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)

The present studies were performed in order to examine the possible role of cyclic GMP-stimulated phosphodiesterase (cGMP-PDE) activity in the inhibitory action of the inflammatory peptide bradykinin on cyclic AMP (cAMP) accumulation in D384 cells. Bradykinin decreased the forskolin-stimulated cAMP accumulation in the presence of the phosphodiesterase inhibitor rolipram, and caused a transient 50% rise in cellular cGMP in the presence of the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX). Both basal and bradykinin-stimulated cGMP accumulation were about 8 times higher in the presence of IBMX than in the presence of rolipram. Sodium nitroprusside, which caused a 20-70-fold increase in cGMP levels reduced forskolin stimulated cAMP accumulation, whereas hydroxylamine, which maximally caused a 16-fold increase in cGMP, did not. 8-bromo-cGMP or dibutyryl cGMP had no effect on cAMP accumulation induced by forskolin. The inhibitory effect of nitroprusside was totally reversed by blocking the soluble guanylate cyclase activity by methylene blue treatment; however, the inhibitory action of bradykinin on cAMP accumulation was not changed by this treatment. Additionally, inhibition of nitric oxide synthesis, which is known to be regulated by Ca2+ and in turn stimulates cGMP production, by N omega-nitro-L-arginine (L-NAME) treatment did not alter the inhibitory effect of bradykinin on forskolin-induced cAMP accumulation. These results indicate that large increases in cGMP may regulate cAMP via cGMP-PDE whereas the small increase induced by bradykinin is insufficient and that cGMP is not involved in the inhibitory action of bradykinin on cAMP levels in D384 cells.
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PMID:Bradykinin inhibition of cyclic AMP accumulation in D384 astrocytoma cells. Evidence against a role of cyclic GMP. 128 20

The interaction of hormones acting via the mobilization of calcium and stimulation of cAMP levels in cells was examined by determining the effects of carbachol and forskolin on cAMP and cGMP accumulation in mouse parotid gland. Treatment of isolated acini with either carbachol (0.01 to 20 microM) or forskolin (1 microM) alone produced little or no increase in cAMP levels; carbachol, however, augmented the effect of forskolin on cAMP accumulation approximately 3- to 4-fold. The effects of carbachol on forskolin-stimulated cAMP levels were further augmented approximately 10-fold in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (MIX) but not in the presence of "low Km" cGMP-inhibited phosphodiesterase inhibitor milrinone. Augmentation of cAMP levels also occurred in the presence of carbachol plus the beta-adrenergic agonist isoproterenol (0.01 microM). In either the presence or absence of forskolin, carbachol increased cGMP levels independently of the inclusion of MIX and in a fashion parallel to that observed for cAMP accumulation. In the presence of forskolin (1 microM), the concentration of carbachol that produced half-maximal effects on cAMP and cGMP levels was 0.62 and 0.72 microM, respectively. Similar values were obtained in the presence of MIX. Cyclic GMP levels were also enhanced by carbachol plus isoproterenol. Hydroxylamine, as well as dibutyryl-cGMP and 8-bromo-cGMP in combination with forskolin, mimicked the effects of carbachol plus forskolin on cAMP levels. LY83583 (6-anillino-5,8-quinolinedione), an agent that lowers cGMP by inhibiting guanylate cyclase, reduced basal levels of cGMP and also completely prevented the increase in cGMP caused by carbachol plus forskolin. In these experiments, however, the augmentation of forskolin-stimulated cAMP levels by carbachol was reduced by approximately 50%. Additional studies suggest that calcium is also required for carbachol augmentation of forskolin-stimulated cAMP accumulation by effects on the adenylate cyclase complex. Augmentation of cAMP levels by carbachol did not involve effects on cAMP degradation. The results suggest that, when cAMP synthesis is stimulated by forskolin or isoproterenol, the muscarinic agonist carbachol augments cAMP accumulation by mechanisms involving cGMP and calcium in mouse parotid gland.
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PMID:Regulation of cAMP metabolism in mouse parotid gland by cGMP and calcium. 170 Feb 70

