes and examined the effect of administration of progesterone or estradiol. EP receptors were widely distributed in cervical blood vessels, epithelium of the cervical canal, circular and longitudinal muscles, and stroma. Estradiol replacement decreased EP1and EP3receptor protein in blood vessel media (by 23 and 31% respectively,P< 0.05) and decreased EP1receptor protein expression in the longitudinal muscle layer (by 27%,P< 0.05). Stromal EP1and EP3receptor protein expression was also reduced by estradiol (by 29 and 20% respectively,P< 0.05). Progesterone replacement had no significant effect on EP receptor protein expression. The arterial changes would favor PGE2-induced vasodilatation, subsequent edema and leukocyte infiltration during the cervical ripening process whereas the muscular alterations would facilitate smooth muscle relaxation and cervical dilatation. Furthermore, estradiol provoked perinuclear localization of EP3receptor protein in the longitudinal muscle layer. This latter result suggests that cellular EP receptor localization is regulated by estradiol and that PGE2may also control smooth muscle contraction and regulate ovine cervical dilatation in an intracrine manner via EP3receptors.
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Zhang, Zhi-Hua, Yang Yu, Shun-Guang Wei, Yoshiko Nakamura, Kazuhiro Nakamura, and Robert B. Felder. "EP3 receptors mediate PGE2-induced hypothalamic paraventricular nucleus excitation and sympathetic activation." American Journal of Physiology-Heart and Circulatory Physiology 301, no. 4 (2011): H1559—H1569. http://dx.doi.org/10.1152/ajpheart.00262.2011.
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Prostaglandin E2 (PGE2), an important mediator of the inflammatory response, acts centrally to elicit sympathetic excitation. PGE2 acts on at least four E-class prostanoid (EP) receptors known as EP1, EP2, EP3, and EP4. Since PGE2 production within the brain is ubiquitous, the different functions of PGE2 depend on the expression of these prostanoid receptors in specific brain areas. The type(s) and location(s) of the EP receptors that mediate sympathetic responses to central PGE2 remain unknown. We examined this question using PGE2, the relatively selective EP receptor agonists misoprostol and sulprostone, and the available selective antagonists for EP1, EP3, and EP4. In urethane-anesthetized rats, intracerebroventricular (ICV) administration of PGE2, sulprostone or misoprostol increased renal sympathetic nerve activity, blood pressure, and heart rate. These responses were significantly reduced by ICV pretreatment with the EP3 receptor antagonist; the EP1 and EP4 receptor antagonists had little or no effect. ICV PGE2 or misoprostol increased the discharge of neurons in the hypothalamic paraventricular nucleus (PVN). ICV misoprostol increased the c-Fos immunoreactivity of PVN neurons, an effect that was substantially reduced by the EP3 receptor antagonist. Real-time PCR detected EP3 receptor mRNA in PVN, and immunohistochemical studies revealed sparsely distributed EP3 receptors localized in GABAergic terminals and on a few PVN neurons. Direct bilateral PVN microinjections of PGE2 or sulprostone elicited sympathoexcitatory responses that were significantly reduced by the EP3 receptor antagonist. These data suggest that EP3 receptors mediate the central excitatory effects of PGE2 on PVN neurons and sympathetic discharge.
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Hillock, Catherine J., and Denis J. Crankshaw. "Inhibitory prostanoid EP receptors in human non-pregnant myometrium." European Journal of Pharmacology 378, no. 1 (1999): 99–108. http://dx.doi.org/10.1016/s0014-2999(99)00442-2.
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Takeuchi, Koji, Shinichi Kato, and Kikuko Amagase. "Prostaglandin EP Receptors Involved in Modulating Gastrointestinal Mucosal Integrity." Journal of Pharmacological Sciences 114, no. 3 (2010): 248–61. http://dx.doi.org/10.1254/jphs.10r06cr.
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Refaat, Bassem, Majedah Al-Azemi, Ian Geary, Adrian Eley, and William Ledger. "Role of Activins and Inducible Nitric Oxide in the Pathogenesis of Ectopic Pregnancy in Patients with or without Chlamydia trachomatis Infection." Clinical and Vaccine Immunology 16, no. 10 (2009): 1493–503. http://dx.doi.org/10.1128/cvi.00221-09.
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ABSTRACT Chlamydia trachomatis infection can lead to pelvic inflammatory disease, ectopic pregnancy (EP), infertility, and chronic pelvic pain in women. Activins and inducible nitric oxide synthase (iNOS) are produced by the human fallopian tube, and we speculate that tubal activins and iNOS may be involved in the immune response to C. trachomatis in humans and their pathological alteration may result in tubal pathology and the development of EP. Blood and fallopian tubes were collected from 14 women with EP. Sera were analyzed by enzyme-linked immunosorbent assay to detect antibodies against chlamydial heat shock protein 60 (chsp60) and the major outer membrane protein of C. trachomatis. Confirmation of C. trachomatis serology was made using the microimmunofluorescence test. The patients were classified into three groups according to their serological results, and immunohistochemistry and quantitative reverse transcription-PCR were performed to investigate the expression of candidate molecules by tubal epithelial cells among the three groups. This is the first study to show an increase in the expression of activin βA subunit, type II receptors, follistatin, and iNOS within the human fallopian tube of EP patients who were serologically positive for C. trachomatis. A similar expression profile was observed in the fallopian tubes with detectable antibodies only against chsp60. These results were shown at the mRNA and protein levels. We suggest that tubal activin A, its type II receptors, follistatin, and NO could be involved in the microbial-mediated immune response within the fallopian tube, and their pathological expression may lead to tubal damage and the development of EP.
