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)

The biochemistry of visual excitation is kinetically explored by measuring the activity of the cGMP phosphodiesterase (PDE) at light levels that activate only a few tens of rhodopsin molecules per rod. At 23 degrees C and in the presence of ATP, the pulse of PDE activity lasts 4 s (full width at half maximum). Complementing the rod outer segments (ROS) with rhodopsin kinase (RK) and arrestin or its splice variant p44 does not significantly shorten the pulse. But when the ROS are washed, the duration of the signal doubles. Adding either arrestin or p44 back to washed ROS approximately restores the pulse width to its initial value, with p44 being 10 times more efficient than arrestin. This supports the idea that, in vivo, capping of phosphorylated R* is mostly done by p44. When myristoylated (14:0) recoverin is added to unwashed ROS, the pulse duration and amplitude increase by about 50% if the free calcium is 500 nM. This effect increases further if the calcium is raised to 1 microM. Whenever R* deactivation is changed--when RK is exogenously enriched or when ATP is omitted from the buffer--there is no impact on the rising slope of the PDE pulse but only on its amplitude and duration. We explain this effect as due to the unequal competition between transducin and RK for R*. The kinetic model issued from this idea fits the data well, and its prediction that enrichment with transducin should lengthen the PDE pulse is successfully validated.
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PMID:Responses of the phototransduction cascade to dim light. 864 63

Proliferation of vascular smooth muscle cells (SMC) in response to platelet-derived growth factor (PDGF) and other mitogens plays an important role in restenosis following coronary angioplasty. Elevation of adenosine 3',5'-cyclic monophosphate (cAMP) concentration in SMC has been shown to inhibit SMC mitogenesis and could be obtained either directly by stimulation of adenylyl cyclase-coupled receptors or indirectly by inhibition of cAMP-specific phosphodiesterase (PDE4) or the cyclic guanosine 3', 5'-monophosphate-inhibitable phosphodiesterase (PDE3). This study compared the effects of the selective PDE3 inhibitors trequinsin and quazinone with the selective PDE4 inhibitors Ro 20-1724 and rolipram on PDGF-induced DNA synthesis, mitogen-activated protein (MAP) kinase activation, cAMP levels, and protein kinase A (PKA) activation in SMC. Both PDE3 and PDE4 inhibitors stimulated intracellular PKA activation as seen from phosphorylation of vasodilator-stimulated phosphoprotein (VASP). However, only PDE3 inhibitors, and not inhibitors of PDE4, reduced PDGF-induced DNA synthesis and inhibited p42/p44 MAP kinase phosphorylation. At antimitogenic concentrations, the PDE3 inhibitors had only minor effects on cAMP levels. In contrast, PDE4 inhibitors increased the forskolin-induced cellular cAMP concentration 13- to 17-fold above control. These data demonstrate that inhibitors of PDE3 are potent antimitogenic agents and that a general increase in cellular cAMP levels and PKA activation per se are not sufficient to inhibit PDGF-induced SMC mitogenesis.
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PMID:Inhibition of platelet-derived growth factor-induced mitogenesis by phosphodiesterase 3 inhibitors: role of protein kinase A in vascular smooth muscle cell mitogenesis. 1085 33

The inhibitory gamma subunits of the retinal rod and cone photoreceptor type 6 retinal cyclic guanosine monophosphate phosphodiesterase (PDEgamma) are expressed in non-retinal tissues. Here, we show that PDEgamma interacts with the G-protein-coupled receptor kinase 2 signaling system to regulate the epidermal growth factor- and thrombin-dependent stimulation of p42/p44 mitogen-activated protein kinase in human embryonic kidney 293 cells. This is based upon several lines of evidence. First, the transfection of cells with an antisense rod PDEgamma plasmid construct, which reduced endogenous rod PDEgamma expression, ablated the epidermal growth factor- and thrombin-dependent stimulation of p42/p44 mitogen-activated protein kinase. Second, the transfection of cells with recombinant rod or cone PDEgamma and/or G-protein-coupled receptor kinase 2 increased the stimulation of p42/p44 mitogen-activated protein kinase by epidermal growth factor or thrombin. In contrast, a G-protein-coupled receptor kinase 2 phosphorylation-resistant rod PDEgamma mutant failed to increase the epidermal growth factor- or thrombin-dependent stimulation of p42/p44 mitogen-activated protein kinase and, in fact, functioned as a dominant negative. Thrombin also stimulated the association of endogenous rod PDEgamma with dynamin II, which was increased in cells transfected with rod PDEgamma or G-protein-coupled receptor kinase 2. Dynamin II plays a critical role in regulating endocytosis of receptor signal complexes required for activation of p42/p44 mitogen-activated protein kinase. Therefore, PDEgamma may have an important role in promoting endocytosis of receptor signal complexes leading to the activation of p42/p44 mitogen-activated protein kinase. We conclude that PDEgamma is an entirely novel intermediate regulating mitogenic signaling from both receptor tyrosine kinase and G-protein-coupled receptors in human embryonic kidney 293 cells.
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PMID:The inhibitory gamma subunit of the type 6 retinal cyclic guanosine monophosphate phosphodiesterase is a novel intermediate regulating p42/p44 mitogen-activated protein kinase signaling in human embryonic kidney 293 cells. 1150 44