2',3'-Cyclic nucleotide-3'-phosphodiesterase (CNP1 and CNP2 with Mr of 46,000 and 48,000, respectively) is the major enzyme of central nervous system myelin. It is associated with oligodendroglial plasma membrane and uncompacted myelin (myelin-like fraction), which are in contact with glial cytoplasm. Proteins of the myelin-like fraction were labeled with [3H]palmitic acid in brain slices from 17-day-old rats and immunoprecipitated with anti-CNP antiserum. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography of immunoprecipitated material revealed intense acylation of CNP1 and CNP2, and radioactivity was released by hydroxylamine. Palmitic acid was covalently bound to CNP because radioactivity was not removed by extraction of immunoprecipitated CNP with organic solvent or by boiling in sodium dodecyl sulfate and dithiothreitol. However, treatment of immunoprecipitated CNP with (a) hydroxylamine-released palmitohydroxamate and palmitic acid, (b) sodium borohydride-released hexadecanol, and (c) methanolic-KOH-released methyl palmitate. Synthesis, acylation, or transport of CNP was not affected by monensin or colchicine. However, acylation of CNP was inhibited 24-32% by cycloheximide. These results provide conclusive evidence that CNP1 and CNP2 are fatty acid acylated with palmitate through a thioester linkage and is posttranslationally modified sometime after synthesis.
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PMID:2',3'-cyclic nucleotide-3'-phosphodiesterase in the central nervous system is fatty-acylated by thioester linkage. 216 18

The roles of Ca2+ and cyclic nucleotides as secondary, intracellular messengers for exflagellation of Plasmodium berghei and Plasmodium falciparum were investigated. Treatment with Ca2+ antagonists such as TMB-8 (an inhibitor of intracellular Ca2+ release) or W-7 (a calmodulin inhibitor) strongly inhibited exflagellation induced by alkaline medium at pH 8.0 whereas EGTA (a Ca2+ chelator) or nicardipine and nifedipine (Ca2+ channel inhibitors) had no effect. These results may indicate that mobilization of parasites' internal resources of Ca2+ is a prerequisite for exflagellation. Agents which increase cAMP levels did not induce exflagellation at the non-permissive pH of 7.3, and had no significant inhibitory effect at the permissive pH of 8.0. IBMX (cAMP/cGMP-phosphodiesterase inhibitor), however, enhanced exflagellation at pH 7.3, indicating the possibility that cGMP, but not cAMP, may be involved in the induction of exflagellation. Furthermore, cGMP or agents which increase cGMP levels such as nitroprusside (a potent activator of guanylate cyclase), enhanced exflagellation at pH 7.3, whereas N-methyl-hydroxylamine (guanylate cyclase inhibitor) inhibited the exflagellation at pH 8.0. From these results, it may be concluded that the induction of exflagellation requires both Ca2+ mobilization and an increase in cGMP levels.
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PMID:Possible roles of Ca2+ and cGMP as mediators of the exflagellation of Plasmodium berghei and Plasmodium falciparum. 217 16

Just as cAMP is regarded as an intracellular mediator of histamine, so has cGMP been connected with cholinergic stimulation of gastric acid secretion. The object of the present investigation was to study the possible role of cellular cGMP on 14C-aminopyrine uptake, an indirect measure of parietal cell H+-production, by using mixtures of isolated rat gastric cells and fractions with different parietal cell content. Cellular cAMP and cGMP. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) enhanced the cAMP and cGMP of gastric cells in a time- and concentration-dependent manner, by 98 and 124% (1 mmol/l) and was included in all further studies. In parietal cell enriched fractions, histamine elevated cAMP by 109% (100 mumol/l) without changing cGMP while carbachol did not influence either nucleotide. Various thiols and nitrogen compounds strongly enhanced cellular cGMP, e.g. hydroxylamine and L-cysteine (1 mmol/l) by 527 and 656%, whereas changes in cAMP were minimal. The hydroxylamine response occurred in parietal cell depleted and enriched fractions. 14C-aminopyrine (AP) uptake. IBMX alone reduced the basal AP uptake, potentiated the effect of histamine, and inhibited the effect of carbachol, which alone stimulated basal accumulation by 302%. The most efficacious stimulant of parietal cell H+-production was dibutyryl cAMP (582%, 100 mumol/l), whereas dibutyryl cGMP was without effect. However, this latter compound (1 mmol/l) reduced AP accumulation due to dibutyryl cAMP almost completely. Thiols and nitrogen compounds all more or less reduced AP uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic GMP and acid production in isolated gastric cells of the rat. 241 74

Hydroxylamine derivatives markedly potentiated responses of the canine colonic mucosa to histamine, but not to carbachol or 5HT. Effects noted were produced upon either luminal or serosal addition of the agents, suggesting an intracellular mechanism. Similar potentiations were observed with a phosphodiesterase inhibitor, IBMX, suggesting that hydroxylamines could act by altering cyclic nucleotide levels. Since such derivatives could be produced as intermediates by colonic bacteria, the effects noted could have pathological implications.
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PMID:Histamine stimulation of canine colonic epithelium: potentiation by hydroxylamines. 243 48

