scholarly journals Nanomolar EP4 Receptor Potency and Expression of Eicosanoid- Related Enzymes in Normal Appearing Colonic Mucosa From Patients with Colorectal Neoplasia

2021 ◽  
Author(s):  
Ulrike Ries Feddersen ◽  
Sebastian Kjærgaard Hendel ◽  
Mark Alexander Berner-Hansen ◽  
Thomas Andrew Jepps ◽  
Niels Bindslev ◽  
...  
Keyword(s):  
Colonic Mucosa ◽  
Colorectal Neoplasia ◽  
Normal Colonic Mucosa ◽  
Receptor Subtypes ◽  
Mrna Levels ◽  
Ep Receptors ◽  
Ussing Chambers ◽  
Cancer Management ◽  
Ep4 Receptor ◽  
Ep Receptor

Abstract BackgroundAberrations in cyclooxygenase and lipoxygenase (LOX) pathways in non-neoplastic, normal appearing mucosa from patients with colorectal neoplasia (CRN), could hypothetically qualify as predisposing CRN-markers. To test this hypothesis, biopsies were obtained during colonoscopy from macroscopically normal colonic mucosa from patients with and without CRN. Prostaglandin E2 (PGE2) receptors, EP1-4, were examined in Ussing-chambers by exposing biopsies to selective EP receptor agonists, antagonists and PGE2. Furthermore, mRNA expression of EP receptors, prostanoid synthases and LOX enzymes were evaluated using qPCR technology.Results Data suggest that PGE2 binds to high and low affinity EP receptors. In particular, PGE2 demonstrated EP4 receptor potency in the low nanomolar range. Similar results were detected using EP2 and EP4 agonists. In CRN patients, mRNA-levels were higher for EP1 and EP2 receptors and for enzymes prostaglandin-I synthase, 5-LOX, 12-LOX and 15-LOX. ConclusionIn conclusion, normal appearing colonic mucosa from CRN patients demonstrates deviating expression in eicosanoid pathways, indicating a likely predisposition for early CRN development. Moreover, PGE2 potency activates high affinity EP4 receptor subtypes, supporting relevance of testing EP4 antagonists in colorectal cancer management.

PGE2 triggers recovery of transmucosal resistance via EP receptor cross talk in porcine ischemia-injured ileum

2001 ◽  
Vol 281 (2) ◽  
pp. G375-G381 ◽  
Author(s):  
Anthony T. Blikslager ◽  
Susan M. Pell ◽  
Karen M. Young
Keyword(s):  
Cross Talk ◽  
Splice Variants ◽  
Camp Content ◽  
Ep Receptors ◽  
Ussing Chambers ◽  
A 23187 ◽  
Receptor Interactions ◽  
Intracellular Ca ◽  
Ep Receptor ◽  
Receptor Cross Talk

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+.

scholarly journals Activation of Prostaglandin E Receptor 4 Triggers Secretion of Gut Hormone Peptides GLP-1, GLP-2, and PYY

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 45-53 ◽  
Author(s):  
Tamer Coskun ◽  
Libbey S. O’Farrell ◽  
Samreen K. Syed ◽  
Daniel A. Briere ◽  
Lisa S. Beavers ◽  
...  
Keyword(s):  
Peptide Yy ◽  
Hormone Secretion ◽  
Prostaglandin E ◽  
Receptor Subtypes ◽  
Inhibitory Peptide ◽  
Ep Receptors ◽  
L Cells ◽  
Ep4 Receptor ◽  
Gut Hormone ◽  
Glucagon Like Peptide

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.

Identification of specific EP receptors responsible for the hemodynamic effects of PGE2

1999 ◽  
Vol 277 (3) ◽  
pp. H924-H930 ◽  
Author(s):  
Laurent P. Audoly ◽  
Stephen L. Tilley ◽  
Jennifer Goulet ◽  
Mikelle Key ◽  
Mytrang Nguyen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Receptor Subtypes ◽  
Ep Receptors ◽  
Relative Contribution ◽  
Complex Interactions ◽  
Ep Receptor ◽  
Males And Females ◽  
Mixed Groups ◽  
Vasodepressor Response

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.

