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)

Calmodulin (CaM)-dependent enzymes, such as CaM-dependent phosphodiesterase (CaM-PDE), CaM-dependent protein phosphatase (CN), and CaM-dependent protein kinase II (CaM kinase II), are found in high concentrations in differentiated mammalian neurons. In order to determine whether neuroblastoma cells express these CaM-dependent enzymes as a consequence of cellular differentiation, a series of experiments was performed on human SMS-KCNR neuroblastoma cells; these cells morphologically differentiate in response to retinoic acid and phorbol esters [12-O-tetradecanoylphorbol 13-acetate (TPA)]. Using biotinylated CaM overlay procedures, immunoblotting, and protein phosphorylation assays, we found that SMS-KCNR cells expressed CN and CaM-PDE, but did not appear to have other neuronal CaM-binding proteins. Exposure to retinoic acid, TPA, or conditioned media from human HTB-14 glioma cells did not markedly alter the expression of CaM-binding proteins; 21-day treatment with retinoic acid, however, did induce expression of novel CaM-binding proteins of 74 and 76 kilodaltons. Using affinity-purified polyclonal antibodies, CaM-PDE immunoreactivity was detected as a 75-kilodalton peptide in undifferentiated cells, but as a 61-kilodalton peptide in differentiated cells. CaM kinase II activity and subunit autophosphorylation was not evident in either undifferentiated or neurite-bearing cells; however, CaM-dependent phosphatase activity was seen. Immunoblot analysis with affinity-purified antibodies against CN indicated that this enzyme was present in SMS-KCNR cells regardless of their state of differentiation. Although SMS-KCNR cells did not show a complete pattern of neuronal CaM-binding proteins, particularly because CaM kinase II activity was lacking, they may be useful models for examination of CaM-PDE and CN expression. It is possible that CaM-dependent enzymes can be used as sensitive markers for terminal neuronal differentiation.
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PMID:Expression of calmodulin-dependent phosphodiesterase, calmodulin-dependent protein phosphatase, and other calmodulin-binding proteins in human SMS-KCNR neuroblastoma cells. 254 Feb 70

[3H]LY186126, an analogue of the cardiotonic agent indolidan, was shown to bind reversibly and with high affinity (Kd = 4 nM) to a single class of binding sites within canine myocardial vesicles. Binding site density measured in various cardiac membrane fractions correlated well with Ca2+-ATPase activity (r = 0.94; p less than 0.01), but not with Na+,K+-ATPase or azide sensitive ATPase, indicating a localization of these sites within sarcoplasmic reticulum membranes. Divalent cations were required for binding and displayed the following order of activation: Zn2+ greater than Mn2+ greater than Mg2+ greater than Ca2+. Differential activation of [3H]LY186126 binding by various divalent cations was due to alterations in binding site density, rather than affinity. cGMP and selective inhibitors of type IV membrane-bound phosphodiesterase (SR-PDE), for example, indolidan, milrinone, imazodan, and enoximone, selectively displaced bound [3H]LY186126 caffeine, theophylline, and rolipram were relatively impotent as inhibitors of radiolabel binding. Kd values from displacement curves were highly correlated with IC50 values for inhibition of SR-PDE (r = 0.92; p less than 0.001). In addition, Kd values correlated well with published ED50 values for increases in cardiac contractility in pentobarbital-anesthetized dogs (r = 0.94; p less than 0.001). The results support the hypothesis that [3H]LY186126 labels the pharmacological receptor for the class of positive inotropic agents characterized as isozyme-selective phosphodiesterase inhibitors. Furthermore, the data suggest that the identity of the site labeled by [3H]LY186126 is SR-PDE, the type IV isozyme of cardiac phosphodiesterase located in the sarcoplasmic reticulum.
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PMID:Characterization and pharmacological relevance of high affinity binding sites for [3H]LY186126, a cardiotonic phosphodiesterase inhibitor, in canine cardiac membranes. 254 18

Distributions and activities of both cyclic adenosine 3',5'-monophosphate phosphodiesterase and cyclic guanosine 3',5'-monophosphate phosphodiesterase (cAMP-PDE and cGMP-PDE) in 43 human stomach cancer tissues were studied histochemically. The relationship between cyclic nucleotide phosphodiesterases and some patho-biologic behaviors of stomach cancer was preliminarily discussed, and so was the application of these two enzymes in clinical practice of gastric cancers. The Results showed that the two cyclic nucleotide phosphodiesterases were closely correlated with some patho-biologic behaviors of stomach cancer. The authors considered that the histochemical investigation of cyclic nucleotide phosphodiesterases in stomach cancer tissues can be useful in determining the malignant degree and estimating the prognosis of stomach cancer objectively.
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PMID:[Relationship between cyclic nucleotide phosphodiesterases (cPDE) and some patho-biologic behaviors of stomach cancer--I. Histochemical studies of CPDE in stomach cancer tissues]. 255 63