Incubated slices of young rat cerebellum were used to examine the possible relationship between the neurotoxic effects of excitatory amino acids and their ability to elicit large increases in the levels of cyclic GMP in this tissue. No cell death was detectable following exposure of the slices to the guanylate cyclase activator, nitroprusside (up to 0.3 mM), the phosphodiesterase inhibitor, isobutylmethylxanthine (0.5 mM), or to cyclic GMP (10 mM) and its dibutyryl and 8-bromo derivatives (0.5 mM). However, incubation of the slices with tbe guanylate cyclase inhibitors, N-methylhydroxylamine and hydroxylamine (0.1-1 mM), methylene blue (10-100 microM), ethacrynic acid (300 microM) and retinol (1 mM) caused a progressive destruction of the differentiating cells. The damage induced by N-methylhydroxylamine and hydroxylamine was inhibited by nitroprusside, cyclic GMP and isobutylmethylxanthine. It could also be reduced by lowering the partial pressure of oxygen, by oxygen radical scavenging enzymes and by omitting Ca2+ from the medium. Oxygen radical generating enzyme systems mimicked the pattern of toxicity of the guanylate cyclase inhibitors but their effects were not reduced by nitroprusside or omission of Ca2+. The results indicate that guanylate cyclase/cyclic GMP does not mediate amino acid neurotoxicity but, instead, may be part of a protective mechanism against oxygen free radicals.
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PMID:Cyclic GMP and cell death in rat cerebellar slices. 290 94

The secretion in Escherichia coli of a C-terminally truncated periplasmic enzyme from Salmonella typhimurium, the glpQ-encoded glycerolphosphate phosphodiesterase, was studied. Plasmid pRH100, carrying the truncated glpQ gene, directs the synthesis of a 30,000-molecular-weight (30 K) protein that is processed to a mature 27.5 K protein. (The mature wild-type protein is a 38 K protein.) The truncated protein is not released into the periplasm but remains membrane associated, although it becomes protease sensitive after conversion of cells to spheroplasts. The presence of pRH100 strongly reduces the amount of some other proteins in the periplasm, including the maltose- and ribose-binding proteins. The reduction does not occur at the level of transcription or early translation, as shown by lacZ fusions to the gene coding for the structural gene of the maltose-binding protein. Outer membrane proteins are not affected. A hydroxylamine-induced mutation in the sequence of glpQ corresponding to the mature polypeptide overcomes the inhibitory effect of pRH100. The mutated gene no longer directs the synthesis of the 30/27.5 K protein but directs that of a new 19 K protein which is not membrane bound. We propose that sorting signals in the mature GIpQ protein are necessary for effective translocation to the periplasm and that the C-terminal third of the protein is essential for release into the periplasm.
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PMID:Defective secretion of maltose- and ribose-binding proteins caused by a truncated periplasmic protein in Escherichia coli. 388 67

In mouse parotid acini both cholinergic and beta-adrenergic agonists increased intracellular levels of cyclic-GMP (c-GMP) as well as amylase release. The derivative of c-GMP, 8-bromo-c-GMP, mimicked the effects of cholinergic and beta-adrenergic stimulation on amylase release. Nitroprusside (NP), hydroxylamine (HA) and sodium azide (NaA) increased c-GMP levels and also enhanced amylase release in a dose-dependent manner; cyclic-AMP (c-AMP) levels were not affected. The phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (MIX) enhanced the effects of carbachol on both c-GMP accumulation and amylase release. These results suggest that c-GMP may mediate the actions of cholinergic agonists and at least partially mediate the actions of beta-adrenergic agonists on mouse parotid enzyme release.
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PMID:Does cyclic GMP mediate amylase release from mouse parotid acini? 618 89

Nuclei isolated from rat liver were incubated with NAD whose two ribose moieties were respectively labeled with 3H or 14C. By enzymatic (phosphodiesterase) and/or chemical (hydroxylamine) attack on doubly labeled ADP-ribosylated nuclear residues, AMP was found after hydroxylaminolysis as well as iso-ADP-ribose after phosphodiesterase plus hydroxylamine, in the absence of detectable amounts of ribose-5-phosphate. This is taken to indicate the existence of additional ribose-protein binding sites in in vitro ADP-ribosylated nuclear proteins: Besides C-1" (Hayaishi et al., Stocken et al.) C-2' and/or C-3' (purine-near) as well as C-2" and/or C-3" (pyrimidine-near), not only at the end but also within the chain of oligo-ADPR.
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PMID:A note on the ADP-ribose-protein linkages in rat-liver nuclei: a possible approach to assessing megavitamin therapy with niacin. 630 20


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