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)

This study demonstrates the postsynaptic localization of one of the isozymes of cyclic nucleotide phosphodiesterase (PDE) activity at asymmetrical, axospinous terminals in the rat corpus striatum and neocortex. Characterization of this enzymatic activity demonstrates that the PDE form surviving aldehyde fixation for electron cytochemistry can be considered to preferentially hydrolyze cyclic 3'5'-guanosine monophosphate, and it requires calcium and a heat-stable calcium-dependent regulator protein (CDR) for full hydrolytic activity. Ion exchange chromatographic analysis of extracts of corresponding unfixed brain regions demonstrates that only one enzyme activity peak exhibits similar aldehyde resistance and calcium and regulator protein activatibility.
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PMID:Biochemical characterization of postsynaptically localized cyclic nucleotide phosphodiesterase. 22 34

The effects of 3', 5'-cyclic nucleotide phosphodiesterase (PDE) inhibitors and of 8-Br 3', 5'-cyclic nucleotide analogs on nerve-muscle transmission were studied in the guinea-pig vas deferens preincubated with 3H-noradrenaline. 8-Br cyclic AMP and the PDE inhibitors 3-isobutyl-1-methylxanthine (IBMX) and 3-propionyl-4-hydrazinopyrazolopyridine (SQ 20006) enhanced the secretion of 3H-NA evoked by transmural nerve stimulation. 8-Br cyclic GMP was without effect in this respect. The muscle contraction evoked by transmural nerve stimulation, high potassium or by application of exogenous noradrenaline was depressed by IBMX and SQ 2006. The contraction evoked by transmural nerve stimulation was enhanced by 8-Br cyclic AMP and depressed by 8-Br cyclic GMP. These findings suggest differential involvement of 3', 5'-adenosine- and guanosine-cyclic nucleotides in excitation-secretion-coupling in the noradrenergic sympathetic nerves, and in excitation-contraction-coupling in the smooth muscle, of guinea-pig vas deferens.
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PMID:The influence of 8-Br 3', 5'-cyclic nucleotide analogs and of inhibitors of 3', 5'-cyclic nucleotide phosphodiesterase, on noradrenaline secretion and neuromuscular transmission in guinea-pig vas deferens. 22 9

A procedure for combined sequential affinity adsorption-electrophoresis has been devised. Its use for the rapid purification of a calcium-dependent cyclic nucleotide phosphodiesterase from bovine brain in high yield is described. In this procedure, proteins bound to a solid phase of calcium-dependent regulatory protein (CDR) linked to Sepharose 4B were electrophoretically eluted, concentrated, and separated, thus avoiding the large losses in activity incurred during attempts to purify further the phosphodiesterase eluted by conventional means. The highly purified phosphodiesterase prepared by this method was stable for months at -60 degrees C in the presence of glycerol. It has a higher affinity for cyclic GMP than for cyclic AMP, and hydrolysis of both substrates is stimulated 5- to 6-fold by calcium plus CDR. Factors that influence adsorption of the enzyme to CDR-Sepharose and selection of optimal conditions for electrophoresis were investigated. Sequential adsorption-electrophoresis should be generally useful in the purification of macromolecules for which affinity adsorbents are available. The procedures described here could be directly applicable to the purification of proteins that, like the phosphodiesterase, interact with CDR.
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PMID:Sequential adsorption-electrophoresis: combined procedure for purification of calcium-dependent cyclic nucleotide phosphodiesterase. 22 70

Prostaglandins (PGs) are synthesised by gastric mucosa, and have been shown to inhibit gastric acid secretion and ulcer formation in man and experimental animals. Recently exogenous PGs, mainly of the E group, have been used for the treatment of peptic ulcer disease. We therefore searched for a drug that would stimulate endogenous gastric prostaglandin E(2) (PGE(2)) synthesis. Rabbit gastric mucosa slices were cultured for 22 hours at 77 degrees C. PGE(2), measured by radioimmunoassay, was found to be linearly secreted into the culture medium. PGE(2) accumulation in the medium during 22 hours of culture was 7.9+/-0.5 (SE) ng/mg tissue (N=20). Addition of papaverine (100 mu/ml), a cyclic nucleotide phosphodiesterase inhibitor, resulted in a significant increase (250% of control) in PGE(2) accumulation in the medium: 24.3+/-1.8 ng/mg tissue (N=25). Isobutylmethylxanthine (IBMX 100 mug/ml), another phosphodiesterase inhibitor, only slightly increased PGE(2) accumulation, while 8 bromo-cyclic AMP (1 mM) had no effect. Under these conditions IBMX increased by 20-fold mucosal cyclic AMP levels: 3.9+/-0.3 pmol/mg tissue (N=8) as compared with control levels: 0.2+/-0.03 pmol/mg tissue (N=8). Papaverine, however, did not alter mucosal cyclic AMP accumulation. These results indicate that papaverine stimulates PGE(2) production by cultured rabbit gastric mucosa and that this stimulation is not related to the inhibition of phosphodiesterase activity and accumulation of mucosal cyclic AMP. Papaverine induced stimulation of PGE(2) production should be further evaluated regarding its possible beneficial effects in protecting gastric mucosa and in reducing acid secretion in peptic ulcer patients.
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PMID:Papaverine stimulation of prostaglandin E2 production by cultured rabbit gastric mucosa. 23 Jan 30