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Michel, Frédéric S., Ricky Y. K. Man, and Paul M. Vanhoutte. "Increased spontaneous tone in renal arteries of spontaneously hypertensive rats." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 3 (2007): H1673—H1681. http://dx.doi.org/10.1152/ajpheart.00289.2007.
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The spontaneous tone of vascular smooth muscle is augmented in hypertension. The present study examined the role of nitric oxide (NO), cyclooxygenase (COX), thromboxane A2/prostanoid (TP) and PGE2/prostanoid (EP-1) receptors, reactive oxygen species, and large-conductance Ca2+-activated K+ (BKCa) channels in the regulation of spontaneous tone in renal arteries of young and mature Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Rings of arteries, with and without endothelium, were suspended in a myograph for isometric force recording. Spontaneous tone (increase above initial tension) was observed only in arteries of mature SHR and was greater in arteries without endothelium. Nω-nitro-l-arginine methyl ester (l-NAME, an inhibitor of NO synthases) induced larger contractions in arteries of SHR than WKY. Indomethacin (a COX inhibitor), SC-19220 (an EP-1 receptor antagonist), and terutroban (a TP receptor antagonist) reduced the l-NAME-evoked contractions. Tiron (a superoxide anion scavenger), catalase (an enzyme that degrades H2O2), and deferoxamine (a hydroxyl radical scavenger) augmented the l-NAME-induced contractions in arteries of mature SHR. Charybdotoxin (a BKCa channel blocker) caused contractions in arteries of mature SHR without endothelium and in arteries with endothelium incubated with l-NAME. A decreased protein level of endothelial NO synthase, an increased release of prostacyclin, and an increased expression of EP-1 receptors were observed in arteries of mature SHR. The present study suggests that spontaneous tone is precipitated by age and hypertension. The reduced production of NO, leading to decreased activation of BKCa channels, may leave the actions of endogenous vasoconstrictors unopposed. COX products that activate EP-1 and TP receptors are involved in the development of spontaneous tone.
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Ueno, M., I. Rondon, B. Beckman, et al. "Increased secretion of erythropoietin in human renal carcinoma cells in response to atrial natriuretic factor." American Journal of Physiology-Cell Physiology 259, no. 3 (1990): C427—C431. http://dx.doi.org/10.1152/ajpcell.1990.259.3.c427.
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The present studies were undertaken to assess the effects of atrial natriuretic factor (ANF) on erythropoietin (Ep) secretion in Ep-producing renal carcinoma (RC) cells using a sensitive radioimmunoassay for Ep. Human ANF produced a significant dose-related increase in Ep secretion at concentrations of 10(-7) and 10(-6) M when compared with vehicle controls. ANF (greater than or equal to 10(-9) M) also significantly increased the intracellular guanosine 3',5'-cyclic monophosphate (cGMP) concentration after 5-min incubation with the RC cells. Scatchard analysis of the human 125I-labeled ANF binding data indicated that the RC cells contain a single class of binding sites with a dissociation constant (Kd) of 93 +/- 1 pM and a binding capacity of 2,190 +/- 750 sites/cell. Incubation of the RC cells with 8-bromo-cGMP in concentrations of 10(-7)-10(-5) M also produced a significant dose-related enhancement of Ep secretion. These findings suggest that the increase in Ep secretion in response to ANF can be attributed, at least in part, to activation of guanylate cyclase, which is coupled to specific ANF receptors on the RC cell.
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Xue, Rui, Zhankui Jia, Xiaomu Kong, Guofu Pi, Shengli Ma, and Jinjian Yang. "Effects of PGE2 EP3/EP4 receptors on bladder dysfunction in mice with experimental autoimmune encephalomyelitis." American Journal of Physiology-Renal Physiology 305, no. 12 (2013): F1656—F1662. http://dx.doi.org/10.1152/ajprenal.00271.2013.
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To investigate the expression of four subtypes of PGE2 E-prostanoid (EP) receptors (EP1–EP4) and the effects of EP3/EP4 on bladder dysfunction in a new neurogenic bladder model induced by experimental autoimmune encephalomyelitis (EAE), the mouse model of EAE was induced using a previously established method, and bladder function in mice with different defined levels of neurological impairment was then examined, including micturition frequencies and voiding weight. Bladders were then harvested for analysis of EP receptor expression by Western blot. Activities of agonists/antagonists of EP3 and EP4 receptors as well as PGE2 were also evaluated at different stages of EAE. The results showed that EAE mice developed profound bladder dysfunction characterized by significantly increased micturition and significantly decreased urine output per micturition. EAE-induced upregulation of EP3 and EP4 receptors in the bladder was accompanied by bladder dysfunction. However, EAE had no significant effect on EP1 and EP2 receptors. Moreover, PGE2 and agonists/antagonists of EP3 and EP4 receptors significantly affected bladder dysfunction in EAE mice. Thus, we believe that EAE mice are useful for investigations of the neurogenic bladder. In addition, EP3 and EP4 receptors play a role in EAE-induced bladder dysfunction, providing us with a new target for the treatment of neurogenic bladders.
