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)

Neurohormone C (NC) is a glycopeptide isolated from bovine hypothalamus, which inhibits Ca-calmodulin (CaM)-dependent cAMP and cGMP phosphodiesterase (PDE) and is a regulator of Ca in the cell. Distribution of [45Ca]CaCl2 in the mitochondria and reticulum (SR) of heart and brain mitochondria and changes of Ca-binding proteins in these organelles under NC influence have been studied in the myocardium before and after isoproterenol-induced necrosis. Intraperitoneal administration of 80-100 mU of PDE inhibitory activity of NC to rats did not cause any noticeable changes in the protein content of intracellular organelles, but altered the affinity of certain proteins to 45Ca2+. This property of NC was especially noticeable after isoproterenol necrosis. Necrotic injury of the myocardium induced Ca2+ storage in the mitochondria and SR of brain, and decreased the Ca2+ concentration in myocardial mitochondria. NC injection to the animals with necrosis was followed by Ca2+ release from all the studied organelles.
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PMID:Neurohormonal regulation of calcium in the cell. 340 76

The interaction of six hydrolysis-resistant analogues of GTP with transducin, the signal-coupling protein in vertebrate photoreceptors, was investigated. GppNHp and GppCH2p differ from GTP at the bridging position between the beta- and gamma-phosphate groups. The other analogues studied (GTP gamma F, GTP gamma OMe, GTP gamma OPh, and GTP gamma S) differ from GTP in containing a substituent on the gamma-phosphorus atom or at a nonbridging gamma-oxygen atom. Competition binding experiments were carried out by adding an analogue, [alpha-32P]GTP, and a catalytic amount of photoexcited rhodopsin (R) to transducin and measuring the amount of bound [gamma-32P]GTP. The order of effectiveness of these analogues in binding to transducin was GTP gamma S greater than GTP much greater than GppNHp greater than GTP gamma OPh greater than GTP gamma OMe greater than GppCH2p greater than GTP gamma F A second assay measured the effectiveness of GTP gamma S, GppNHp, and GppCH2p in eluting transducin from disc membranes containing R. The basis of this assay is that transducin is released from disc membranes when it is activated to the GTP form. The relative potency of these three analogues in converting transducin from a membrane-bound to a soluble form was 1000, 75, and 1, respectively. Stimulation of cGMP phosphodiesterase activity served as a third criterion of the interaction of these analogues with transducin. The order of effectiveness of these analogues in promoting the transducin-mediated activation of the phosphodiesterase was GTP gamma S greater than GTP much greater than GppNHp greater than GTP gamma OPh much greater than GppCH2p greater than GTP gamma OMe greater than GTP gamma F GTP gamma S was more than a 1000 times as potent as GTP gamma F in activating the phosphodiesterase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of retinal transducin with guanosine triphosphate analogues: specificity of the gamma-phosphate binding region. 346 46

A monoclonal antibody that blocks the light-activated cyclic GMP (cGMP) pathway in frog photoreceptor outer segments (ROS) has been obtained. The antibody (4A) inhibits guanine nucleotide binding to G-protein, the intermediate that links rhodopsin excitation to cGMP phosphodiesterase (PDE), inhibiting light-induced PDE activity as a consequence. Antibody inhibition of the light-activated cGMP pathway is complete at a stoichiometry of approximately one antibody per G-protein in the mixture, which indicates high specificity of the inhibition. Inhibition is more pronounced than that caused by PDE inhibitors such as isobutylmethylxanthine (IBMX) or Ro 20-1724. Antibody 4A has the further effect of inhibiting the phosphorylation of two low molecular weight proteins, components I and II, whose phosphorylation normally can be stimulated by raising cGMP levels. The inhibition is not overridden by adding cGMP, which suggests that the G-protein influences these phosphorylations by a pathway distinct from its action on cGMP concentration. Antibody 4A may prove useful as a probe of the relevance of the cGMP pathway to visual transduction in living photoreceptors. Six other monoclonal antibodies to G-protein, as well as six monoclonal antibodies to rhodopsin and one to PDE, do not block light-activated guanine nucleotide binding, PDE activity, or ROS protein phosphorylations.
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PMID:A monoclonal antibody to guanine nucleotide binding protein inhibits the light-activated cyclic GMP pathway in frog rod outer segments. 609 16