Orthovanadate (vanadate) as well as insulin stimulated phosphodiesterase 3 (PDE3) in the particulate fraction of rat hepatocytes. The vanadate-induced activations of PDE3 and mitogen-activated protein kinase (MAPK) were inhibited by H-89 and PD98059, suggesting that the MAPK activation via cAMP-dependent protein kinase (PKA) and MAPK kinase is involved in the vanadate action. On the other hand, the insulin-induced activations of PDE3 and Akt were inhibited by wortmannin, suggesting involvement of the Akt activation via phosphatidylinositol 3-kinase (PI3K) in the insulin action. The vanadate-induced activations of PKA and PDE3 were inhibited in part by propranolol or genistein, suggesting that vanadate may exert its actions via dual signaling pathways of beta-adrenergic receptors and receptor tyrosine kinases of growth factors. Vanadate, in contrast to insulin, did not promote the phosphorylation of insulin receptor substrate-1. The vanadate-induced increase in the phosphorylation of a main isoform of MAPKs, p44 protein, was detected by immunoblotting migration patterns of SDS-PAGE. A partially purified PDE3 activity was increased by addition of MAPK or Akt to the reaction mixture, suggesting that MAPK as well as Akt acts upstream of PDE3. The activation of PDE3 by insulin was independent of a transient increase in the MAPK activity, probably due to the dephosphorylated inactivation mediated by the induced activation of MAPK phosphatases (MKPs). Vanadate did not affect the MKP activity. These results indicate that vanadate stimulates the particulate PDE3 activity by activating mainly p44 MAPK via a PKA-dependent process, and that it differs from insulin with regard to a phosphorylation cascade of PDE3 activation.
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PMID:Orthovanadate stimulates cAMP phosphodiesterase 3 activity in isolated rat hepatocytes through mitogen-activated protein kinase activation dependent on cAMP-dependent protein kinase. 1518 19

Chlamydophila pneumoniae, an obligately intracellular Gram-negative bacterium and a common causative agent of respiratory tract infections, has been implicated in the induction and progression of atherosclerosis and coronary artery disease. In this study, the signalling mechanism of C. pneumoniae in human fibroblasts, a prominent cell population in chronic inflammation and persistent infection, contributing to plaque formation, was investigated. C. pneumoniae elementary bodies were demonstrated to up-regulate the phosphorylation of p44/p42 mitogen-activated protein kinase (MAPK) in human fibroblasts. The effect was independent of the chlamydial lipopolysaccharide and was likely to be mediated by a heat-labile chlamydial protein. Furthermore, an anti-Toll-like receptor 4 (TLR4) antibody was shown to abolish C. pneumoniae-induced cell activation, whereas an anti-TLR2 antibody had no effect, indicating the role of TLR4 in p44/p42 MAPK activation. Ca2+/calmodulin-dependent protein kinase inhibitor KN-62 and phosphodiesterase 4 (PDE 4) inhibitor Rolipram enhanced C. pneumoniae-induced MAPK phosphorylation and attenuated C. pneumoniae infectivity in vitro. Together the results indicate that C. pneumoniae triggers rapid TLR4-mediated p44/p42 MAPK activation in human fibroblasts and chemical enhancement of MAPK phosphorylation modulates in vitro infection at the molecular level.
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PMID:Chlamydophila pneumoniae induces p44/p42 mitogen-activated protein kinase activation in human fibroblasts through Toll-like receptor 4. 1558 96

