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)

Walker carcinoma cell lines sensitive or resistant to bifunctional alkylating agents have been found to contain multiple forms of cyclic AMP phosphodiesterase (3':5'-cyclic AMP 5'-nucleotidohydrolase, EC 3.1.4.17). These activities have been resolved using Sepharose 6B gel filtration and their apparent molecular weights have been estimated. The enzyme appears to occur in four active forms of apparent mol. wts of greater than 1 000 000, 430 000, 350 000 and 225 000, when assayed at low substrate concentrations. Evidence has been obtained which suggests that all four forms of the enzyme are composed of subunits of mol. wt of approximately 15 000 and are interconvertible. While the ionic strength of the buffer affected the predominance of the different forms, the presence of cyclic AMP at 10(-6) M had no effect on aggregation or dissociation of the enzyme. An activity shift from high molecular weight forms of the enzyme to low molecular weight forms has been found in the resistant tumour at low substrate concentration. No change in elution profile between sensitive and resistant tumours was observed for the low affinity form of the enzyme. The pH optima of the enzymes with both high and low affinity for the substrate was found to be pH 8.0 in the sensitive line. In the resistant tumour the pH optima of the high affinity form is shifted to pH 8.4 while the low affinity form remains at pH 8.0. The high affinity forms of the phosphodiesterase in the sensitive and resistant tumour also differed in their inhibition by theophylline. In both cases inhibition was of the competitive type with Ki values for the sensitive and resistant lines being 2.35 and 0.32 mM, respectively. There was no significant difference in the inhibition of the low affinity form between the sensitive and resistant tumour.
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PMID:Characterisation of cyclic adenosine 3':5'-monophosphate phospodiesterase from Walker carcinoma sensitive and resistant to bifunctional alkylating agents. 23 30

The inhibitors of cyclic AMP phosphodiesterase (papaverine and 4-(-3-butoxy-4-methoxybenzyl)-2-imidazolidinone), serum-free medium, and x irradiation caused cell death and neurite formation in human neuroblastoma cells in culture (IMR-32), whereas theophylline was ineffective. Prostaglandin (PG) E1, N6O'2-dibutyryl adenosine 3',5'-cyclic monophosphate (dbcAMP) induced neurites without causing cell lethality. Inhibitors of phosphodiesterase and PGE1 increased the intracellular level of cAMP by about 2- and 4-fold respectively, whereas serum-free medium and x irradiation did not. The combination of PGE1 and phosphodiesterase inhibitor was more effective in causing morphological differentiation and in increasing the cAMP level than the individual agent. Sodium butyrate induced cell death and neurites, probably in part by increasing the cAMP level. cAMP, guanosine 3',5'-cyclic monophosphate, and adenosine had no detectable effect on the growth or morphology of neuroblastoma cells in culture. Adenosine 5'-monophosphate produced cell death without causing neurite formation. DbcAMP, and to a much lesser degree, sodium butyrate increased the tyrosine hydroxylase activity.
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PMID:Role of cyclic AMP in differentiation of human neuroblastoma cells in culture. 24 May 3

1. Arrhenius plots of the glucagon-stimulated adenylate cyclase, 5'-nucleotidase, (Na+ + K+)-stimulated adenosine triphosphatase and Mg2+-dependent adenosine triphosphatase activities of control hamster liver plasma membranes exhibited two break points at around 25 and 13 degrees C, whereas Arrhenius plots of their activities in hibernating hamster liver plasma membranes exhibited two break points at around 25 and 4 degrees C. 2. A single break occurring between 25 and 26 degrees C was observed in Arrhenius plots of the activities of fluoride-stimulated adenylate cyclase, basal adenylate cyclase and cyclic AMP phosphodiesterase of liver plasma membranes from both control and hibernating animals. 3. Arrhenius plots of phosphodiesterase I activity showed a single break at 13 degrees C for membranes from control animals, and a single break at around 4 degrees C for liver plasma membranes from hibernating animals. 4. The temperature at which break points occurred in Arrhenius plots of glucagon- and fluoride-stimulated adenylate cyclase activity were decreased by about 7--8 degrees C by addition of 40 mm-benzyl alcohol to the assays. 5. Discontinuities in the Arrhenius plots of 4-anilinonaphthalene-1-sulphonic acid fluorescence occurred at around 24 and 13 degrees C for liver plasma membranes from control animals, and at around 25 and 4 degrees C for membranes from hibernating animals. 6. We suggest that in hamster liver plasma membranes from control animals a lipid phase separation occurs at around 25 degrees C in the inner half of the bilayer and at around 13 degrees C in the outer half of the bilayer. On hibernation a change in bilayer asymmetry occurs, which is expressed by a decrease in the temperature at which the lipid phase separation occurs in the outer half of the bilayer to around 4 degrees C. The assumption made is that enzymes expressing both lipid phase separations penetrate both halves of the bilayer, whereas those experiencing a single break penetrate one half of the bilayer only.
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PMID:Changes in the form of Arrhenius plots of the activity of glucagon-stimulated adenylate cyclase and other hamster liver plasma-membrane enzymes occurring on hibernation. 72 95