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Joseph, D. P., and S. S. Miller. "Alpha-1-adrenergic modulation of K and Cl transport in bovine retinal pigment epithelium." Journal of General Physiology 99, no. 2 (1992): 263–90. http://dx.doi.org/10.1085/jgp.99.2.263.
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Intracellular microelectrode techniques were used to characterize the electrical responses of the bovine retinal pigment epithelium (RPE)-choroid to epinephrine (EP) and several other catecholamines that are putative paracrine signals between the neural retina and the RPE. Nanomolar amounts of EP or norepinephrine (NEP), added to the apical bath, caused a series of conductance and voltage changes, first at the basolateral or choroid-facing membrane and then at the apical or retina-facing membrane. The relative potency of several adrenergic agonists and antagonists indicates that EP modulation of RPE transport begins with the activation of apical alpha-1-adrenergic receptors. The membrane-permeable calcium (Ca2+) buffer, amyl-BAPTA (1,2-bis(o-aminophenoxy)-ethane-N,N,N',N' tetraacetic acid) inhibited the EP-induced voltage and conductance changes by approximately 50-80%, implicating [Ca2+]i as a second messenger. This conclusion is supported by experiments using the Ca2+ ionophore A23187, which mimics the effects of EP. The basolateral membrane voltage response to EP was blocked by lowering cell Cl, by the presence of DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid) in the basal bath, and by current clamping VB to the Cl equilibrium potential. In the latter experiments the EP-induced conductance changes were unaltered, indicating that EP increases basolateral membrane Cl conductance independent of voltage. The EP-induced change in basolateral Cl conductance was followed by a secondary decrease in apical membrane K conductance (approximately 50%) as measured by delta [K]o-induced diffusion potentials. Decreasing apical K from 5 to 2 mM in the presence of EP mimicked the effect of light on RPE apical and basolateral membrane voltage. These results indicate that EP may be an important paracrine signal that provides exquisite control of RPE physiology.
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Testa, U., E. Pelosi, M. Gabbianelli, et al. "Cascade transactivation of growth factor receptors in early human hematopoiesis." Blood 81, no. 6 (1993): 1442–56. http://dx.doi.org/10.1182/blood.v81.6.1442.1442.
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Abstract Highly purified progenitors (including erythroid [BFU-E], granulo- monocytic [CFU-GM], multipotent [CFU-GEMM] progenitors, as well as multipotent progenitors with self-renewal capacity [CFU-B]) express high-affinity growth factor receptors (GFRs), with prevalent interleukin-3 receptors (IL-3Rs) (2,700/cell), a > or = 10-fold lower number of IL-6Rs (145/cell) and granulocyte-macrophage colony- stimulating factor receptors (GM-CSFRs) (300/cell), and a barely detectable level of erythropoietin (Ep) receptors (75/cell). Hematopoietic growth factor (HGF) dosages inducing peak clonogenetic effects are associated with partial/subtotal occupancy of the homologous HGF receptor (HGFR). Cross-reactivity between GFRs and heterologous GFs (including IL-6, IL-3, GM-CSF, Ep, and the kit ligand [KL]) was explored by competition experiments on purified progenitors with radiolabeled and excess cold HGFs at +4 degrees C. No cross- reaction was observed between IL-6R, IL-3R, EpR, and the heterologous GFs, whereas the GM-CSFR showed cross-reactivity with IL-3 and, to a lesser extent, KL. Modulation of GFRs was examined after 18 or 40 hours of incubation with GF(s) at 37 degrees C, followed by ligand-binding assay at 20 degrees C. IL-6, IL-3, GM-CSF, and Ep induce a marked down- modulation of their own receptors. Interestingly, each GF induces the transactivation of the R(s) for the “distal” GF(s): (1) IL-6 induces transactivation of IL-3R, but not of GM-CSFR/EpR; (2) IL-3 causes a rapid upmodulation of GM-CSFR/EpR (“pure” progenitors treated with IL-3 show upmodulation of GM-CSFR alpha-chain mRNA by reverse transcriptase- polymerase chain reaction); whereas (3) GM-CSF induces the transactivation of the EpR. This chain upmodulation of HGFRs may underlie the synergistic interactions between the HGFs in clonogenetic culture. It is emphasized that KL does not induce upmodulation of the other GFRs. Finally, Ep, GM-CSF, and IL-3 do not modulate the expression of the “proximal” HGFRs (ie, GM-CSFR/IL-3R/IL-6R, IL-3R/IL- 6R, and IL-6R, respectively). These results allow insight into the cellular basis of hematopoiesis, ie, the complex and coordinate interactions between HGFs and their receptors. They are compatible with a model of cascade transactivation via upmodulation of GFRs in the initial key steps of hematopoietic differentiation, whereby the action of each GF enhances the effect of the distal GF(s) by a multistep chain- potentiation mechanism.
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Testa, U., E. Pelosi, M. Gabbianelli, et al. "Cascade transactivation of growth factor receptors in early human hematopoiesis." Blood 81, no. 6 (1993): 1442–56. http://dx.doi.org/10.1182/blood.v81.6.1442.bloodjournal8161442.