It is clear that multiple signalling pathways regulate the critical balance between cell death and survival in myocardial ischaemia-reperfusion. Recent attention has focused on the activation of survival or salvage kinases, particularly during reperfusion, as a common mechanism of many cardioprotective interventions. The phosphatidyl inositol 3'-hydroxy kinase/Akt complex (PI3K/Akt) and p42/p44 mitogen-activated protein kinase cascades have been widely promoted in this respect but the cyclic guanosine 3',5'-monophosphate/cGMP-dependent protein kinase (cGMP/PKG) signal transduction cassette has been less systematically investigated as a survival cascade. We propose that activation of the cGMP/PKG signalling pathway, following activation of soluble or particulate guanylate cyclases, may play a pivotal role in survival signalling in ischaemia-reperfusion, especially in the classical preconditioning, delayed preconditioning and postconditioning paradigms. The resurgence of interest in reperfusion injury, largely as a result of postconditioning-related research, has confirmed that the cGMP/PKG pathway is a pivotal salvage mechanism in reperfusion. Numerous studies suggest that the infarct-limiting effects of preconditioning and postconditioning, exogenously donated nitric oxide (NO), natriuretic peptides, phosphodiesterase inhibitors, and other diverse drugs and mediators such as HMG co-A reductase inhibitors (statins), Rho-kinase inhibitors and adrenomedullin, whether given before and during ischaemia, or specifically at the onset of reperfusion, may be mediated by activation or enhancement of the cGMP pathway, either directly or indirectly via endogenous NO generation downstream of PI3K/Akt. Putative mechanisms of protection include PKG regulation of Ca(2+) homeostasis through the modification of sarcoplasmic reticulum Ca(2+) uptake mechanisms, and PKG-induced opening of ATP-sensitive K(+) channels during ischaemia and/or reperfusion. At present, significant technical obstacles in defining the precise roles played by cGMP/PKG signalling include the heavy reliance on pharmacological PKG inhibitors of uncertain selectivity, difficulties in determining PKG activity in intact tissue, and the growing recognition that intracellular compartmentalisation of the cGMP pool may contribute markedly to the nucleotide's biological actions and biochemical determination. Overall, the body of experimental evidence suggests that cGMP/PKG survival signalling ameliorates irreversible injury associated with ischaemia-reperfusion and may be a tractable therapeutic target.
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PMID:Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion: opportunities and obstacles for survival signaling. 1787 5

Hypercholesterolemia is associated with impaired neovascularization in response to ischemia. Potential mechanisms include defective NO bioactivity and a reduction in the number/function of endothelial progenitor cells (EPCs). Here we tested the hypothesis that sildenafil, a phosphodiesterase 5 inhibitor that increases NO-driven cGMP levels, could stimulate EPC function and improve ischemia-induced neovascularization in hypercholesterolemic conditions. Apolipoprotein E-deficient (ApoE(-/-)) mice were treated (or not treated) with sildenafil (40 mg/kg per day in water), and hindlimb ischemia was surgically induced by femoral artery removal. Sildenafil treatment led to an improved blood flow recovery, an increased capillary density, and a reduction of oxidative stress levels in ischemic muscles at day 7 after surgery. Sildenafil therapy is associated with an increased activation of angiogenic transduction pathways, including Akt, p44/42 mitogen-activated protein kinase, and p38. In vitro, sildenafil increases cellular migration and tubule formation of mature endothelial cells (human umbilical vascular endothelial cells) in a cGMP-dependent manner. In vivo, ApoE(-/-) mice treated with sildenafil exhibit a significant increase in the number of bone marrow-derived EPCs. Moreover, the angiogenic activities of EPCs (migration and adhesion) are significantly improved in ApoE(-/-) mice treated with sildenafil. In summary, this study demonstrates that sildenafil treatment is associated with improved ischemia-induced neovascularization in hypercholesterolemic ApoE(-/-) mice. The mechanisms involve beneficial effects on angiogenic transduction pathways together with an increase in the number and the functional activity of EPCs. Sildenafil could constitute a novel therapeutic strategy to reduce tissue ischemia in atherosclerotic diseases.
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PMID:Sildenafil increases endothelial progenitor cell function and improves ischemia-induced neovascularization in hypercholesterolemic apolipoprotein E-deficient mice. 1977 Apr

