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)

In previous studies we have shown that the activation of bovine heart cyclic nucleotide phosphodiesterase by purified protein activator is completely dependent on the presence of Ca2+ and that the protein activator Ca2+ complex is probably the true activator for the enzyme (Teo, T.S. and Wang, J.H. (1973) J. Biol. Chem. 248, 5930-5955). More recent studies have led us to believe that the mechanism of the Ca2+ activation of phosphodiesterase resembles that of the Ca2+ activation of muscle contraction and that the protein activator may play a role similar to troponin. In the present study we show that the protein activator resembles rabbit muscle troponin C in amino acid composition, molecular weight, isoelectric point, and ultraviolet absorption spectrum. Preliminary structural studies also indicate that these two proteins may have evolved from a common ancestral protein through gene duplication. This argument is strengthened by the finding that the tryptic peptide map of the bovine heart protein activator is indistinguishable from that of the bovine brain phosphodiesterase activator protein for which preliminary sequence information also suggests homology to troponin C (Watterson, D.M., Harrelson, W.G., Jr., Keller, P.M., Sharief, F., and Vanaman, T.C. (1976) J. Biol. Chem. 251, 4501-4513).
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PMID:Comparison of calcium-binding proteins. Bovine heart and brain protein activators of cyclic nucleotide phosphodiesterase and rabbit skeletal muscle troponin C. 18 74

The effect of five phosphodiesterase (PDE) inhibitors (papaverine, IBMX, theophyllamine, dipyridamol and M & B 22,948) was studied on adenylate cyclase and on cyclic nucleotide phosphodiesterase activities in extracts of rat caudate nucleus. For comparison the effect on DA turnover and on turning behaviour in rats with unilateral lesions of the nigro-neostriatal DA nerurons was studied. Cyclic AMP PDE was inhibited by papaverine, dipyridamol, IBMX, M & B 22,948 and theophyllamine in that order of potency. Cylcic GMP PDE was inhibited by IBMX, papaverine, M & B 22,948 and theophyllamine, but not by dipyridamol. Basal adenylate cyclase washigher if assayed in the presence of papaverine or dipyridamol than if theophyllamine or IBMX was present. The degree of stimulation caused by DA was not significantly influenced by the PDE inhibitors. Papaverine and dipyridamol enhanced DA disappearance in the caudate nucleus and the tuberculum accumbens, but not in the median eminence. Caffeine had no significant effect. Papaverine (1-28 mg/kg) had no signigicant effect on L-dopa (5 mg/kg)-induced turning, and actually inhibited turning induced by the combination of L-dopa (10 mg/kg) and atropine (5 mg/kg). The other four PDE inhibitors all potentiated L-dopa-induced turning. Theophyllamine (20 mg/kg) and IBMX (5 mg/kg) even caused turning when given alone. The data are compatible with the opinion that PDE inhibition leads to an enhanced effect of DA in the caudate nucleus. However, the results also demonstrate that several of the PDE inhibitors have effects on central DA mechanisms that are difficult to explain solely on the basis of PED inhibition.
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PMID:Effect of some phosphodiesterase inhibitors on central dopamine mechanisms. 18 7

Bio-Gel A-5m chromatography has been used to separate apparent multiple forms of cyclic nucleotide phosphodiesterase from rat erythrocytes. Cyclic AMP phosphodiesterase was resolved by gel filtration into three peaks of activity with apparent molecular weights of about 300,000, 225,000 and 100,000, while cyclic GMP phosphodiesterase activity in gel column fractions was too low to permit meaningful estimates of its molecular weight. All three of the separated peaks of cyclic AMP phosphodiesterase activity displayed anomalous kinetic behaviour suggestive of negative cooperativity. The possibility that multiple phosphodiesterase activities could arise from in vitro alterations of a single enzyme was investigated. Similar changes in gel filtration profiles resulted when erythrocyte extracts were treated with trypsin or ammonium sulfate or were incubated at 37 degrees C. After these treatments, a large proportion of the enzyme activity occurred in low (ca. 100,000) molecular weight regions. The low molecular weight phosphodiesterase activities from untreated, incubated, and trypsin-treated extracts possessed similar properties. All were inhibited by methylxanthines, had pH optima of approximately 8.0, and similar kinetic properties and requirements for divalent cations. These observations raise the possibility that preparative procedures or limited proteolysis occurring during preparation and handling of extracts can contribute to the apparent multiplicity of enzyme forms seen after gel filtration of phosphodiesterase from rat erythrocytes and perhaps other cell types.
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PMID:Apparent multiple forms of cyclic AMP phosphodiesterase from rat erythrocytes. 18 74