The mechamism of action of theophylline was studied by investigating the relationship between relaxant effect and inhibition of cyclic nucleotide phosphodiesterase (PDE) and by studying interactions with adenosine actions. Guinea pig tracheal smooth muscle cyclic AMP PDE had two apparent KmS': 0.4 and 70 microM for cyclic AMP. Theophylline and papaverine competetively inhibited the low Km form. Hydrolysis of 2.0 microM cyclic AMP and cyclic GMP was inhibited by several drugs. Some agents (e.g. ZK 62 711, ICI 63,197, Ro 20--1724, dipyridamol) were considerably more potent as inhibitors of cyclic AMP than of cyclic GMP hydrolysis, while other agents (M & B 22.948 and dilazep) selectively inhibited cyclic GMP breakdown, and some (theophylline, papaverine, IBMX and SQ 20,006) showed little selectivity. There was a weak but significant correlation between inhibition of cyclic AMP phosphodiesterase and relaxation of tracheal smooth muscle in vitro. There was also a correlation between the ratio of IC25 cyclic AMP/IC25 cyclic GMP and the smooth muscle relaxation, indicating that inhibition of cyclic AMP rather than cyclic GMP hydrolysis determined relaxation. However, there was a marked tachyphylaxis to the relaxant effect of the cyclic AMP selective PDE-inhibitors, while the nonselective methylxanthines did not show tachyphylaxis. The effect of theophylline was antagonized by low concentrations of adenosine, which by itself caused a weak tracheal contraction. The effect of PDI-inhibitors can be partly explained by decreased cyclic AMP breakdown but other mechanisms, such as antagonism of endogenous adenosine, may contribute to the observed relaxant action.
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PMID:On the mechanism of relaxation of tracheal muscle by theophylline and other cyclic nucleotide phosphodiesterase inhibitors. 23 92

Transplantable Brown-Pearce carcinoma was adapted successfully in the rabbit anterior chamber. Regression of tumor growth was attained on tri-weekly perfusion of the AC with 10 micromolar of methotrexate. Tumor cyclic nucleotide phosphodiesterase (PDE) and protein activator were found to be markedly depressed during the course of chemotherapy and the PDE cAMP/cGMP ratio was similarly altered. Corroborative light and electron-microscopic studies showed specific alterations of intracellular organelles in relation to MTX and tumor cell death. These findings suggest that metabolic pathways of cyclic nucleotides are important biochemical modulators of neoplastic cells. The method of intraocular perfusion precludes systemic toxic effects and avoids compromising the animals' immunocompetence.
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PMID:Experimental intraocular malignancy: the effect of intracameral perfusion. 23 85

Studies were carried out to characterize the cyclic nucleotide phosphodiesterase from rat calvaria. 25-40% of the total enzyme activity was membrane-bound. pH, magnesium, and temperature requirements conformed closely to those established for phosphodiesterase from other tissues. Kinetic evidence was found for dual enzyme activities with different substrate affinities for both the particulate and soluble enzyme. Apparent Kms for the soluble enzyme (3.5 times 10-6 and 2.5 times 10-5M) approximated those for the particulate enzyme (5.7 times 10-6 and 2.5 times 10-5M). L-Thyroxine, 10-5M, inhibited competitively the low- and high-Km enzymes from both the particulate and soluble fractions (Ki equals 1.7 times 10-5M). T4 was more potent an inhibitor than T3 with all enzyme fractions, but this relationship could be altered by adding protein to the incubation mixtures. Tests of diverse thyroid hormone analogues showed that 1) T4 and its derivatives were more potent than T3 and its analogues; 2) acetic and propionic acid derivatives were more potent than the thyronines; 3) "reverse T3," an antagonist of some T3 actions, also inhibited phosphodiesterase. These effects were not attributable to chelation, and were not duplicated by iodide or by other physiologically inactive thyroid hormone analogues.
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PMID:Cyclic nucleotide phosphodiesterase from bone: characterization of the enzyme and studies of inhibition by thyroid hormones. 23 82