The effect of a new cardiotonic agent Y-20487 [6-(3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl)-3,4-dihydro-2(1H)- quinolinone] on cyclic AMP levels of rat ventricular cardiomyocytes and the contractile force of papillary muscles was investigated in comparison with selective cyclic AMP phosphodiesterase (PDE) inhibitors, milrinone (PDE-III selective), rolipram and Ro 20-1724 (PDE-IV selective), and a nonselective inhibitor 3-isobutyl-1-methylxanthine (IBMX). Rolipram and Ro 20-1724 did not elicit cyclic AMP accumulation and positive inotropy, but they potentiated the isoproterenol (ISO)-induced cyclic AMP accumulation more effectively than IBMX. Rolipram was more effective than Ro 20-1724 in enhancing ISO-induced cyclic AMP accumulation but was less effective in enhancing the ISO-induced positive inotropic effect, indicating that these agents produce a differential action on cyclic AMP metabolism and inotropy. Milrinone and Y-20487 elicited cyclic AMP accumulation and positive inotropy by themselves. Whereas milrinone scarcely affected the ISO-induced effects, Y-20487 shifted the concentration-response curve for the positive inotropic effect of ISO to the left to the same extent that IBMX did. Y-20487, however, was much less effective than IBMX in enhancing the ISO-induced cyclic AMP accumulation. The present results indicate that in rat ventricular myocardium, PDE-IV may play a crucial role in breakdown of cyclic AMP generated by beta-adrenoceptor stimulation, whereas other types of PDE isoenzymes, including PDE-III, may be responsible for the cyclic AMP accumulation and direct positive inotropic effect induced by PDE inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of a cardiotonic quinolinone derivative Y-20487 on the isoproterenol-induced positive inotropic action and cyclic AMP accumulation in rat ventricular myocardium: comparison with rolipram, Ro 20-1724, milrinone, and isobutylmethylxanthine. 128 Jul 32

To evaluate the effects of milrinone (MIL) on hemodynamics and lung water content, we used 10 mongrel dogs with pulmonary hypertension (PH). To induce pulmonary hypertension, we administered two injections of glass beads stirred in saline to dogs. Mean pulmonary arterial pressure (PAP) and pulmonary vascular resistance significantly increased following induction. Milrinone, which inhibits cyclic AMP phosphodiesterase-(PDE) demonstrated pulmonary vasodilation, indicated a reduction in these two parameters. To clarify the drug mechanism, we measured lung water content as extravascular lung thermal volume (ETVL) using a thermo/sodium double-indicator dilution method. The induction of pulmonary hypertension produced a transient reduction in extravascular lung thermal volume. The parameter remained constant following milrinone administration, whereas the control showed a gradual increase. Of the 10 dogs, five were killed to measure gravimetrically the volume of lung water content as a comparison with extravascular lung thermal volume. We concluded that milrinone produced pulmonary vasodilation which induced a reduction in the transmural capillary pressure gradient according to Starling's hypothesis. This study suggests that the reduction in the transmural pressure gradient induced by milrinone may also prevent the re-elevation in extravascular lung thermal volume. Milrinone increases the cyclic AMP level in the endothelium and in the platelet which may affect either directly or indirectly the permeability of capillary endothelium.
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PMID:Effects of milrinone on lung water content in dogs with acute pulmonary hypertension. 129 25

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

The interactions of the antiestrogenic drug tamoxifen with the calcium-binding protein calmodulin have been studied by computerized molecular modeling methods. Sites in both the N and C domains of the protein have been established, with one in the C domain having the highest calculated enthalpy of binding. The residues involved in the sites have been detailed. Modeling studies are reported for six tamoxifen derivatives, and their calculated enthalpies of binding are compared with the ability of the analogues to inhibit calmodulin-dependent cyclic AMP phosphodiesterase (PDE) (Rowlands et al. Biochem, Pharmacol. 1990, 40, 283-289). The poor binding properties of the piperazino and C-methyl derivatives are correctly predicted, whereas the superior affinity of 4-iodotamoxifen is not fully explained by the model.
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PMID:A molecular modeling study of the interactions between the antiestrogen drug tamoxifen and several derivatives, and the calcium-binding protein calmodulin. 132 85

