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)

One model of synaptic transmission suggests that transmitters modify postsynaptic permeability through the intermediary of cyclic AMP. Thus, serotonin (5-hydroxytryptamine) evokes in molluscan neurones a decrease in a voltage-dependent K+ conductance which in turn generates a slow inward current when studied in steady voltage-clamp conditions. The serotonin-induced increase of the plateau phase of the spike of an Aplysia sensory neurone can be mimicked by both intracellularly injected cyclic AMP and extracellularly applied phosphodiesterase inhibitors, suggesting that cyclic AMP mediates the effect. We have tested whether a similar mechanism could account for the serotonin slow inward current in identified snail neurones and have found that the intracellular injection of cyclic AMP, but not of cyclic GMP or 5'-AMP, evokes a slow inward current showing similar voltage dependence, inversion potential and ionic properties to the serotonin slow inward current. Phosphodiesterase inhibitors at low concentrations (1-20 microM) potentiate the serotonin slow inward current and at higher concentrations evoke by themselves an inward current, partially or totally occluding the serotonin and cyclic AMP currents. Finally, we have found that in homogenates of pooled identified snail neurones serotonin stimulates the adenylate cyclase, increasing its activity by 50-100%.
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PMID:Role of cyclic AMP in a serotonin-evoked slow inward current in snail neurones. 626 Nov 54

The assay for cyclic nucleotide phosphodiesterase has been applied, with certain modifications, to the measurement of the soluble forms of these enzymes in the rat testis. The homogenization and incubation conditions were adjusted to achieve linear product formation as a function of time and protein concentrations and the resulting products were isolated by ion exchange chromatography using 5 mM HCl as the eluting agent. Phosphodiesterase activities were present in the testicular cytosol (105,000 g supernatant) of adult rats which were capable of hydrolyzing cAMP with a high (Km2 microM) and low Km20 microM) affinity and GMP with a relatively high affinity (Km3 microM). The low affinity cAMP enzyme activity could be stimulated with divalent ions such as calcium, magnesium, and manganese. At 18 days of age, all three enzyme activities were present in the testis, although both the high and low affinity cAMP phosphodiesterase displayed maximal rates (Vmax) that were only one third of the adult testis (when expressed per mg protein).
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PMID:Testicular cyclic nucleotide phosphodiesterase in the rat. Kinetic properties and changes with age. 626 77

Phosphodiesterase activity was studied in cultures derived from 19-day-old rats and enriched with Sertoli cells. Pretreatment of such cultures with follicle-stimulating hormone or L-isoproterenol increased cAMP-phosphodiesterase activity 5.2 and 2.0 times, respectively. cGMP-phosphodiesterase activity was not affected. Similar effects were observed in freshly isolated cells. The stimulatory effect was enhanced by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine and was mimicked by cholera toxin and dbcAMP. Increased activity was observed after a latent period of 1 h. Stimulation was blocked by cycloheximide and actinomycin D. The enzyme had an apparent Km for cAMP of 1.4 micro M. Its activity was enhanced by Mg2+ but not by Ca2+. It is concluded that phosphodiesterases play an important role in the hormonal control of Sertoli-cell function and may contribute to the refractory state of these cells after stimulation with various agonists.
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PMID:Hormonal control of phosphodiesterase activity in cultured rat Sertoli cells. 627 46

Fibroblast phosphodiesterase activity was studied using 4-methylumbelliferyl pyrophosphate diester as substrate. Release of the fluorogen, 4-methylumbelliferone, was found to be dependent on acid phosphatase activity, normally present in excess in crude cell extracts. Phosphodiesterase activity had an acid pH optimum, was deficient in Niemann-Pick disease fibroblasts, and, when assayed in the presence of exogenous acid phosphatase, had an identical electrofocusing profile to that of sphingomyelinase. These findings suggest that 4-methylumbelliferyl pyrophosphate diesterase and acid sphingomyelinase activities are dependent on the same enzyme.
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PMID:Studies on pyrophosphate diesterase activity in cultured human fibroblasts: a deficiency in Niemann-Pick disease. 627 31