Cross-linking of surface IgM or IgD receptors on B cells initiates a signaling cascade involving the activation of an (uncharacterized) G-protein: this in turn activates a polyphosphoinositide-specific phosphodiesterase (PPI-PDE), thereby leading to the release of inositol phosphates. In order to investigate if the two isotypes of sIg share a common G-protein, we stimulated B cells sequentially with anti-mu and anti-delta antibodies. Ligation of either class of receptor for 1 h led to the activation of the PPI-PDE, which persisted for several hours. However, this was accompanied by inhibition of further stimulation of the enzyme via the heterologous receptors. This desensitization was shown to operate at the level of the coupling between G-protein and the PPI-PDE. These effects waned after 4-8 h of stimulation, when signaling via the heterologous receptors had essentially returned to normal. In addition, stimulation of B cells by anti-mu and anti-delta together did not elicit additive responses, either in terms of increases in inositol phosphate production, or in terms of increases in intracellular Ca2+ levels. Taken together, these results indicate that sIgM and IgD receptors share a common G-protein and that signaling via these receptors is under both positive and negative feedback control. The mechanisms involved are unknown, but these effects may well be due to modulation of the activities of components of the signaling cascade by protein kinase C.
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PMID:Regulation of surface IgM- and IgD-mediated inositol phosphate formation and Ca2+ mobilization in murine B lymphocytes. 255 96

3':5'-Cyclic nucleotide phosphodiesterase was isolated from human brain and characterized. After the first stage of purification on phenyl-Sepharose, the enzyme activity was stimulated by Ca2+ and micromolar concentrations of cGMP. High pressure liquid chromatography on a DEAE-TSK-3SW column permitted to identify three ranges of enzymatic activity designated as PDE I, PDE II and PDE III. Neither of the three enzymes possessed a high selectivity for cAMP and cGMP substrates. The catalytic activity of PDE I and PDE II increased in the presence of Ca2+-calmodulin (up to 6-fold); the degradation of cAMP was decreased by cGMP. The Ca2+-calmodulin stimulated PDE I and PDE II activity was decreased by W-7. PDE I and PDE II can thus be classified as Ca2+-calmodulin-dependent phosphodiesterases. With cAMP as substrate, the PDE III activity increased in the presence of micromolar concentrations of cGMP (up to 10-fold), Ca2+ and endogenous calmodulin (up to 2-3-fold). No additivity in the effects of saturating concentrations of these compounds on PDE III was observed. Ca2+ did not influence the rate of cGMP hydrolysis catalyzed by PDE III. In comparison with PDE I and PDE II, the inhibition of PDE III was observed at higher concentrations of W-7 and was not limited by the basal level of the enzyme. These results do not provide any evidence in favour of the existence of several forms of the enzyme in the PDE III fraction. The double regulation of PDE III creates some difficulties for its classification.
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PMID:[3',5'-cyclic nucleotide phosphodiesterase from human brain]. 255 85

We have investigated the effects of imazodan, a potent inhibitor of phosphodiesterase III (PDE III) and dazoxiben, a selective inhibitor of thromboxane synthetase on cAMP levels and PGI2 production in cultured bovine aortic endothelial cells by radioimmunoassay. When cultured endothelial cells were incubated with imazodan, intracellular levels of cAMP were increased in a dose-dependent manner. PGI2 production induced by arachidonic acid (AA) was not affected by imazodan 0.1-10 mumol/L. But imazodan 100 mumol/L caused a 35% inhibition of PGI2 production. In the presence of AA, dazoxiben could also elevate intracellular levels of cAMP. Furthermore, dazoxiben 1-10 mumol/L caused a marked increase in PGI2 production, but 1000 mumol/L inhibited PGI2 production.
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PMID:[Effects of imazodan and dazoxiben on cAMP levels and PGI2 production in cultured bovine aortic endothelial cells]. 255 80