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Highly purified progenitors (including erythroid [BFU-E], granulo- monocytic [CFU-GM], multipotent [CFU-GEMM] progenitors, as well as multipotent progenitors with self-renewal capacity [CFU-B]) express high-affinity growth factor receptors (GFRs), with prevalent interleukin-3 receptors (IL-3Rs) (2,700/cell), a > or = 10-fold lower number of IL-6Rs (145/cell) and granulocyte-macrophage colony- stimulating factor receptors (GM-CSFRs) (300/cell), and a barely detectable level of erythropoietin (Ep) receptors (75/cell). Hematopoietic growth factor (HGF) dosages inducing peak clonogenetic effects are associated with partial/subtotal occupancy of the homologous HGF receptor (HGFR). Cross-reactivity between GFRs and heterologous GFs (including IL-6, IL-3, GM-CSF, Ep, and the kit ligand [KL]) was explored by competition experiments on purified progenitors with radiolabeled and excess cold HGFs at +4 degrees C. No cross- reaction was observed between IL-6R, IL-3R, EpR, and the heterologous GFs, whereas the GM-CSFR showed cross-reactivity with IL-3 and, to a lesser extent, KL. Modulation of GFRs was examined after 18 or 40 hours of incubation with GF(s) at 37 degrees C, followed by ligand-binding assay at 20 degrees C. IL-6, IL-3, GM-CSF, and Ep induce a marked down- modulation of their own receptors. Interestingly, each GF induces the transactivation of the R(s) for the “distal” GF(s): (1) IL-6 induces transactivation of IL-3R, but not of GM-CSFR/EpR; (2) IL-3 causes a rapid upmodulation of GM-CSFR/EpR (“pure” progenitors treated with IL-3 show upmodulation of GM-CSFR alpha-chain mRNA by reverse transcriptase- polymerase chain reaction); whereas (3) GM-CSF induces the transactivation of the EpR. This chain upmodulation of HGFRs may underlie the synergistic interactions between the HGFs in clonogenetic culture. It is emphasized that KL does not induce upmodulation of the other GFRs. Finally, Ep, GM-CSF, and IL-3 do not modulate the expression of the “proximal” HGFRs (ie, GM-CSFR/IL-3R/IL-6R, IL-3R/IL- 6R, and IL-6R, respectively). These results allow insight into the cellular basis of hematopoiesis, ie, the complex and coordinate interactions between HGFs and their receptors. They are compatible with a model of cascade transactivation via upmodulation of GFRs in the initial key steps of hematopoietic differentiation, whereby the action of each GF enhances the effect of the distal GF(s) by a multistep chain- potentiation mechanism.
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Tavakoli, S., M. J. Cowan, T. Benfield, C. Logun, and J. H. Shelhamer. "Prostaglandin E2-induced interleukin-6 release by a human airway epithelial cell line." American Journal of Physiology-Lung Cellular and Molecular Physiology 280, no. 1 (2001): L127—L133. http://dx.doi.org/10.1152/ajplung.2001.280.1.l127.
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Human airway epithelial cell release of interleukin (IL)-6 in response to lipid mediators was studied in an airway cell line (BEAS-2B). Prostaglandin (PG) E2(10−7M) treatment caused an increase in IL-6 release at 2, 4, 8, and 24 h. IL-6 release into the culture medium at 24 h was 3,396 ± 306 vs. 1,051 ± 154 pg/ml (PGE2-treated cells vs. control cells). PGE2(10−7to 10−10M) induced a dose-related increase in IL-6 release at 24 h. PGF2α(10−6M) treatment caused a similar effect to that of PGE2(10−7M). PGE2analogs with relative selectivity for PGE2receptor subtypes were studied. Sulprostone, a selective agonist for the EP-3 receptor subtype had no effect on IL-6 release. 11-Deoxy-16,16-dimethyl-PGE2, an EP-2/4 agonist, and 17-phenyl trinor PGE2, an agonist selective for the EP-1 > EP-3 receptor subtype (10−6to 10−8M), caused dose-dependent increases in IL-6 release. 8-Bromo-cAMP treatment resulted in dose-related increases in IL-6 release. RT-PCR of BEAS-2B cell mRNA demonstrated mRNA for EP-1, EP-2, and EP-4 receptors. After PGE2treatment, increases in IL-6 mRNA were noted at 4 and 18 h. Therefore, PGE2increases airway epithelial cell IL-6 production and release.
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Hébert, Richard L., Richard M. Breyer, Harry R. Jacobson, and Matthew D. Breyer. "Functional and molecular aspects of prostaglandin E receptors in the cortical collecting duct." Canadian Journal of Physiology and Pharmacology 73, no. 2 (1995): 172–79. http://dx.doi.org/10.1139/y95-026.
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Endogenous prostaglandin (PG) E2 production potently modulates salt and water transport in the kidney. Multiple direct effects of PGE2 on epithelial water and sodium transport have been demonstrated in the rabbit cortical collecting duct (CCD). Both functional and molecular studies now suggest that these disparate effects of PGE2 on CCD function are mediated by different EP receptors. When added in the presence of vasopressin, PGE2 inhibits cyclic AMP generation and water absorption. These effects are mediated via an inhibitory G-protein (Gi). In situ hybridization demonstrates high levels of expression of the Gi-coupled EP3 receptor in the rabbit collecting duct. However, by itself, PGE2 also stimulates cyclic AMP generation and water permeability. These effects appear to be mediated via a distinct EP receptor (possibly an EP4 receptor). PGE2 also increases intracellular Ca2+ in the CCD and inhibits Na+ absorption via a Ca2+-dependent mechanism. The EP1 receptor is postulated to be responsible for this action of PGE2. We suggest receptor-selective prostaglandin analogs may be used to selectively modulate sodium and water transport in the kidney.Key words: EP receptor subtypes, G-proteins, in situ hybridization, prostaglandin E2, phosphatidylinositol biphosphate hydrolysis.