1. [3H]-adenosine 3':5'-cyclic monophosphate ([3H]-cyclic AMP) responses were studied in primary cultures of human tracheal smooth muscle cells derived from explants of human trachealis muscle and in short term cultures of acutely dissociated trachealis cells. 2. Isoprenaline induced concentration-dependent [3H]-cyclic AMP formation with an EC50 of 0.2 microM. The response to 10 microM isoprenaline reached a maximum after 5-10 min stimulation and remained stable for periods of up to 1 h. After 10 min stimulation, 1 microM isoprenaline produced a 9.5 fold increase over basal [3H]-cyclic AMP levels. The response to isoprenaline was inhibited by ICI 118551 (10 nM), (apparent KA 1.9 x 10(9) M-1) indicating the probable involvement of a beta 2-adrenoceptor in this response in human cultured tracheal smooth muscle cells. However, with 50 nM ICI 118551 there was a reduction in the maximum response to isoprenaline. Prostaglandin E2 also produced concentration-dependent [3H]-cyclic AMP formation (EC50 0.7 microM, response to 1 microM PGE2 6.4 fold over basal). 3. Forskolin (1 nM - 100 microM) induced concentration-dependent [3H]-cyclic AMP formation in these cells. A 1.6 fold (over basal) response was also observed following stimulation with NaF (10 mM). 4. The nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) (0.1 mM) and the type IV, cyclic AMP selective, phosphodiesterase inhibitor rolipram (0.1 mM) both elevated basal [3H]-cyclic AMP levels by 1.8 and 1.5 fold respectively. IBMX (1-100 microM) and low concentrations of rolipram (< 10 microM), also potentiated the response to 1 microM isoprenaline. Inhibitors of the type III phosphodiesterase isoenzyme (SK&F 94120 and SK&F 94836) were without effect upon basal or isoprenaline-stimulated cyclic AMP responses in these cells.5. Carbachol (1 nM-I 00 microM) produced concentration-dependent inhibition of the [3H]-cyclic AMP response to 1 microM isoprenaline in human cultured tracheal smooth muscle cells (IC50 0.24 JM). Carbachol(1 JM) inhibited the [3H]-cyclic AMP response to 1 JM isoprenaline by 60%. This effect of carbachol was itself inhibited by atropine (50 nM) (KA 2.3 x 109 M-') indicating the involvement of a muscarinic receptor.6. These results show that primary cultures of human tracheal smooth muscle cells demonstrate cyclic AMP responses to direct receptor stimulation, adenylyl cyclase activation and inhibition with nonselective and type IV-selective cyclic AMP phosphodiesterase isoenzyme inhibitors, and that the cyclic AMP response to isoprenaline can be inhibited by muscarinic receptor stimulation.
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PMID:Control of cyclic AMP levels in primary cultures of human tracheal smooth muscle cells. 138 13

Binding of the bronchodilators N3-alkylxanthine and N3-alkyl-N1-methylxanthine derivatives to guinea pig serum albumin was investigated in vitro using the ultrafiltration method. A marked difference in the binding parameters of xanthine derivatives was observed, and binding was shown to be concentration dependent. Significant relations were observed among their binding parameter, dissociation constant (Kd), and hydrophobicity (log PC). The extent of binding of xanthine derivatives was increased both when a N3-methyl group was replaced by a longer alkyl chain and when a N3-alkylxanthine molecule was additionally replaced by a methyl group. Reversed-phase HPLC retention, as an index of hydrophobicity of xanthine derivatives, was also determined. Significant relationships were found between the adjusted retention time data for each xanthine derivative and their hydrophobicity or biological activities, such as their abilities to cause muscle relaxation and cyclic AMP phosphodiesterase (PDE) inhibition. These findings indicate that the difference in the extent of binding among xanthine derivatives is related to hydrophobicity, which is an important determinant of their biological activities.
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PMID:Protein binding of xanthine derivatives to guinea pig serum albumin. 165 Aug 23

The effect of regucalcin, a calcium-binding protein isolated from rat liver cytosol, on Ca2+/calmodulin-dependent cyclic nucleotide (AMP) phosphodiesterase activity in rat liver cytosol was investigated. The addition of Ca2+ (50 microM) and calmodulin 160 U/ml in the enzyme reaction mixture caused a significant increase in cyclic AMP phosphodiesterase activity. This increase was inhibited by the presence of regucalcin (0.5-3.0 microM); the inhibitory effect was complete at 1.0 microM. Regucalcin (1.0 microM) did not have an appreciable effect on basal activity without Ca2+ and calmodulin. The inhibitory effect of regucalcin was still evident even at several fold higher concentrations of calmodulin (160-480 U/ml). However, regucalcin (1.0 microM) did not inhibit Ca2+/calmodulin-dependent cyclic AMP phosphodiesterase activity in the presence of 100 and 200 microM Ca2+ added. Meanwhile, Cd2+ (25-100 microM)-induced decrease in Ca2+/calmodulin-dependent cyclic AMP phosphodiesterase activity was not reversed by the presence of regucalcin (1.0 microM). The present results suggest that regucalcin can regulate Ca2+/calmodulin-dependent cyclic AMP phosphodiesterase activity due to binding Ca2+ in liver cells.
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PMID:Inhibitory effect of calcium-binding protein regucalcin on Ca2+/calmodulin-dependent cyclic nucleotide phosphodiesterase activity in rat liver cytosol. 165 6


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