Because recent observations indicate that metabolism of cyclic nucleotides may be altered in neoplastic cells, the intracellular levels of cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) were measured in mononuclear leukaemic and normal human leucocytes. The activities of adenylate cyclase, guanylate cyclase and cyclic nucleotide phosphodiesterases were also determined. Under basal conditions, cAMP levels were always higher in the normal leucocytes, whilst cGMP levels were of the same order of magnitude in both normal and leukaemic cells, causing the cAMP/cGMP ratios to be significantly lower in leukaemic leucocytes. Leukaemic cells significantly increased cyclic nucleotide levels in response to theophylline, but did not respond to serotonin, carbamylcholine or D,L-isoproterenol. Preincubation of these leucocytes with theophylline produced a detectable cAMP response to D,L-isoproterenol but no cGMP response to serotonin or carbamylcholine was found. Adenylate cyclase and guanylate cyclase were significantly lower in leukaemic than in normal cells, which could largely explain the abnormal cyclic nucleotide pattern found in human leukaemic leucocytes. In our experiments, cAMP phosphodiesterase activity was comparable in normal and leukaemic cells, whereas cGMP phosphodiesterase activity was undetectable inall mononuclear-leucocyte preparations with the methods used.
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PMID:Patterns of cyclic nucleotides in normal and leukaemic human leucocytes. 610 1

Activities of cyclic-nucleotide-hydrolysing enzymes cAMP-, cCMP- and cGMP phosphodiesterase, the intracellular concentrations of cAMP, cCMP, and cGMP, and the activity of the cAMP-dependent protein kinase were studied in serum-starved 3T3 cells stimulated to proliferate by serum. Within 1 and 2 min after stimulation the activities of cAMP- and cGMP phosphodiesterase were unaffected while the concentration of cGMP was raised and that of cAMP lowered, suggesting increased synthesis of cGMP and simultaneously reduced synthesis of cAMP. 48 h after stimulation, when the cells multiplied rapidly, both the cAMP phosphodiesterase and the cCMP phosphodiesterase were reduced. Evidence was also obtained that cAMP-dependent protein kinase is important for expressing the cAMP effect in the 3T3 cells.
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PMID:Changes in cyclic nucleotide levels and phosphodiesterase and protein kinase activities in mitogenically stimulated 3T3 fibroblasts. 611 70

Levels of cGMP phosphodiesterase, guanylate cyclase, and GTPase activities were determined in homogenates of chick pineal glands. Only small variations in vivo were observed with glands removed at different times of the day from birds under a standard cycle of illumination. Glands cultured under the cycle of illumination from late in the photoperiod showed a progressive loss of about half the phosphodiesterase activity in 24 h, and an increase of roughly 75% in GTPase activity within 12 h. No simple correlations were found between variations in levels of enzyme activity and the diurnal cycles in pineal content of cGMP and level of serotonin N-acetyltransferase (NAT) activity. However, onset of rapid increases in 3',5'-cyclic GMP (cGMP) content and NAT activity was correlated with a transient decrease of about 30% in the phosphodiesterase activity, both in vivo and in culture. Further, known inhibitors of phosphodiesterase activity previously shown to elicit increase of cGMP content and marked elevation of NAT activity in cultured glands only inhibited phosphodiesterase activity of homogenates by 25-30%. It was therefore concluded that the transient decrease in level of phosphodiesterase may facilitate onset of increase in pineal cGMP content. However, it seems improbable that changes in pineal content of enzymes of guanine nucleotide metabolism are essential to regulation of diurnal cycles in cGMP content or level of NAT activity.
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PMID:Enzymes of guanine nucleotide metabolism and the diurnal cycle in cGMP content of the chick pineal gland. 613 5

