Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta2-adrenergic receptor (beta2AR) agonists acutely relieve bronchoconstriction via cAMP-mediated relaxation of airway smooth muscle (ASM). Airway constrictor responsiveness may be significantly heightened, however, following protracted exposure to these agents, presumably reflecting the effects of beta2AR desensitization in ASM accompanying prolonged cAMP signaling. Because cAMP phosphodiesterase (PDE) activity can significantly modulate ASM contractility, we investigated the mechanism regulating PDE expression and its potential role in mediating changes in agonist-induced constrictor and relaxation responsiveness in ASM following its heterologous beta2AR desensitization by prolonged exposure to cAMP-elevating agents. Isolated rabbit ASM tissues and cultured human ASM cells treated for 24 h with the receptor- or nonreceptor-coupled cAMP-stimulating agent, prostaglandin E(2) (PGE(2)) or forskolin, respectively, exhibited constrictor hyperresponsiveness to acetylcholine and impaired beta2AR-mediated relaxation and cAMP accumulation. These proasthmatic-like changes in ASM function were associated with upregulated PDE4 activity, reflective of increased transcription of the PDE4D5 isoform, and were prevented by pretreatment of the ASM with a PDE4 inhibitor. Extended studies using gene silencing and pharmacological approaches to inhibit specific intracellular signaling molecules demonstrated that the mechanism underlying PGE(2)-induced transcriptional upregulation of PDE4D5 involves PKA-dependent activation of G(i) protein signaling via the betagamma-subunits, the latter eliciting downstream activation of ERK1/2 and its consequent induction of PDE4D5 transcription. Collectively, these findings identify that beta2AR desensitization in ASM following prolonged exposure to cAMP-elevating agents is associated with proasthmatic-like changes in ASM responsiveness that are mediated by upregulated PDE4 expression induced by activated cross talk between the PKA and ERK1/2 signaling pathways.
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PMID:Prolonged heterologous beta2-adrenoceptor desensitization promotes proasthmatic airway smooth muscle function via PKA/ERK1/2-mediated phosphodiesterase-4 induction. 1835 89

(+/-)-(E)-4-Ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide] (NOR-3), a nitric-oxide (NO) donor, is known to increase HCO(3)(-) secretion in rat stomachs, intracellularly mediated by cGMP; yet, there is no information about the phosphodiesterase (PDE) isozyme involved in this process. We examined the effects of various isozyme-selective PDE inhibitors on the secretion of HCO(3)(-) in the mouse stomach in vitro and the type(s) of PDE isozymes involved in the response to NO. The gastric mucosa of DDY mice was stripped of the muscle layer and mounted on an Ussing chamber. HCO(3)(-) secretion was measured at pH 7.0 using a pH-stat method and by adding 2 mM HCl. NOR-3, 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP), and various PDE inhibitors were added to the serosal side. Vinpocetine (PDE1 inhibitor) or zaprinast (PDE5 inhibitor) was also added serosally 30 min before NOR-3 or 8-Br-cGMP. Both NOR-3 and 8-Br-cGMP stimulated HCO(3)(-) secretion in a dose-dependent manner, and the response to NOR-3 was significantly inhibited by methylene blue. Likewise, the secretion induced by NOR-3 or 8-Br-cGMP was significantly attenuated by 6-((2S,3S)-3-(4-chloro-2-methylphenylsulfonylaminomethyl)-bicyclo(2.2.2)octan-2-yl)-5Z-hexenoic acid (ONO-8711), the PGE receptor (EP)1 antagonist, as well as indomethacin and potentiated by both vinpocetine and zaprinast at doses that had no effect by themselves on the basal secretion, whereas other subtype-selective PDE inhibitors had no effect. NOR-3 increased the mucosal PGE(2) content in a methylene blue-inhibitable manner. These results suggest that NO stimulates gastric HCO(3)(-) secretion mediated intracellularly by cGMP and modified by both PDE1 and PDE5, and this response is finally mediated by endogenous PGE(2) via the activation of EP1 receptors.
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PMID:Phosphodiesterase isozymes involved in regulation of formula secretion in isolated mouse stomach in vitro. 1855 Jun 92