Differential localization of prostaglandin E receptor subtypes in human kidney

1996 ◽  
Vol 270 (5) ◽  
pp. F912-F918 ◽  
Author(s):  
M. D. Breyer ◽  
L. Davis ◽  
H. R. Jacobson ◽  
R. M. Breyer
Keyword(s):  
In Situ Hybridization ◽  
Collecting Duct ◽  
Human Kidney ◽  
Prostaglandin E ◽  
Receptor Subtypes ◽  
Ep Receptors ◽  
Inner Medullary Collecting Duct ◽  
Ep Receptor ◽  
Medullary Collecting Duct

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.

scholarly journals Transporter function and cyclic AMP turnover in normal colonic mucosa from patients with and without colorectal neoplasia

2012 ◽  
Vol 12 (1) ◽  
Author(s):  
Karen Kleberg ◽  
Gerda Majgaard Jensen ◽  
Dan Ploug Christensen ◽  
Morten Lundh ◽  
Lars Groth Grunnet ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Colonic Mucosa ◽  
Colorectal Neoplasia ◽  
Normal Colonic Mucosa

EP receptor subtypes implicated in the PGE2-induced sensitization of polymodal receptors in response to bradykinin and heat

1996 ◽  
Vol 75 (6) ◽  
pp. 2361-2368 ◽  
Author(s):  
T. Kumazawa ◽  
K. Mizumura ◽  
H. Koda ◽  
H. Fukusako
Keyword(s):  
Receptor Subtypes ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ep Receptors ◽  
Ep1 Receptor ◽  
Ep Receptor ◽  
High Concentrations ◽  
Ep2 Receptor ◽  
Ep3 Receptor

1. Our previous studies, in which we used in vitro canine testispermatic nerve preparations, showed that prostaglandin E2 (PGE2) augments both bradykinin (BK)- and heat-induced discharges of polymodal receptors. However, the PGE2 concentration required to augment the BK responses were 100 times lower than those necessary for the heat responses, suggesting that different receptors are involved in these phenomena. We studied which receptors for E series of prostaglandins (EP receptors) were responsible, using the antagonist and agonists for three subtypes of EP receptors. 2. PGE2-induced augmentation of the BK responses was unaffected when treated with an antagonist for the EP1 receptor, AH6809. 3. An agonist for the EP3 receptor, M&B28767, at > or = 10 nM, significantly augmented the BK responses in a concentration-dependent manner that mimics the PGE2-induced effect. An agonist for the EP1 receptor, 17-phenyl trinor PGE2 (17-phen PGE2), at the high concentrations of 0.1 and 1 microM, augmented the BK responses in two and four of nine cases tested, respectively. However, this augmentation was not suppressed by the antagonist for the EP1 receptor, AH6809. In addition, an agonist for the EP2 receptor, butaprost, did not affect the BK responses even when applied at 10 microM. 4. In contrast, butaprost at > or = 10 nM significantly augmented the heat responses in a concentration-dependent manner. M&B28767 and 17-phen PGE2, respectively, augmented the heat responses at higher concentrations of 100 nM and 1 microM. 5. These results indicate that the EP3 and EP2 receptor subtypesx are differentially implicated in the respective PGE2-induced augmentation of BK responses and heat responses of polymodal receptors.

Abstract TP346: Pge2 Ep1-4 Temporospatial Expression Level Changes in the Brain After Intracerebral Hemorrhage in Young, Aged, and Ep1 Deficient Mice Suggests Cross-talk Interactions

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Jenna L Leclerc ◽  
Andrew R Fadool ◽  
Julie C Bailes ◽  
Chase Chambers ◽  
Sylvain Doré
Keyword(s):  
Intracerebral Hemorrhage ◽  
Cross Talk ◽  
Time Course ◽  
Expression Profiles ◽  
Receptor Expression ◽  
Prostaglandin E ◽  
Mrna Levels ◽  
Expression Levels ◽  
Ep Receptors ◽  
Ep Receptor