The in vitro effects of insulin on different phosphodiesterase activities present in rat epididymal fat cells from normal and hypothyroid rats have been studied. Evidence is presented that insulin increases the maximum velocity of a particulate, low Km, cyclic adenosine-3', 5'-monophosphate (cyclic AMP) phosphodiesterase in both types of cells, this effect being more clearly evident with the fat cells from hypothyroid animals; combination of insulin and thyroidectomy resulted in a 400% stimulation with 10-10 - 10-9 M insulin. A clear and significant effect was apparent at 10-11 M insulin. However, the dose-response curve was biphasic, since stimulation by insulin was suppressed for doses of hormone higher 10-8 - 10-7 M. Moreover, insulin effects were very fast, since clear stimulation was observed after only 2 min of incubation; the maximal increase was obtained after 10 min. Insulin did not significantly affect the soluble cyclic AMP phosphodiesterase activity in normal cells, thus confirming results obtained by others. However, the soluble cyclic AMP phosphodiesterase activity was clearly stimulated by insulin when the fat cells were prepared from hypothyroid rats. Maximal stimulation was obtained with 10-9 M insulin; the response was again very fast. Soluble cyclic GMP phosphodiesterase activity was also increased additively by hypothyroidism and insulin, maximal stimulation being obtained with 10-9 M insulin. With this dose of insulin the additive effects of thyroidectomy and insulin produced a 5-fold stimulation. The effect of insulin on the soluble cyclic GMP phosphodiesterase was very fast (2-5 min). With both soluble cyclic nucleotide phosphodiesterase activities, insulin increased the maximal velocity but not apparent Km of the enzyme. Thus, hypothyroidism and insulin produced additive effects suggesting a different mechanism of action of these two hormonal situations on the degradation of the intracellular pools of cyclic AMP and cyclic GMP.
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PMID:Cyclic nucleotide phosphodiesterases, insulin and thyroid hormones. 18 75