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Pirzadeh, Samaneh, Javad Sajedianfard, Anna Maria Aloisi та Mahboobeh Ashrafi. "Effects of Intracerebroventricular and Intra-Arcuate Nucleus Injection of Ghrelin on Pain Behavioral Responses and Met-Enkephalin and β-Endorphin Concentrations in the Periaqueductal Gray Area in Rats". International Journal of Molecular Sciences 20, № 10 (2019): 2475. http://dx.doi.org/10.3390/ijms20102475.
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Ghrelin is an endogenous ligand for orphan growth hormone secretagogue receptors. Ghrelin receptors have been found in central nervous system (CNS) areas responsible for pain modulation and transmission. This study investigated the effects of intracerebroventricular (ICV) and intra-arcuate nucleus (ARC) injection of ghrelin on pain behavioral responses and levels of β-endorphin (β-EP) and met-enkephalin (MENK) in the periaqueductal gray area (PAG) during the formalin test in rats. Thirty-five male rats were studied in five groups. Ghrelin was injected into the left lateral ventricle (ICV, 5 µL) or into the ARC (1 µL). After 15 min, formalin (2.5%) was subcutaneously injected into the left hind paw. Behavioral nociceptive scores were recorded for 60 min. MENK and β-EP were collected by microdialysis in the PAG and determined by high-performance liquid chromatography (HPLC). ICV and ARC injection of ghrelin significantly reduced pain in all phases of the formalin test (p < 0.001). Dialysate concentrations of MENK and β-EP in the PAG increased in all the phases (p < 0.01). In conclusion, the present study shows that the ARC nucleus and the endogenous opioid system are involved in ghrelin-induced pain modulation.
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Refaat, Bassem, Ahmed Mohamed Ashshi, Sarah Abdullah Batwa, et al. "The prevalence of Chlamydia trachomatis and Mycoplasma genitalium tubal infections and their effects on the expression of IL-6 and leukaemia inhibitory factor in Fallopian tubes with and without an ectopic pregnancy." Innate Immunity 22, no. 7 (2016): 534–45. http://dx.doi.org/10.1177/1753425916662326.
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This was a prospective case–control study that measured the prevalence of Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Mycoplasma genitalium (MG) by an IVD CE multiplex PCR kit in fresh Fallopian tubes (FT) obtained from 96 ectopic pregnancies (EP) and 61 controls in the midluteal phase of the cycle. We later measured the expression profile of IL-6, leukaemia inhibitory factor (LIF) and their signalling molecules, in respect to the type and number of infections, by immunohistochemistry, ELISA and quantitative RT-PCR. The frequencies of CT, and MG mono- and co-infections were significantly higher in EP. IL-6, LIF, their receptors and intracellular mediators were significantly up-regulated at the gene and protein levels in positive compared with negative FTs within each group ( P < 0.05). EP tubal samples with co-infections showed the highest significant expression of the candidate cytokines by all techniques ( P < 0.05). CT and MG are frequent in EP and up-regulate the tubal expression of IL-6, LIF and their signalling molecules. Both cytokines could be involved in the tubal immune response against bacterial infections, as well as the pathogenesis of EP. Further studies are needed to explore the roles of IL-6 family in infection-induced tubal inflammation and EP.
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Blikslager, Anthony T., Susan M. Pell, and Karen M. Young. "PGE2 triggers recovery of transmucosal resistance via EP receptor cross talk in porcine ischemia-injured ileum." American Journal of Physiology-Gastrointestinal and Liver Physiology 281, no. 2 (2001): G375—G381. http://dx.doi.org/10.1152/ajpgi.2001.281.2.g375.
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16,16-Dimethyl-PGE2 (PGE2) may interact with one of four prostaglandin type E (EP) receptors, which signal via cAMP (via EP2 or EP4 receptors) or intracellular Ca2+ (via EP1 receptors). Furthermore, EP3 receptors have several splice variants, which may signal via cAMP or intracellular Ca2+. We sought to determine the PGE2 receptor interactions that mediate recovery of transmucosal resistance ( R) in ischemia-injured porcine ileum. Porcine ileum was subjected to 45 min of ischemia, after which the mucosa was mounted in Ussing chambers. Tissues were pretreated with indomethacin (5 μM). Treatment with the EP1, EP2, EP3, and EP4 agonist PGE2 (1 μM) elevated R twofold and significantly increased tissue cAMP content, whereas the EP2 and EP4 agonist deoxy-PGE1 (1 μM) or the EP1 and EP3 agonist sulprostone (1 μM) had no effect. However, a combination of deoxy-PGE1 and sulprostone stimulated synergistic elevations in R and tissue cAMP content. Furthermore, treatment of tissues with deoxy-PGE1 and the Ca2+ ionophore A-23187 stimulated synergistic increases in R and cAMP, indicating that PGE2 triggers recovery of R via EP receptor cross talk mechanisms involving cAMP and intracellular Ca2+.