Eight-position substituted cAMP and cGMP derivatives, and phosphodiesterase inhibitors, modify endogenous 'bursting' activity in Aplysia neuron R15. Several different patterns of activity were elicited depending on the agent used. 8-Benzylthio-cAMP or 8-parachlorophenylthio-cAMP, at concentrations between 5 muM and 0.3 mM, markedly enhanced the depth and duration of the interburst hyperpolarization, and in some cells bursting was inhibited completely. In contrast, 8-parachlorophenyl-thio-cGMP treatment led to some depolarization and to the appearance of long slow bursts, with little effect on the interburst phase. When the parachlorophenylthio-derivatives of cAMP and cGMP were added together at equal concentrations, a pattern consisting of long bursts interrupted by long and deep interburst hyperpolarizations was observed. This pattern could also be elicited by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). IBMX inhibited cAMP and cGMP phosphodiesterases and caused both cAMP and cGMP to accumulate in intact ganglia and in individual identified neuronal cell bodies including that of R15. Another phosphodiesterase inhibitor, Ro 7-2956, was a more potent inhibitor of cAMP than of cGMP phosphodiesterase; Ro 7-2956 also modified bursting activity, and seemed to enhance preferentially the interburst hyperpolarization. At high concentrations the 8-substituted cAMP and cGMP derivatives also inhibited cAMP and cGMP phosphodiesterases. The 8-parachlorophenylthio-derivatives of cAMP and cGMP were indistinguishable from each other in this assay, and thus phosphodiesterase inhibition cannot be responsible for their differential effects on bursting activity. The derivatives stimulated protein kinase activity in Aplysia ganglion homogenates, as measured by the incorporation of 32P from ATP into histone. IBMX and Ro 7-2956 had no detectable effect on protein kinase activity. The concentrations of cAMP and cGMP derivatives required for protein kinase activation (10(-8)M-10(-6)M) were much lower than those required for phosphodiesterase inhibition (10(-5)M-10(-3)M). Thus, differential protein phosphorylation is more likely to be responsible for the effects of cAMP and cGMP derivatives on neuron R15 bursting activity than is differential phosphodiesterase inhibition.
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PMID:Different effects of cAMP and cGMP derivatives on the activity of an identified neuron: biochemical and electrophysiological analysis. 615 97

3T3-L1 cells contain multiple forms of cyclic nucleotide phosphodiesterase in both supernatant (100,000 X g, 40 min) and particulate fractions. Supernatant fractions from both undifferentiated and differentiated cells contained calmodulin-sensitive activity. In undifferentiated 3T3-L1 cells, only a small fraction of the total cAMP phosphodiesterase activity was found in the particulate fraction and the specific activity of the particulate was lower than the supernatant. With differentiation the specific activity of the particulate doubled, and there was a dramatic increase in total activity in this fraction, while in the supernatant total cAMP phosphodiesterase activity increased less and specific activity decreased. The particulate fraction accounted for approximately 70% of the total cAMP phosphodiesterase activity in differentiated cells in contrast to about one-third in undifferentiated cells. In addition, there was a qualitative change in particulate phosphodiesterase activity. In fractions from 3T3-L1 adipocytes, with either cAMP or cGMP as substrate, Lineweaver-Burk plots were nonlinear, with low Km components of less than 1 microM, and cGMP inhibited cAMP hydrolysis. In particulate fractions from undifferentiated cells, cGMP did not inhibit and often enhanced hydrolysis of cAMP. With differentiation, there was also a marked increase in particulate cGMP phosphodiesterase activity. cAMP and cGMP phosphodiesterase activities solubilized from particulate fraction of differentiated cells coeluted from DEAE-Biogel and exhibited kinetic properties similar to the crude particulate fractions. During differentiation, there seems to be an alteration in the distribution of phosphodiesterase activity as well as the appearance of a particulate phosphodiesterase with kinetic properties similar to a particulate phosphodiesterase found in mature rat adipocytes.
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PMID:Alterations in cyclic AMP phosphodiesterase activities during differentiation of 3T3-L1 cells. 619 86