1. The role of adenosine 3':5'-phosphate (cyclic AMP) and guanosine 3':5'-phosphate (cyclic GMP) as second messengers for the enzyme secretory response evoked by the autonomic neurotransmitters, noradrenaline and acetylcholine, is examined in this in vitro study on the guinea-pig submandibular gland. 2. Noradrenaline increased enzyme (kallikrein) secretion. The initial stimulation of enzyme release appeared to be dose-dependent. The time course of cumulative kallikrein secretion revealed a complex pattern. Isoprenaline and phenylephrine were almost as potent as noradrenaline in releasing kallikrein. Both propranolol and phentolamine were required to fully inhibit the noradrenaline-stimulated enzyme secretion. 3. The cumulative secretion of kallikrein evoked by acetylcholine was dose-dependent. The onset of secretion showed a significantly greater time-lag than that observed with noradrenaline. Atropine effectively blocked the release of kallikrein by acetylcholine. 4. Dibutyryl cyclic AMP stimulated enzyme secretion. Dibutyryl cyclic GMP caused an initial increase which was not maintained. 5. The cyclic nucleotide phosphodiesterase inhibitors, theophylline and papaverine, increased basal kallikrein secretion. The action of the cyclic phosphodiesterase inhibitors on the secretory response to noradrenaline, acetylcholine, dibutyryl cyclic AMP and dibutyryl cyclic GMP was complex. In general, the increase in enzyme release produced by the secretagogues was additively enhanced by both inhibitors. 6. Omission of calcium inhibited both acetylcholine and dibutyryl cyclic GMP stimulated kallikrein release, but to a lesser degree than that of noradrenaline and dibutyryl cyclic AMP. High concentrations of extracellular calcium (10 mM) appeared to enhance the action of acetylcholine. 7. Noradrenaline produced a rise in the intracellular level of cyclic AMP. The increase preceded the stimulated secretion of kallikrein. Of the various adrenergic agonists, noradrenaline and isoprenaline were the most potent, whereas phenylephrine was significantly less effective in raising basal cyclic AMP values. Acetylcholine was without effect, even in the presence of a cyclic phosphodiesterase inhibitor. 8. Acetylcholine and noradrenaline raised intracellular levels of cyclic GMP only when the tissue incubations were performed in the presence of a cyclic phosphodiesterase inhibitor. The increase in cyclic GMP produced by acetylcholine preceded enzyme secretion. 9. Morphological data substantiated the finding that the in vitro release of kallikrein evoked by the secretagogues was associated with the depletion of secretory granules and vacuolations in acinar cells of the gland slices. 10. The molecular mechanisms which control enzyme secretion in the exocrine submandibular gland are discussed. Models are presented for the role of transmitter-specific cyclic nucleotides and calcium in stimulus-secretion coupling.
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PMID:Stimulus-secretion coupling: role of cyclic AMP, cyclic GMP and calcium in mediating enzyme (kallikrein) secretion in the submandibular gland. 18 62

Ovine growth hormone (1 mug/ml) antagonized the lipolytic action of epinephrine (0.25 mug/ml) in segments of adipose tissue obtained from hypophysectomized rats, but a lag period of about 10 min was required. When added simultaneously with epinephrine, growth hormone neither reduced the maximal accumulation of cyclic AMP which occurred at 3 min nor accelerated the return to basal levels. Only when tissues were exposed to epinephrine 15 min after preincubation with growth hormone was cyclic AMP accumulation compromised. Growth hormone also produced a delayed increase of about 20% in the activity of a low Km cyclic nucleotide phosphodiesterase, which might have contributed to the decrease in cyclic AMP accumulation. The increase in phosphodiesterase activity probably did not account for the antilipolytic effect, however, since antilipolysis was evident before the increase in phosphodiesterase activity could be detected. The antilipolytic effects of growth hormone similarly could not be attributed to the decrease in cyclic AMP concentrations, for when added simultaneously with epinephrine the antilipolytic effects did not occur until after the evanescent changes in cyclic AMP had passed. Growth hormone added simultaneously with epinephrine or 30 min later significantly decreased the activity of protein kinase assayed in the absence of exogenous cyclic AMP, but did not change total protein kinase activity as measured in the presence of a saturating concentration of cyclic AMP. This effect of growth hormone was evident as early as 3 min after addition of the hormone and may at least partially account for the antilipolytic effect.
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PMID:Studies on the mechanism of the antilipolytic effects of growth hormone. 18 54

This study has been undertaken to elucidate the localization and the activity of cyclic nucleotide phosphodiesterase (PDE) in psoriatic epidermis compared to normal. The results showed that the evaluation of cytochemical methods may be difficult because of the various factors which interfere with the reaction and the considerable amount of background staining. Additionally, only the tissue bound particulate enzyme fraction may be demonstrated by cytochemical means. Nevertheless, the method did reveal that the activity of PDE, if any, is localized on the cytoplasmic membranes of the cells, independent of their origin, and not on the cell surface. Moreover, no differences were found between normal and psoriatic skin. It seems, therefore, that the intracellular degradation of cAMP remains unaltered in psoriasis.
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PMID:Localization and activity of tissue bound cyclic nucleotide phosphodiesterase in normal and lack of changes in psoriatic human skin. 18 39