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Athirakul, Krairerk, Dennis W. Thomas, Jean-Etienne Fabre, Beverly Koller, and Thomas M. Coffman. "Modulation of Platelet Aggregation by the Ep 3 Receptor for Prostaglandin E 2." Hypertension 36, suppl_1 (2000): 721. http://dx.doi.org/10.1161/hyp.36.suppl_1.721.
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P153 Prostaglandins (PGs) are vasoactive eicosanoids that regulate vascular tone and platelet functions. PGE 2 is produced by activated platelets and is known to have dual effects on platelet function. At high concentrations, PGE 2 inhibits platelet aggregation while at lower concentrations, PGE 2 may potentiate aggregation. The physiologic functions of PGE 2 are mediated through binding to specific PGE 2 receptors (EPs). Four EP receptor isoforms (EP1-4) have been identified, each with distinctive tissue distributions and signaling mechanisms. However, roles for the individual EP receptor isoforms in regulating platelet functions are not clearly defined. In some cell types, the EP 3 receptor couples to the inhibitory protein Gi, resulting in reduced intra-cellular cAMP levels. As reduced cAMP levels enhance platelet aggreation, we hypothesized that the EP3 receptor might mediate the pro-aggregatory actions of PGE 2 . To address this issue, we studied mice with targeted disruption of EP 3 receptor gene (EP 3 -/- ). Bleeding times in EP 3 -/- mice were similar to wild type controls (70±18 sec vs. 84±18 sec, p=0.57). To study the effects of EP 3 receptor on platelet function in vitro, platelet aggregation was determined by light absorbance. PGE 2 at a dose of 10 nM had no significant effect on platelet aggregation in either EP 3 -/- or wild type mice. However, in platelets from wild-type mice, the combination of 10 nM PGE 2 and 500 nM of thromboxane receptor (TP) agonist U46619 caused vigorous aggregation (75±3.5%). In contrast, 10 nM of PGE 2 with 500 nM TP agonist had no effect on EP 3 -deficient platelets (4.3±2.8%, p<0.01 vs wild-type). These studies identify actions of the EP 3 receptor to promote platelet aggregation.
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Martin, L. W., L. B. Deeter, and J. M. Lipton. "Acute-phase response to endogenous pyrogen in rabbit: effects of age and route of administration." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 257, no. 1 (1989): R189—R193. http://dx.doi.org/10.1152/ajpregu.1989.257.1.r189.
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Aspects of host defense, collectively called the acute phase response (APR), can be induced by central actions of cytokines. To determine whether aging alters this response, aged and young rabbits were given endogenous pyrogen (EP), a crude preparation containing interleukin 1 and other cytokines, via an intracerebroventricular cannula. Arterial blood was sampled before EP administration and 2, 4, and 24 h later. Measurements were made of changes in body temperature, white blood cells, neutrophils, concentration of antipyretic, anti-inflammatory peptide alpha-melanocyte stimulating hormone (alpha-MSH), corticosterone, and C-reactive protein (CRP) concentrations. EP caused greater fever and increases in corticosterone and CRP in young rabbits. EP-induced changes in circulating neutrophils did not show age-related differences. There was no significant change in alpha-MSH in either age group; thus only certain aspects of APR induced by central actions of EP were altered with aging. To determine whether changes in APR caused by peripherally administered cytokines are similar to those after central injection, young female rabbits were given EP by both routes. Although administration caused greater fever, increases in alpha-MSH and corticosterone concentrations and in neutrophil counts were greater after intravenous administration, perhaps the result of a combined influence on peripheral and central receptors. The EP-induced increase in circulating alpha-MSH is a new finding that indicates that this antipyretic and anti-inflammatory peptide is rapidly available to modulate host responses after challenge.
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Gray, S. G., N. Al-Sarraf, and K. J. O'Byrne. "EP receptors in NSCLC, and their regulation by epigenetic modifications." Lung Cancer 60 (April 2008): S11—S12. http://dx.doi.org/10.1016/s0169-5002(08)70034-5.
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Moreland, R. B., N. Kim, A. Nehra, I. Goldstein, and A. Traish. "Functional prostaglandin E (EP) receptors in human penile corpus cavernosum." International Journal of Impotence Research 15, no. 5 (2003): 362–68. http://dx.doi.org/10.1038/sj.ijir.3901042.
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Fulton, Amy M., Xinrong Ma, and Namita Kundu. "Targeting Prostaglandin E EP Receptors to Inhibit Metastasis: Figure 1." Cancer Research 66, no. 20 (2006): 9794–97. http://dx.doi.org/10.1158/0008-5472.can-06-2067.
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Reader, Jocelyn, Dawn Holt, and Amy Fulton. "Prostaglandin E2 EP receptors as therapeutic targets in breast cancer." Cancer and Metastasis Reviews 30, no. 3-4 (2011): 449–63. http://dx.doi.org/10.1007/s10555-011-9303-2.
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Norel, Xavier. "Prostanoid Receptors in the Human Vascular Wall." Scientific World JOURNAL 7 (2007): 1359–74. http://dx.doi.org/10.1100/tsw.2007.184.