The existence of two forms of cyclic AMP phosphodiesterase (3',5'-cyclic AMP 5'-nucleotidohydrolase, EC 3.1.4.17) was demonstrated in silkworm larvae by kinetic analysis and DEAE-cellulose column chromatography. The two forms of the enzyme (phosphodiesterase II and III) differ apparently in their characteristics from the previously reported cyclic nucleotide phosphodiesterase (phosphodiesterase I) of silkworm. The higher K-m form (phosphodiesterase II) has a molecular weight of approx. 50 000 and optimum pH of 7.8, and requires Mn-2-+ for maximum activity. The lower K-m form (phosphodiesterase III) has a molecular weight of approx. 97 000 and optimum pH of 7.2, and requires Mg-2-+ for maximum activity. Phosphodiesterase II and probably phosphodiesterase III are specific enzymes for the hydrolysis of cyclic AMP.
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PMID:Cyclic nucleotide phosphodiesterase in silkworm. Separation and characterization of multiple forms of the enzyme. 23 60

Cyclic nucleotide phosphodiesterase activity of human peripheral blood mononuclear cells was significantly increased following a short (30 min) incubation with the mitogenic lectin Concanavalin A. Con A stimulated phosphodiesterase activity to the same extent whatever the subcellular compartment (homogenate, cytosol or pellet). Further separation of the Con A-activated mononuclear cells into lymphocyte-enriched and monocyte-enriched populations showed that the Con A-induced increase of phosphodiesterase activity exclusively affected the lymphocyte-enriched population. In lymphocytes, cyclic GMP phosphodiesterase activity was more importantly enhanced by Con A (+275%) than cyclic AMP phosphodiesterase activity (+75%). The increase of both activities occurred as early as from 10 min of Con A incubation and proved to be maximal with Con A doses of 2.5 and 5 micrograms per 10(6) cells, lower and higher doses being less effective. Inhibition experiments with reference inhibitors suggested that, among the high affinity phosphodiesterase isoforms, the cyclic GMP-inhibited enzyme might be more selectively enhanced by Con A than the cyclic AMP-specific, Rolipram-sensitive one. The non-mitogenic lectin Helix pomatia hemagglutinin, was not able to enhance cyclic nucleotide phosphodiesterase activity of human mononuclear cells whereas anti-CD3 monoclonal antibody, although being less effective than Con A, exhibited a significant stimulatory effect. Putting together these results suggest that the early increase in phosphodiesterase activity might be a normal step involved in the mitogenic activation of human lymphocyte.
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PMID:Early increase in lymphocyte cyclic nucleotide phosphodiesterase activity upon mitogenic activation of human peripheral blood mononuclear cells. 130 23

Purified porcine erythrocyte membrane Ca(2+)-ATPase and 3':5'-cyclic nucleotide phosphodiesterase were stimulated in a dose-dependent, saturable manner with the vitamin D-dependent calcium binding protein from rat kidney, calbindin-D28k (CaBP-D28k). The concentration of CaBP-D28k required for half-maximal activation (K0.5 act.) of the Ca(2+)-ATPase was 28 nM compared to 2.2 nM for calmodulin (CaM), with maximal activation equivalent upon addition of either excess CaM or CaBP-D28k. 3':5'-Cyclic nucleotide phosphodiesterase (PDE) also showed equivalent maximum saturable activation by calbindin (K0.5 act. = 90 nM) or calmodulin (K0.5 act. = 1.2 nM). CaBP-D28k was shown to effectively compete with CaM-Sepharose for PDE binding. Immunoprecipitation with CaBP-D28k antiserum completely inhibited calbindin-mediated activation of PDE but had no effect on calmodulin's ability to activate PDE. While the physiological significance of these results remains to be established, they do suggest that CaBP-D28k can activate enzymes and may be a regulator of yet to be identified target enzymes in certain tissues.
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PMID:In vitro enzyme activation with calbindin-D28k, the vitamin D-dependent 28 kDa calcium binding protein. 131 45


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