The chemotaxis and adhesion of monocytes to the injured endothelium in the early atherosclerosis is important. Cilostazol, a specific phosphodiesterase type III inhibitor, is known to exhibit anti-atherosclerotic effects mediated by different mechanisms. This study aimed to investigate the modulating effect of cilostazol on the MCP-1-induced chemotaxis and adhesion of monocytes. The gene expression of CCR2, the major receptor of MCP-1 in THP-1 monocytes, was also analyzed. The chemotaxis of monocytes toward MCP-1 was investigated using the transwell filter assay. Cilostazol dose-dependently inhibited the MCP-1-induced chemotaxis of monocytes which was shown to be cAMP-dependent. Using western blot analysis and flow cytometry method, we demonstrated the decrease of CCR2 protein at the cell membrane of monocytes by cilostazol treatment. Results from RT/real-time PCR confirmed the decrease of CCR2 mRNA expression by cilostazol which was also mediated by cAMP. Similar inhibition was also noted in human peripheral monocytes. The post-CCR2 signaling pathways including p44/42 and p38 MAPK were examined by western blot analysis. Result confirmed the inhibitory effect of cilostazol on the phosphorylation of p44/42 and p38 MAPK after MCP-1 stimulation. The activation of monocytes after MCP-1 treatment exhibited enhanced adhesion to vascular endothelial cells which was dose-dependently suppressed by cilostazol. Together, cilostazol was demonstrated, for the first time, to inhibit the CCR2 gene expression and MCP-1-induced chemotaxis and adhesion of monocytes which might therefore reduce the infiltration of monocytes during the early atherosclerosis. The present study provides an additional molecular mechanism underlying the anti-atherosclerotic effects of cilostazol.
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PMID:Cilostazol reduces MCP-1-induced chemotaxis and adhesion of THP-1 monocytes by inhibiting CCR2 gene expression. 2175 80

Theobromine, a caffeine derivative, is the primary methylxanthine produced by Theobroma cacao. We previously showed that methylxanthines, including caffeine and theophylline, have antitumor and antiinflammatory effects, which are in part mediated by their inhibition of phosphodiesterase (PDE). A member of the PDE family, PDE4, is widely expressed in and promotes the growth of glioblastoma, the most common type of brain tumor. The purpose of this study was to determine whether theobromine could exert growth inhibitory effects on U87-MG, a cell line derived from human malignant glioma. We show that theobromine treatment elevates intracellular cAMP levels and increases the activity of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, whereas it attenuates p44/42 extracellular signal-regulated kinase activity and the Akt/mammalian target of rapamycin kinase and nuclear factor-kappa B signal pathways. It also inhibits cell proliferation. These results suggest that foods and beverages containing cocoa bean extracts, including theobromine, might be extremely effective in preventing human glioblastoma.
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PMID:Theobromine, the primary methylxanthine found in Theobroma cacao, prevents malignant glioblastoma proliferation by negatively regulating phosphodiesterase-4, extracellular signal-regulated kinase, Akt/mammalian target of rapamycin kinase, and nuclear factor-kappa B. 2454 61

Ras-p44/42 mitogen-activated protein kinase (MAPK) and Akt signaling are the key pathways involved in the promotion of glioblastoma formation. Notably, phosphodiesterase 4 (PDE4) is widely expressed in brain tumors and promotes their growth. PDE4 inhibitors have been reported to suppress glioblastoma growth in vitro and in vivo. The mechanisms underlying these actions, however, have yet to be elucidated. The aim of this study was to investigate whether intracellular cyclic adenosine monophosphate (cAMP) was able to suppress the Ras-p44/42 MAPK signaling pathway via protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac) in U87MG human malignant glioma cells. Forskolin, an activator of adenylate cyclase, inhibited cell growth and the phosphorylation of p44/42 MAPK in U87MG cells, whereas the non-hydrolyzable cAMP analog 8-bromoadenosine 3',5'-cAMP (8-Br-cAMP) considerably suppressed cell growth and phosphorylation of p44/42 MAPK. The inhibitory effects of forskolin were partially prevented by the PKA inhibitor H89. The Epac-selective agonist 8-(4-chlorophenylthio)-2'-O-methyladenosine cAMP (8-CPT-cAMP) inhibited phosphorylation of p44/42 MAPK. These findings suggest that PKA and Epac are involved in the effect of intracellular cAMP on the Ras-p44/42 MAPK signaling pathway.
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PMID:Targeted activation of PKA and Epac promotes glioblastoma regression in vitro. 2464 61


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