Prostaglandin E(2) (PGE(2)) is the major vasodilator prostanoid of the mammalian ductus arteriosus (DA). In the present study we analyzed the response of isolated DA rings from 15-, 19- and 21-day-old chicken embryos to PGE(2) and other vascular smooth muscle relaxing agents acting through the cyclic AMP signaling pathway. PGE(2) exhibited a relaxant response in the 15-day DA, but not in the 19- and 21-day DA. Moreover, high concentrations of PGE(2) (>or= 3 microM in 15-day and >or= 1 microM in 19-day and 21-day DA) induced contraction of the chicken DA. The presence of the TP receptor antagonist SQ29,548, unmasked a relaxant effect of PGE(2) in the 19- and 21-day DA and increased the relaxation induced by PGE(2) in the 15-day DA. The presence of the EP receptor antagonist AH6809 abolished PGE(2)-mediated relaxation. The relaxant responses induced by PGE(2) and the beta-adrenoceptor agonist isoproterenol, but not those elicited by the adenylate cyclase activator forskolin or the phosphodiesterase 3 inhibitor milrinone, decreased with maturation. High oxygen concentrations (95%) decreased the relaxation to PGE(2). The relaxing potency and efficacy of isoproterenol and milrinone were higher in the pulmonary than in the aortic side of the DA, whereas no regional differences were found in the response to PGE(2). We conclude that, in contrast to the mammalian situation, PGE(2) is a weak relaxant agent of the chicken DA and, with advancing incubation, it even stimulates TP vasoconstrictive receptors.
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PMID:Developmental changes in the effects of prostaglandin E2 in the chicken ductus arteriosus. 1872 1

Monocytes/macrophages committed to death by peroxynitrite nevertheless survive with a signaling response promoting Bad phosphorylation, as well as its cytosolic localization, via upstream activation of cytosolic phospholipase A(2), 5-lipoxygenase, and protein kinase C alpha. We now report evidence for an alternative mechanism converging in Bad phosphorylation when the expression/activity of the above enzymes are suppressed. Under these conditions, also associated with peroxynitrite-dependent severe inhibition of Akt, an additional Bad kinase, Bad dephosphorylation promoted its accumulation in the mitochondria and a prompt lethal response. PGE(2) prevented toxicity via EP(2) receptor-mediated protein kinase A-dependent Bad phosphorylation. This notion was established in U937 cells by the following criteria: 1) there was a strong correlation between survival and cAMP accumulation, both in the absence and presence of phosphodiesterase inhibitors; 2) direct activation of adenylyl cyclase afforded cytoprotection; and 3) PGE(2) promoted loss of mitochondrial Bad and cytoprotection, mimicked by EP(2) receptor agonists, and prevented by EP(2) receptor antagonists or protein kinase A inhibitors. Finally, selected experiments performed in human monocytes/macrophages and in rat peritoneal macrophages indicated that the above cytoprotective pathway is a general response of cells belonging to the monocyte/macrophage lineage to both exogenous and endogenous peroxynitrite. The notion that two different pathways mediated by downstream products of arachidonic acid metabolism converge in Bad phosphorylation emphasizes the relevance of this strategy for the regulation of macrophage survival to peroxynitrite at the inflammatory sites.
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PMID:Prostaglandin E2 signals monocyte/macrophage survival to peroxynitrite via protein kinase A converging in bad phosphorylation with the protein kinase C alpha-dependent pathway driven by 5-hydroxyeicosatetraenoic acid. 1883 22

Extracts of Tanacetum parthenium (L.) Sch. Bip., a plant known under the common name "Feverfew", contains the sesquiterpene lactone parthenolide, a potent skin sensitizer. To eliminate the risk of skin sensitization from Feverfew, we developed a parthenolide-depleted extract of Feverfew (PD-Feverfew) and determined its effectiveness as an anti-inflammatory agent. We confirmed that PD-Feverfew was sufficiently depleted of parthenolide since PD-Feverfew did not inhibit TNF-alpha induced-NF-kappaB activity unlike parthenolide containing whole Feverfew. PD-Feverfew directly inhibited the activity of pro-inflammatory enzymes 5-lipoxygenase, phosphodiesterase-3 and phosphodiesterase-4. PD-Feverfew inhibited the release of pro-inflammatory mediators nitric oxide, PGE(2) and TNF-alpha from macrophages and TNF-alpha, IL-2, IFN-gamma and IL-4 from human peripheral blood mononuclear cells. Additionally, PD-Feverfew inhibited TPA-induced release of PGE(2) from human skin equivalents. In vivo, PD-Feverfew inhibited oxazolone-induced dermatitis, and was more potent than whole Feverfew in reducing TPA-induced dermatitis. Finally the efficacy of PD-Feverfew was confirmed clinically by a reduction in erythema in a methyl nicotinate-induced vasodilation model. In conclusion, our results indicate that PD-Feverfew extracts have potent anti-inflammatory activity suggesting that this botanical would be efficacious in relieving inflammation without inducing immune sensitization.
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PMID:Anti-inflammatory activity of parthenolide-depleted Feverfew (Tanacetum parthenium). 1911 86