Erythrocyte soluble phosphodiesterase activities show at least two interconvertible states: "aggregated' and "non-aggregated'. In the former state the existence of a high affinity component for cyclic AMP is favoured and the system is more active with cyclic AMP than with cyclic GMP as substrate. When the system is in the "non-aggregated state', no activity with cyclic GMP is detected. Conversion to the "non-aggregated state' is enhanced by dilution or by addition of magnesium ions. Upon isoelectric focusing of erythrocyte soluble extracts. Phosphodiesterase activities can be resolved in two peaks: one specific for cyclic AMP located at pH 4.66 and the other specific for cyclic GMP focused at pH 4.95. Evidence would indicate that aggregation affects the enzyme specific for cyclic AMP.
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PMID:Cyclic nucleotide phosphodiesterase activities in rat erythrocytes. 628 33

Retinal rod outer segments contain a phosphodiesterase specific for cyclic GMP. This enzyme is virtually inactive in the dark. Photoexcitation of rhodopsin results in the formation of hundreds of molecules of GTP-transducin, which in turn activate many molecules of phosphodiesterase. The phosphodiesterase is also known to be activated by the proteolytic action of trypsin. We have investigated the nature of the inhibitory constraint on the catalytic activity of the phosphodiesterase in the dark state. Phosphodiesterase purified by hexylagarose chromatography followed by gel filtration high pressure liquid chromatography consists of three kinds of subunits: alpha (88 kilodaltons), beta (84 kilodaltons), and gamma (11 kilodaltons). Three lines of evidence show that the phosphodiesterase in the dark state is inhibited by its gamma subunit. First, inhibitor activity copurifies with the catalytic activity of this enzyme. Second, trypsin degrades the gamma subunit, resulting in a concomitant increase in catalytic activity. The high pressure liquid chromatography elution position of trypsin-activated phosphodiesterase suggests that it is an alpha beta complex. Third, nearly all of the catalytic activity of trypsin-activated phosphodiesterase can be inhibited by the addition of gamma subunit purified either by heat treatment or by gel filtration at pH 2.1. The addition of gamma subunit to trypsin-activated phosphodiesterase decreases its Vmax from 1.2 mmol of cyclic GMP hydrolyzed/min/mg to less than 1% of this value with relatively little change in the value of Km. The gamma subunit has high affinity for trypsin-activated phosphodiesterase. The dissociation constant of this complex is 0.13 nM. These experiments show that the phosphodiesterase in the dark state has very little catalytic activity because of the inhibitory constraint imposed by its gamma subunit.
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PMID:Purification and characterization of the gamma regulatory subunit of the cyclic GMP phosphodiesterase from retinal rod outer segments. 628 81

Cyclic nucleotide phosphodiesterase activities in soluble Neurospora crassa mycelial extracts were resolved into two peaks, phosphodiesterase I and II, by chromatography on DEAE-cellulose columns. Phosphodiesterase I hydrolysed cyclic AMP and cyclic GMP equally well. Phosphodiesterase II was active on cyclic GMP but scarcely active on cyclic AMP. Phosphodiesterase I was resolved by gel filtration and sucrose-density-gradient centrifugation into three peaks having molecular weights of about 57 000, 125 000 and 225 000. This suggests that this enzyme activity has at least three aggregation forms, tentatively defined as monomeric, dimeric and tetrameric. Similarly, phosphodiesterase II was resolved into two forms, having molecular weights of about 170 000 and 320 000. Evidence on the interconversion between phosphodiesterase I forms was obtained.
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PMID:Cyclic nucleotide phosphodiesterase activities in Neurospora crassa. 628 7