Intracerebral hemorrhage (ICH) is the most severe form of stroke with the highest mortality. Neuroinflammation contributes to ICH-induced brain injury and the upregulation of prostaglandin E 2 (PGE 2 ) has been implicated in modulating these deleterious pathways. PGE 2 acts mainly on four G-protein-coupled E Prostanoid (EP) receptors, EP1-4, each having different downstream pathways, tissue distributions, and expression profiles. Our previous studies demonstrate that EP1 receptor deletion promotes injury following ICH; whereas, deletion of EP2 and EP3 is neuroprotective in an equivalent approach. Here, we aimed to investigate the time course, brain sub-region expression profile, and relative level of EP1-4 mRNA expression in young (5-7mo) and aged (12-13mo) wildtype (WT) and EP1-/- mice. Following ICH or sham surgery, EP1-4 mRNA levels were assessed by RT-qPCR whereby the relative fold change of the gene of interest were determined using the reference gene Tbp and the 2 -ΔΔCT method relative to the control. Minimal EP1-4 expression changes are seen at 24h after ICH; although, EP2 (p=0.036) and EP4 (p=0.066) are 1.6X increased in the cortex of young WT mice. At 72h post-ICH, EP1 is 3.9x elevated in the cortex (p=0.0003) and 4.6x in the striatum (p=0.012). EP3 is also 1.6x elevated in the cortex (p=0.044). In the contralateral hemisphere, a mean 2.4x increase of EP1-4 (p<0.01) expression is seen. In contrast, at 72h after ICH, EP1-/- mice have 0.53x reduced EP3 in the cortex (p=0.030) and 0.68x and 0.71x decreased EP3 (p=0.016) and EP4 (p=0.049), respectively, in the contralateral. Aged EP1 -/- mice show significantly decreased expression levels of EP2-4 in nearly all areas. Due to the contralateral differences, basal expression levels of EP2-4 were investigated in the EP1-/- mice, where EP2 is 2.6x, 3.4x, and 3.8x increased in the cortex, hippocampus, and cerebellum; whereas, EP3 trended oppositely. These data indicate a cross talk between EP1 and the other EP receptors pre- and post-ICH and an association between age and EP receptor expression levels. A better understanding of EP receptor localization and dynamic expression levels after ICH will spark the development of effective pharmacological treatments. Funding: NIH F31NS086441 (JLL) and R01NS046400 (SD)

scholarly journals Differential responses to salt supplementation in adult male and female rat adrenal glands following intrauterine growth restriction

2011 ◽  
Vol 209 (1) ◽  
pp. 85-94 ◽  
Author(s):  
Karine Bibeau ◽  
Mélissa Otis ◽  
Jean St-Louis ◽  
Nicole Gallo-Payet ◽  
Michèle Brochu
Keyword(s):  
Protein Expression ◽  
Adrenal Glands ◽  
Salt Intake ◽  
High Salt ◽  
Receptor Subtypes ◽  
Mrna Levels ◽  
Female Rat ◽  
Angiotensin Ii Receptor ◽  
Intrauterine Growth ◽  
High Salt Intake

In low sodium-induced intrauterine growth restricted (IUGR) rat, foetal adrenal steroidogenesis as well as the adult renin–angiotensin–aldosterone system (RAAS) is altered. The aim of the present study was to determine the expression of cytochrome P450 aldosterone synthase (P450aldo) and of angiotensin II receptor subtypes 1 (AT1R) and 2 (AT2R) in adult adrenal glands and whether this expression could be influenced by IUGR and by high-salt intake in a sex-specific manner. After 6 weeks of 0.9% NaCl supplementation, plasma renin activity, P450aldo expression and serum aldosterone levels were decreased in all groups. In males, IUGR induced an increase in AT1R, AT2R, and P450aldo levels, without changes in morphological appearance of the zona glomerulosa (ZG). By contrast, in females, IUGR had no effect on the expression of AT1R, but increased AT2R mRNA while decreasing protein expression of AT2R and P450aldo. In males, salt intake in IUGR rats reduced both AT1R mRNA and protein, while for AT2R, mRNA levels decreased whereas protein expression increased. In females, salt intake reduced ZG size in IUGR but had no affect on AT1R or AT2R expression in either group. These results indicate that, in response to IUGR and subsequently to salt intake, P450aldo, AT1R, and AT2R levels are differentially expressed in males and females. However, despite these adrenal changes, adult IUGR rats display adequate physiological and adrenal responses to high-salt intake, via RAAS inhibition, thus suggesting that extra-adrenal factors likely compensate for ZG alterations induced by IUGR.

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