The elevation of [cAMP](i) is an important mechanism of platelet inhibition and is regulated by the opposing activity of adenylyl cyclase and phosphodiesterase (PDE). In this study, we demonstrate that a variety of platelet agonists, including thrombin, significantly enhance the activity of PDE3A in a phosphorylation-dependent manner. Stimulation of platelets with the PAR-1 agonist SFLLRN resulted in rapid and transient phosphorylation of PDE3A on Ser(312), Ser(428), Ser(438), Ser(465), and Ser(492), in parallel with the PKC (protein kinase C) substrate, pleckstrin. Furthermore, phosphorylation and activation of PDE3A required the activation of PKC, but not of PI3K/PKB, mTOR/p70S6K, or ERK/RSK. Activation of PKC by phorbol esters also resulted in phosphorylation of the same PDE3A sites in a PKC-dependent, PKB-independent manner. This was further supported by the finding that IGF-1, which strongly activates PI3K/PKB, but not PKC, did not regulate PDE3A. Platelet activation also led to a PKC-dependent association between PDE3A and 14-3-3 proteins. In contrast, cAMP-elevating agents such as PGE(1) and forskolin-induced phosphorylation of Ser(312) and increased PDE3A activity, but did not stimulate 14-3-3 binding. Finally, complete antagonism of PGE(1)-evoked cAMP accumulation by thrombin required both G(i) and PKC activation. Together, these results demonstrate that platelet activation stimulates PKC-dependent phosphorylation of PDE3A on Ser(312), Ser(428), Ser(438), Ser(465), and Ser(492) leading to a subsequent increase in cAMP hydrolysis and 14-3-3 binding.
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PMID:Protein kinase C-mediated phosphorylation and activation of PDE3A regulate cAMP levels in human platelets. 1926 11

Abscess formation is a classic host response to infection by many pathogenic microorganisms. Here, we studied the role of prostaglandins (PGs) and their signal transduction in abscess formation. Zymosan was injected into the pleural cavity of rats. Expression of enzymes involved in PG synthesis, their receptors, and cytokines in exudate leukocytes and abscesses were analyzed by polymerase chain reaction, Western blotting, and immunohistochemistry. Treatment with ketorolac, a cyclooxygenase (COX)-1 inhibitor, or N-[2-cyclohexyloxy-4-nitrophenyl] methanesulfonamide (NS-398), a COX-2 inhibitor, reduced the size of abscesses and the number of cells recovered from the abscess. COX-2 was detected in leukocytes of the exudate and a marginal area of abscesses. Among detected terminal PG synthases, the major one was cytosolic PGE synthase. Membrane-bound PGE synthase (mPGES)-1 was detected in cells that were similar to the COX-2-expressing cells in morphology and localization. A high level of the E-prostanoid (EP)(2) receptor and a low level of the EP(4) receptor were detected. The expression pattern of the EP(2) receptor paralleled that of COX-2 and mPGES-1. 11,15-O-Dimethyl PGE(2) (ONO-AE1-259), an EP(2) receptor agonist, and rolipram, a phosphodiesterase type-4 inhibitor, reversed the effects of COX inhibitors on abscess formation. In contrast, 16-(3-methoxymethyl) phenyl-omega-tetranor-3,7-dithia PGE(1) (ONO-AE1-329), an EP(4) receptor agonist, did not reverse the effects of NS-398. Moreover, NS-398 reduced the mRNA levels in exudate leukocytes of some proinflammatory and fibrogenic cytokines, which was reversed by ONO-AE1-259. These results suggest that PGE(2) generated via COX-1 and COX-2 may interact with the EP(2) receptor and may up-regulate in cAMP-dependent fashion the production of cytokines that promote abscess formation.
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PMID:Contribution of the prostaglandin E2/E-prostanoid 2 receptor signaling pathway in abscess formation in rat zymosan-induced pleurisy. 1972 96