A Ca2+-activatable cyclic nucleotide phosphodiesterase from bovine heart can be eluted from a DEAE-cellulose column either in the free form by buffers containing 0.1 mM ethylene glycol bis(beta-aminoethyl ether)N-N,N'N'-tetraacetic acid (EGTA) or as a complex of the enzyme with its protein modulator by buffers containing 0.01 mM CaCl2. A purification procedure based primarily on the significantly different affinity of the two forms of the enzyme for DEAE-cellulose was developed for the purification of the enzyme from bovine heart. The procedure involves ammonium sulfate fractionation, three chromatographic steps on DEAE-cellulose, and gel filtration on Sephadex G-200 with a 5000-fold purification over the crude extract. The purified enzyme has a specific activity of 120 mumol of cAMP/mg/min, can be activated 5-fold by Ca2+, but is only 80% pure as judged by analytical disc gel electrophoresis. The purified enzyme is unstable but can be stabilized by addition of Ca2+ and the protein modulator; this is in contrast to the less pure preparations of Ca2+-activatable phosphodiesterase which are destabilized by the protein modulator in the presence of Ca2+.
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PMID:Purification of a Ca2+-activatable cyclic nucleotide phosphodiesterase from bovine heart by specific interaction with its Ca2+-dependent modulator protein. 18 13

Exceptionally high levels of guanosine 3'-5'-cyclic monophosphate (cyclic GMP) in the accessory reproductive gland of the male house cricket, Acheta domesticus, led to an investigation of cyclic nucleotide phosphodiesterase (EC 3.1.4.--) as a possible regulatory enzyme. Cricket cyclic nucleotide phosphodiesterase activity with cyclic GMP or cyclic AMP as substrate had a pH optimum around 9.0, required Mg2+ or Mn2+ for maximal activity, and was inhibited by EDTA and methylxanthines. Cyclic GMP phosphodiesterase occurred mainly in the soluble fraction of homogenates of accessory glands or whole crickets, but cyclic AMP phosphodiesterase in the accessory gland was primarily particulate. Kinetic analysis indicated three forms of cyclic GMP phosphodiesterase, with Km values at 2.9 muM, 71 muM and 1.5 mM. Chromatography of whole cricket or accessory gland extracts on DEAE cellulose gave an initial peak having comparable activity with either cyclic GMP or cyclic AMP, and a second peak specific for cyclic AMP. There were no appreciable changes in the specific activity or kinetic properties of accessory gland cyclic GMP phosphodiesterase during a developmental period over which cyclic GMP levels rise more than 500-fold. Thus, the accumulation of cyclic GMP in the accessory gland is probably not associated with concomitant developmental modulation of phosphodiesterase activity.
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PMID:Cyclic nucleotide phosphodiesterases in the cricket, Acheta domesticus. 18 17

The properties of adenylyl cyclase and cyclic nucleotide phosphodiesterases from GH-strains of rat pituitary tumor cells have been investigated. Adenylyl cyclase was inhibited by calcium ion and stimulated by fluoride ion, 5'-guanylylimidodiphosphate and by prior treatment of intact releasing hormone (TRH), which stimulates prolactin releasing hormone (TRH), which stimulates prolactin release and synthesis in GH-cells, did not cause a significant stimulation of adenylyl cyclase activity under a wide variety of assay conditions; under the same conditions, [3H]TRH bound to a previously characterized membrane receptor. GH-cells contain phosphodiesterase activity catalyzing the hydrolysis of cAMP which gives nonliner Lineweaver-Burk plots with apparent Km's for cAMP of 1.5 muM and 4mM. TRH did not affect the activity of cyclic nucleotide phosphodiesterase at high or low cAMP concentrations when added to broken cell preparations. Treatment of intact cells with TRH caused no changes in the total adenylyl cyclase and cyclic nucleotide phosphodiesterase activites within the first 2 h of incubation, when stimulation of prolactin release occurs, but did lead to slight decrease in adenylyl cyclase and the apparent low Km phosphodiesterase after 72 h of treatment.
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PMID:Adenylyl cyclase and cyclic nucleotide phosphodiesterases in GH-Strains of rat pituitary cells. 18 95


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