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The mechanisms involved in vascular homeostasis and disease are mostly dependent on the interactions between blood, vascular smooth muscle, and endothelial cells. There is an accumulation of evidence for the involvement of prostanoids, the arachidonic acid metabolites derived from the cyclooxygenase enzymatic pathway, in physiological and/or pathophysiological conditions. In humans, the prostanoids activate different receptors. The classical prostanoid receptors (DP, EP1–4, FP, IP, and TP) are localized at the cell plasma or nuclear membrane. In addition, CRTH2 and the nuclear PPAR receptors are two other targets for prostanoids, namely, prostacyclin (PGI2) or the natural derivatives of prostaglandin D2. While there is little information on the role of CRTH2, there are many reports on PPAR activation and the consecutive expression of genes involved in the human vascular system. The role of the classical prostanoid receptors stimulated by PGI2and thromboxane in the control of the vascular tone has been largely documented, whereas the other receptor subtypes have been overlooked. There is now increasing evidence that suggests a role of PGE2and the EP receptor subtypes in the control of the human vascular tone and remodeling of the vascular wall. These receptors are also present on leukocytes and platelets, and they are implicated in most of the inflammatory processes within the vascular wall. Consequently, the EP receptor subtypes or isoforms would provide a novel and specific cardiovascular therapeutic approach in the near future.
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Takemiya, Takako, Marumi Kawakami та Chisen Takeuchi. "Endothelial Microsomal Prostaglandin E Synthetase-1 Upregulates Vascularity and Endothelial Interleukin-1β in Deteriorative Progression of Experimental Autoimmune Encephalomyelitis". International Journal of Molecular Sciences 19, № 11 (2018): 3647. http://dx.doi.org/10.3390/ijms19113647.
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Microsomal prostaglandin E synthetase-1 (mPGES-1) is an inducible terminal enzyme for the production of prostaglandin E2 (PGE2). In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, mPGES-1 is induced in vascular endothelial cells (VECs) around inflammatory foci and facilitates inflammation, demyelination, and paralysis. Therefore, we investigated the role of CD31-positive VECs in mPGES-1-mediated EAE aggravation using immunohistochemical analysis and imaging of wild-type (wt) and mPGES-1-deficient (mPGES-1−/−) mice. We demonstrated that EAE induction facilitated vascularity in inflammatory lesions in the spinal cord, and this was significantly higher in wt mice than in mPGES-1−/− mice. In addition, endothelial interleukin-1β (IL-1β) production was significantly higher in wt mice than in mPGES-1−/− mice. Moreover, endothelial PGE2 receptors (E-prostanoid (EP) receptors EP1–4) were expressed after EAE induction, and IL-1β was induced in EP receptor-positive VECs. Furthermore, IL-1 receptor 1 expression on VECs was increased upon EAE induction. Thus, increased vascularity is one mechanism involved in EAE aggravation induced by mPGES-1. Furthermore, mPGES-1 facilitated the autocrine function of VECs upon EP receptor induction and IL-1β production, modulating mPGES-1 induction in EAE.
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Maccarinelli, Giuseppina, Valeria Sibilia, Antonio Torsello, et al. "Ghrelin regulates proliferation and differentiation of osteoblastic cells." Journal of Endocrinology 184, no. 1 (2005): 249–56. http://dx.doi.org/10.1677/joe.1.05837.
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It has previously been reported that growth hormone secretagogues (GHS) may have a role in the regulation of bone metabolism in animals and humans. In this study we evaluated the effect of ghrelin, the endogenous ligand of GHS receptors, on the proliferation rate and on osteoblast activity in primary cultures of rat calvaria osteoblasts. In the same experiments, we compared the effects of ghrelin with those of hexarelin (HEXA) and EP-40737, two synthetic GHS with different characteristics. Both ghrelin and HEXA (10−11−10−8 M) significantly stimulated osteoblast proliferation at low concentrations (10−10 M). Surprisingly, EP-40737 demonstrated an antiproliferative effect at 10−9−10−8 M, whereas lower concentrations had no effect on cell proliferation. Ghrelin and HEXA significantly increased alkaline phosphatase (ALP) and osteocalcin (OC) production. At variance with these peptides, EP-40737 did not significantly stimulate ALP and OC. The mRNA for GHS-R1a receptors and the corresponding protein were detected in calvarial osteoblasts by RT-PCR and Western blot respectively, indicating that ghrelin and GHS may bind and activate this specific receptor. We conclude that endogenous ghrelin and synthetic GHS modulate proliferation and differentiation of rat osteoblasts, probably by acting on their specific receptor.
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Zahner, Gunther, Melanie Schaper, Ulf Panzer, et al. "Prostaglandin EP2 and EP4 receptors modulate expression of the chemokine CCL2 (MCP-1) in response to LPS-induced renal glomerular inflammation." Biochemical Journal 422, no. 3 (2009): 563–70. http://dx.doi.org/10.1042/bj20090420.