The enantiomers of the positive inotropic and a1-adrenoceptor blocking agent saterinone (+/-)-1,2-dihydro-5-[4-[2-hydroxy-3- [4-(2-methoxyphenyl)-1-piperazinyl]propoxy] phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) have been investigated with in vitro and in vivo models in laboratory animals. In the guinea pig papillary muscle, saterinone enantiomers had equipotent inotropic activity and were also as potent as racemic saterinone; the (R)-enantiomer, however, exhibited a greater efficacy than the related compounds. Saterinone and its enantiomers were equipotent in the inhibition of phosphodiesterase PDE III activity in the guinea pig myocardium. The equipotent inotropic effects were also observed after parenteral and enteral administration in cats. In receptor binding studies, (S)-saterinone was 10-fold more potent than (R)-saterinone by inhibiting [3H]-prazosin binding to specific alpha 1-adrenoceptor sites in rat brain cortex membranes. However, in the isolated thoracic aorta of the rabbit, (S)-saterinone was only 3-fold more potent than (R)-saterinone at preventing the pressor effects of phenylephrine. When the enantiomers were tested in vivo against the pressor effects of phenylephrine in the pithed rat, (S)-saterinone was only 2-fold more potent than (R)-saterinone in its alpha 1-adrenoceptor blocking potency. Thus the enantiomers of saterinone do not display enantio-selectivity in their inotropic and PDE III inhibitory effects in vitro, nor in their cardiotonic effects in vivo. There is a slight enantio-selectivity at alpha 1-adrenoceptors in receptor binding studies, but this is reduced to biologically irrelevant magnitude in functional studies in vitro and in vivo.
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PMID:Lack of stereoselectivity in the inotropic and phosphodiesterase inhibitory effects of saterinone enantiomers. 255 38

S-antigen (48-kDa protein) is a soluble protein of the retina and the pineal gland that is believed to play an important role in the visual process. S-antigen is involved in the regulation of the activity of rod photoreceptor-specific cGMP-phosphodiesterase (cGMP-PDE). The activity of this enzyme has been shown to be deficient in the retina of the rd mouse, which is affected by an autosomal recessive disease characterized by degeneration of the photoreceptor cells. The abnormal cGMP-PDE activity could result from, among other things, a lesion in the enzyme itself or in any of the proteins that regulate it, such as the S-antigen. We have used a mouse cDNA clone for the S-antigen to map the corresponding gene, Sag, to mouse chromosome 1 near Idh-1. Since the rd gene is located on mouse chromosome 5, our results suggest that Sag is not the site of the rd mutation.
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PMID:The gene for retinal S-antigen (48-kDa protein) maps to the centromeric portion of mouse chromosome 1 near Idh-1. 257 83

Published c-AMP phosphodiesterase inhibitory activities of 7-substituted-1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolines are used in a QSAR study to analyse a proposed model of the c-AMP PDE (type IV) active site. Based on the regression equations involving hydrophobic parameters and activities, additional subsites G1 and G2 are identified in the secondary binding region G, and steric hydrophobic tolerance at these subsites is discussed.
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PMID:QSAR study of phosphodiesterase inhibitory activity of imidazo[2,1-b]-quinazolines: active site analysis. 257 89

Cyclic 3':5'-adenosinmonophosphate phosphodiesterase (cAMP-PDE), high KM value type isoenzyme, and cyclic 3':5'-guanosino-monophosphate phosphodiesterase (cGMP-PDE), high KM value type isoenzyme, were determined in granulocytes of patients with chronic myelogenous leukemia (CML) in the chronic phase of the disease. Granulocyte cAMP-PDE activity was similar in the general group of CML patients to that in normal granulocytes; the cGMP-PDE, however, was somewhat higher. By dividing the CML general group into the "low leukocyte count" subgroup including granulocytes of patients with WBC number ranging from 10,300 to 40,000 per microliter (mean 22,000 per microliter), and the "high leukocyte count" subgroup including patients with leukocyte count above 40,000 per microliter (mean 67,000) remarkable differences in the activities of cyclic nucleotide phosphodiesterases between these subgroups could be found: cAMP-PDE activity for the high leukocyte count subgroups was significantly higher than for that in normals, and in CML-low leukocyte count subgroup. On the other hand, cGMP-PDE activity in granulocytes of the high leukocyte count subgroup was found to be remarkably lower than that in normals, in the low leukocyte count subgroup and general CML group. In CML patients the ratio of cAMP-PDE activity to cGMP-PDE activity was always considerably higher than that in controls. The obtained results suggest CML granulocytes to differ from normal ones in respect to their control of intracellular cyclic nucleotide levels. This difference is related to the accumulation of CML granulocytes.
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PMID:Activity of cyclic nucleotide phosphodiesterases in granulocytes of chronic myelogenous leukemia (CML). A preliminary report. 258 58


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