Macrophages are central mediators of the innate immune system that can be differentiated from monocytes upon exposure to cytokines. While increased cyclic adenosine monophosphate (cAMP) levels are known to inhibit many lipopolysaccharide-elicited macrophage inflammatory responses, the effects of elevated cAMP on monocyte/macrophage differentiation are not as well understood. We show here that during differentiation, cAMP agonists can cause a large increase in the mRNA and protein levels of several of the pro-inflammatory CXCL and CCL chemokines. The cAMP mediator-exchange protein activated by cAMP (Epac) contributes substantially to the increase in these chemokines. These chemokines are known to play an important role in the regulation of immune responses, particularly regarding the pathogenesis of asthma and chronic obstructive pulmonary disorder. We also found that a selective cAMP-degrading phosphodiesterase (PDE) 4 inhibitor can potentiate the chemokine expression elicited by low-dose forskolin or Prostaglandin E2 (PGE(2)). These data suggest that chemokine receptor antagonists administered in conjunction with a PDE4 inhibitor may improve both the efficacy and safety of PDE4-inhibitor therapy for chronic inflammatory disorders.
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PMID:Elevated cyclic AMP and PDE4 inhibition induce chemokine expression in human monocyte-derived macrophages. 1995 69

Interleukin-1beta (IL-1beta) and basic fibroblast growth factor (bFGF) are important regulators of proliferation, and their expression is increased in lungs of patients with asthma, idiopathic pulmonary fibrosis (IPF), or chronic obstructive pulmonary disease (COPD). We investigated the effect of IL-1beta and bFGF on proliferation of human lung fibroblasts and the role of COX-2, PGE(2), and cAMP in this process. Furthermore, the effect of phosphodiesterase (PDE) 3 and 4 inhibition was analyzed. In primary human lung fibroblasts low concentrations of IL-1beta (<10 pg/ml) potentiated the bFGF-induced DNA synthesis, whereas higher concentrations revealed antiproliferative effects. Higher concentrations of IL-1beta-induced COX-2 mRNA and protein associated with an increase in PGE(2) and cAMP, and all of these parameters were potentiated by bFGF. The PDE4 inhibitor piclamilast concentration-dependently reduced proliferation by a partial G1 arrest. The PDE3 inhibitor motapizone was inactive by itself but enhanced the effect of the PDE4 inhibitor. This study demonstrates that bFGF and IL-1beta act in concert to fine-tune lung fibroblast proliferation resulting in amplification or reduction. The antiproliferative effect of IL-1beta is likely attributed to the induction of COX-2, which is further potentiated by bFGF, and the subsequent generation of PGE(2) and cAMP. Inhibition of PDE4 inhibition (rather than PDE3) may diminish proliferation of human lung fibroblasts and therefore could be useful in the therapy of pathological remodeling in lung diseases.
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PMID:Cytokine-dependent balance of mitogenic effects in primary human lung fibroblasts related to cyclic AMP signaling and phosphodiesterase 4 inhibition. 2008 9

Gastroduodenal HCO(3)(-) secretion is a key process that aids in preventing acid-peptic injury. The HCO(3)(-) secretion in rats and mice was increased in response to PGE(2) as well as mucosal acidification, the latter response occurring with a concomitant enhancement of mucosal PG production. The duodenal responses to PGE(2) and acid were decreased in mice lacking EP3 receptors and reduced by coadministration of an EP3 or EP4 antagonist in rats, complete inhibition being observed when the EP3 and EP4 antagonists were given together. By contrast, the gastric responses disappeared in EP1-knockout mice and were prevented by an EP1 antagonist but not other EP antagonists. Furthermore, duodenal HCO(3)(-) secretion was stimulated by the EP3 and EP4 agonists, whereas gastric HCO(3)(-) secretion was increased only by the EP1 agonist. In addition, the HCO(3)(-) stimulatory effect of sulprostone (an EP1/EP3 agonist) in the duodenum was inhibited by verapamil, a Ca(2+) antagonist, and enhanced by isobutyl- methylxanthine, a phosphodiesterase (PDE) inhibitor, but the response in the stomach was inhibited by verapamil and not affected by isobutylmethylxanthine. In the mouse duodenum but not stomach, the response to PGE(2) was potentiated by both vinpocetine (a PDE1 inhibitor) and cilostamide (a PDE3 inhibitor). These results suggest that the HCO(3)(-) stimulatory effect of PGE(2) in the duodenum is mediated by both EP3 and EP4 receptors, being coupled intracellularly with Ca(2+) and cAMP, while that in the stomach is mediated by EP1 receptors, coupled with Ca(2+). In addition, both PDE1 and PDE3 are involved in the regulation of duodenal HCO(3)(-) secretion.
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PMID:Prostaglandin EP receptor subtypes involved in regulating HCO(3)(-) secretion from gastroduodenal mucosa. 2016 95


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