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The pro-inflammatory chemokine CCL2 [chemokine (Cys-Cys motif) ligand 2; also known as MCP-1 (monocyte chemotactic protein-1)] is up-regulated in the glomerular compartment during the early phase of LPS (lipopolysaccharide)-induced nephritis. This up-regulation also occurs in cultured MCs (mesangial cells) and is more pronounced in MCs lacking the PGE2 (prostaglandin E2) receptor EP2 or in MCs treated with a prostaglandin EP4 receptor antagonist. To examine a possible feedback mechanism of EP receptor stimulation on CCL2 expression, we used an in vitro model of MCs with down-regulated EP receptor expression. Selectively overexpressing the various EP receptors in these cells then allows the effects on the LPS-induced CCL2 expression to be examined. Cells were stimulated with LPS and CCL2 gene expression was examined and compared with LPS-stimulated, mock-transfected PTGS2 [prostaglandin-endoperoxide synthase 2, also known as COX-2 (cyclo-oxygenase-2)]-positive cells. Overexpression of EP1, as well as EP3, had no effect on LPS-induced Ccl2 mRNA expression. In contrast, overexpression of EP2, as well as EP4, significantly decreased LPS-induced CCL2 expression. These results support the hypothesis that PTGS2-derived prostaglandins, when strongly induced, counter-balance inflammatory processes through the EP2 and EP4 receptors in MCs.
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Kato, Shinichi, Eitaro Aihara, Katsuhide Yoshii, and Koji Takeuchi. "Dual action of prostaglandin E2 on gastric acid secretion through different EP-receptor subtypes in the rat." American Journal of Physiology-Gastrointestinal and Liver Physiology 289, no. 1 (2005): G64—G69. http://dx.doi.org/10.1152/ajpgi.00397.2004.
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We examined the role of prostaglandin E (EP) receptor subtypes in the regulation of gastric acid secretion in the rat. Under urethane anesthesia, the stomach was superfused with saline, and the acid secretion was determined at pH 7.0 by adding 50 mM NaOH. The acid secretion was stimulated by intravenous infusion of histamine or pentagastrin. Various EP agonists were administered intravenously, whereas EP antagonists were given subcutaneously 30 min or intravenously 10 min before EP agonists. PGE2 suppressed the acid secretion stimulated by either histamine or pentagastrin in a dose-dependent manner. The acid inhibitory effect of PGE2 was mimicked by sulprostone (EP1/EP3 agonist) but not butaprost (EP2 agonist) or AE1–329 (EP4 agonist). The inhibitory effect of sulprostone, which was not affected by ONO-8711 (EP1 antagonist), was more potent against pentagastrin- (50% inhibition dose: 3.6 μg/kg) than histamine-stimulated acid secretion (50% inhibition dose: 18.0 μg/kg). Pentagastrin increased the luminal release of histamine, and this response was also inhibited by sulprostone. On the other hand, AE1–329 (EP4 agonist) stimulated the acid secretion in vagotomized animals with a significant increase in luminal histamine. This effect of AE1–329 was totally abolished by cimetidine as well as AE3–208 (EP4 antagonist). These results suggest that PGE2 has a dual effect on acid secretion: inhibition mediated by EP3 receptors and stimulation through EP4 receptors. The former effect may be brought about by suppression at both parietal and enterochromaffin-like cells, whereas the latter effect may be mediated by histamine released from enterochromaffin-like cells.
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Aoi, Masako, Eitaro Aihara, Masato Nakashima, and Koji Takeuchi. "Participation of prostaglandin E receptor EP4 subtype in duodenal bicarbonate secretion in rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 287, no. 1 (2004): G96—G103. http://dx.doi.org/10.1152/ajpgi.00038.2004.
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We examined, by using a specific PGE receptor subtype EP4 agonist and antagonist, the involvement of EP4 receptors in duodenal HCO3− 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 HCO3− 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 acid-induced HCO3− 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 HCO3− response induced by PGE2 or acidification in addition to EP3 receptors. The process by which HCO3− is secreted through these receptors differs regarding second-messenger coupling. Stimulation through EP4 receptors is mediated by cAMP, whereas that through EP3 receptors is regulated by both cAMP and Ca2+; 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.
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Bouayad, Asmàa, Hiroki Kajino, Nahid Waleh, et al. "Characterization of PGE2 receptors in fetal and newborn lamb ductus arteriosus." American Journal of Physiology-Heart and Circulatory Physiology 280, no. 5 (2001): H2342—H2349. http://dx.doi.org/10.1152/ajpheart.2001.280.5.h2342.
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Although the role of PGE2 in maintaining ductus arteriosus (DA) patency is well established, the specific PGE2 receptor subtype(s) (EP) involved have not been clearly identified. We used late gestation fetal and neonatal lambs to study developmental regulation of EP receptors. In the fetal DA, radioligand binding and RT-PCR assays virtually failed to detect EP1 but detected EP2, EP3D, and EP4 receptors in equivalent proportions. In the newborn lamb, DA total density was one-third of that found in the fetus and only EP2 was detected. Stimulation of EP2 and EP4 increased cAMP formation and was associated with DA relaxation. Though stimulation of EP3 inhibited cAMP formation, it surprisingly relaxed the fetal DA both in vitro and in vivo. This EP3-induced relaxation was specifically diminished by the ATP-sensitive K+ (KATP) channel blocker glibenclamide. In conclusion, PGE2 dilates the late gestation fetal DA through pathways that involve either cAMP (EP2 and EP4) or KATP channels (EP3). The loss of EP3 and EP4receptors in the newborn DA is consistent with its decreased responsiveness to PGE2.