Membrane-bound 3'.5'-cyclic nucleotide phosphodiesterase (EC 3.1.4.17) is closely associated physically with nucleotidase and deaminase, thus forming an enzyme cluster of unique catalytic behaviour [H. Wombacher, Archs. Biochem. Biophys. 201, 8 (1980)]. This multienzyme cluster, which was found in the microsomal fraction of beef adrenal cortex, catalyses the degradation of cyclic AMP, via AMP and adenosine, to inosine. The present study shows how theophylline, a well-known inhibitor of the phosphodiesterase, acts on the membrane-bound multienzyme sequence. The findings were as follows. Firstly, as expected, theophylline inhibited the phosphodiesterase competitively. In particular, the high-affinity enzyme was inhibited by mM concentrations of theophylline. Phosphodiesterase activity was tentatively ascribed to two enzymes, one with a low Km [0.3 microM], one with a high Km [60 microM]. Secondly, theophylline inhibited the nucleotidase activity to a great extent. A detailed kinetic analysis showed the inhibition to be hyperbolic noncompetitive (alpha = 1, beta = 0.35 and Ki = 0.25 mM). Thirdly, theophylline did not inhibit the deaminase activity of the multienzyme sequence. A model of theophylline inhibition is suggested explaining how an effector could modulate the kinetic behaviour of an enzyme cluster by acting at a single allosteric site. Finally, in view of the existence of the cyclic AMP degrading multienzyme sequence and the effect of theophylline on it, the possibility is discussed that physiologically active adenosine is derived from cyclic AMP.
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PMID:Theophylline effect on the cyclic AMP degrading multienzyme sequence. 629 12

Cyclic adenosine 3', 5'-monophosphate (cyclic AMP) and adenyl cyclase and phosphodiesterase activities were determined in the specialized myocardial tissue of the conduction system of bovine heart and then compared with those in the ordinary myocardial tissue. The conduction system was comprised of the atrioventricular node (A-V node), the His bundle and the right and the left bundle branches (RBB and LBB). The content of cyclic AMP was higher in the ordinary myocardial tissue than in the specialized myocardial tissue. In the specialized myocardial tissue, its content was highest in the A-V node and lower in the His bundle than in the LBB and the difference between the contents in the RBB and the LBB was not significant. Adenyl cyclase activity as well as the content of cyclic AMP was higher in the ordinary myocardial tissue than in the specialized myocardial tissue. Its activity was higher in the A-V node than in the His bundle or the RBB, and the activities in the His bundle, the RBB and the LBB were similar. Phosphodiesterase activity was higher in the ordinary myocardial tissue than in the A-V node, and the activities in these 4 sections of the conduction system were similar.
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PMID:Cyclic adenosine 3', 5'-monophosphate, adenyl cyclase and phosphodiesterase in the conduction system of bovine heart. 630 Apr 81

The activity of a plasma membrane cAMP-phosphodiesterase in cultured ovarian granulosa cells was regulated by follicle-stimulating hormone (FSH) and the gonadotropin-releasing hormone (GnRH) agonist [D-Ala6]des-Gly10-GnRH N-ethylamide (GnRHa). Degradation of cAMP was similar in cultures treated with FSH alone or FSH plus GnRHa when the labeled cyclic nucleotide was added from 24 to 42 h of culture. However, at 48 h and subsequent times of incubation, cAMP phosphodiesterase activity was significantly higher in cells incubated with FSH plus GnRHa. Phosphodiesterase activity was progressively increased by GnRHa concentrations between 10(-13) and 10(-10) M, and was maximally stimulated by 10(-9) M GnRHa. In comparison with control cells, FSH lowered the Vmax of cAMP catabolism by the high (1 microM cAMP substrate) and the low (50 microM) affinity phosphodiesterase, while GnRHa raised enzyme activity toward control levels. These actions of FSH and GnRHa were specific for a plasma membrane phosphodiesterase that was accessible to extracellular cAMP, since extracellular substrate was hydrolyzed, no intracellular uptake of [3H]cAMP was observed, and only a small fraction (10%) of cAMP was catabolized in the incubation medium in the absence of cells. Further, the actions of FSH and GnRHa on the membrane enzyme were the opposite of those observed when total phosphodiesterase activity was measured in cellular sonicates. Hormonal changes in phosphodiesterase activity were not due to leakage of the enzyme from damaged cells since a constant percentage of cAMP hydrolysis in the medium was observed during culture. Analysis of cAMP catabolites in granulosa cells indicated that the phosphodiesterase reaction product, 5'-AMP, was rapidly converted to adenosine by a plasma membrane 5'-nucleotidase, independent of the cellular hormonal status. These results indicate that the opposing actions of FSH and GnRHa upon granulosa cell differentiation include modulation of cAMP degradation at the plasma membrane level.
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PMID:Hormonal regulation of a plasma membrane phosphodiesterase in differentiating granulosa cells. Reciprocal actions of follicle-stimulating hormone and a gonadotropin-releasing hormone agonist on cAMP degradation. 631 58


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