3T3-L1 adipocytes contain both soluble and particulate cAMP phosphodiesterases which can be distinguished by several criteria. Particulate phosphodiesterase activity of 3T3-L1 adipocytes, but not undifferentiated fibroblasts, was selectively increased by incubation of cells with insulin or lipolytic hormones. Particulate cAMP phosphodiesterase activity from 3T3-L1 adipocytes was very sensitive to inhibition by cilostamide in an apparently competitive fashion. Particulate activity from undifferentiated 3T3-L1 fibroblasts or supernatant activity from either type of cell was much less sensitive to cilostamide. On the other hand, supernatant cAMP phosphodiesterase activity from both undifferentiated fibroblasts and 3T3-L1 adipocytes was very sensitive to inhibition by Ro-20-1724 in an apparently competitive fashion. Ro-20-1724 was not an effective inhibitor of particulate activity from either type of cell. In fractions from 3T3-L1 adipocytes, isobutylmethylxanthine (IBMX) effectively inhibited both supernatant and particulate cAMP phosphodiesterase activities. In addition, however, IBMX was relatively more specific in inhibiting supernatant calmodulin-activated cGMP phosphodiesterase activity than supernatant calmodulin-independent or particulate cGMP phosphodiesterase activities. In intact 3T3-L1 adipocytes, cilostamide enhanced lipolysis in the absence or presence of isoproterenol and had no effect on cAMP content in the presence of low concentrations of isoproterenol. Ro-20-1724 increased lipolysis to a lesser extent than cilostamide and did not enhance isoproterenol-stimulated lipolysis, but did increase isoproterenol-stimulated accumulation of cAMP to a greater extent than cilostamide. Like cilostamide, Ro-20-1724 did not enhance accumulation of cAMP in the absence of isoproterenol. IBMX enhanced lipolysis and cAMP accumulation with or without isoproterenol. Taken together, these results support the idea that although particulate and soluble low Km phosphodiesterases influence cAMP content, the particulate enzyme may be more important in the metabolism of cAMP involved in the regulation of lipolysis. Since combinations of Ro-20-1724 and cilostamide were not as effective as IBMX in increasing cAMP content, perhaps the calmodulin-dependent phosphodiesterase, which is selectively inhibited by IBMX, is also involved in the regulation of total cell cAMP content.
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PMID:Selective effects of phosphodiesterase inhibitors on different phosphodiesterases, adenosine 3',5'-monophosphate metabolism, and lipolysis in 3T3-L1 adipocytes. 620 9

After incubation with 0.5 mM isobutylmethylxanthine, 1 microM dexamethasone, and 1 microM insulin for 72 h, 3T3-L1 cells acquire the phenotypic characteristics of mature adipocytes, including a hormone-sensitive particulate cAMP phosphodiesterase activity. In addition, adipocytes contain soluble cAMP and calmodulin-sensitive and -insensitive cGMP phosphodiesterase activities. After exposure of the differentiated cells to 1 microM epinephrine, cAMP content increased, reaching a maximum in 2-4 min, and then declined to the control level by 20 min. After incubation of adipocytes with 10 nM dexamethasone for 72 h, the initial increment in cAMP produced by epinephrine was not altered, but the decline in cellular cAMP to basal levels was delayed. Treatment with 10 nM dexamethasone prevented hormonal activation of particulate cAMP phosphodiesterase activity without altering basal activity (11). Soluble cAMP and calmodulin-sensitive and -insensitive cGMP phosphodiesterase activities were also reduced by exposure to 10 nM dexamethasone; higher concentrations were required to decrease basal particulate phosphodiesterase activities. Estradiol did not alter phosphodiesterase activities. Incubation of either undifferentiated (fibroblasts) or differentiated (adipocytes) 3T3-L1 cells with 1 microM dexamethasone for 48 h reduced cAMP and cGMP phosphodiesterase activities. After removal of dexamethasone, phosphodiesterase activities were restored to control levels in 4-6 days. The effects of dexamethasone on phosphodiesterase activities could in part account for the observed alterations in hormone-induced accumulation of cAMP in steroid-treated cells and for the permissive effects of glucocorticoids on certain cAMP-mediated processes.
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PMID:Effect of dexamethasone on adenosine 3',5'-monophosphate content and phosphodiesterase activities in 3T3-L1 adipocytes. 620 10


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