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 study was designed to investigate the direct effect of dynorphin on atrial natriuretic polypeptide (ANP) secretion in cultured rat atrial cardiocytes via a kappa-opioid receptor activation as well as the involvement of adenosine 3',5'-cyclic monophosphate (cAMP) system in the secretion of ANP from cardiocytes. Dynorphin stimulated ANP secretion dose and time dependently from 2-day cultured atrial cardiocytes. The dynorphin-induced ANP secretion was partially antagonized by MR2266, a selective kappa-opioid receptor antagonist. U-62066E, a selective kappa-opioid receptor agonist, stimulated ANP secretion. This stimulation was also antagonized by MR2266. However, no stimulation of ANP secretion was seen with [D-Ala2,D-Leu5]enkephalin, methionine (Met)-enkephalin, or [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin. Dynorphin at 10(-6) M significantly decreased the production of cAMP in the cultured cardiocytes. However, 10(-6) M Met-enkephalin had no effect on cAMP at all. The decrease in cAMP production by the addition of dynorphin was partially antagonized with a simultaneous addition of MR2266. The dynorphin-induced ANP secretion, as well as the basal secretion, were significantly decreased by the addition of 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, as compared with the respective controls. Dibutyryl cAMP at 10(-3) M significantly decreased the basal secretion of ANP as compared with the control. Therefore, the present studies show that dynorphin selectively stimulates ANP secretion, at least in part, via the activation of a specific kappa-opioid receptor.
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PMID:Atrial natriuretic polypeptide secretion via selective activation of kappa-opioid receptor: role of dynorphin. 171 56

Effect of protein deficient diet on hepatic plasma membrane fluidity has been studied in rats using (i) steady state fluorescence polarization and anisotropy, (ii) phospholipid and cholesterol contents, (iii) phospholipid fatty acid composition, (iv) turnover of phosphatidyl choline (PC), and (v) activities of membrane-bound enzymes as parameters and rats fed casein (20%) diet as standard group. A significant increase in steady state fluorescence and anisotropy values was registered in the deficient group, indicating increased resistance and hence decrease in fluidity of the plasma membrane. Supplementation of the diet with lysine and threonine improved these values, thereby suggesting the significance of diet for membrane fluidity. Simultaneous significant alterations in other parameters, viz. (i) decrease in PC, PE and free cholesterol and increase in esterified cholesterol contents, (ii) decrease in unsaturation of fatty acids of PC, (iii) decrease in incorporation of NaH2 32PO4, [CH3-14C]choline and [CH3-14C]methionine into plasma membrane PC, and (iv) decrease in activities of plasma membrane 5'-nucleotidase and phosphodiesterase along with increase of (Na(+)-K+)ATPase and adenyl cyclase, were observed in the deficient group which on supplementation with lysine and threonine showed improvement over alterations.
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PMID:Hepatic plasma membrane fluidity and dietary proteins. 175 32

In past studies, we have demonstrated that in streptozotocin-induced diabetic or spontaneously diabetic (BB) animal models, low Km cAMP phosphodiesterase and calmodulin are decreased while a low MW inhibitor of calmodulin is increased. To extend these studies, we have determined the rate of [35S]-methionine incorporation into calmodulin in isolated fat cells from these diabetic animals, i.e. streptozotocin-induced diabetic and the BB rats, spontaneous diabetic rat, non-diabetic rat, and control. We found markedly decreased rates of synthesis of calmodulin in the fully diabetic BB rat. In order to investigate the mechanism of the reduced calmodulin biosynthesis, we probed poly A+ mRNA from control and diabetic rat livers with a calmodulin specific anti-sense oligonucleotide probe and found that the fully diabetic animals, streptozotocin-induced diabetic and genetically diabetic BB, contained markedly reduced levels of calmodulin transcripts. Thus, both calmodulin protein and its putative mRNA are decreased in diabetic rat liver. We believe that in uncontrolled diabetes, the observed elevation in the levels of cyclic AMP in plasma and tissue results in part from decreased activity of phosphodiesterase. The insulin-sensitive phosphodiesterase appears to be regulated by calmodulin. We hypothesize that cyclic AMP phosphodiesterase inactivation in diabetes results in part from insulin insufficiency and to a less well-defined genetic lesion leading to calmodulin down-regulation.
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PMID:Expression of calmodulin gene is down-regulated in diabetic BB rats. 197 47

Apoprotein E (apo-E) is a surface component of several classes of plasma lipoproteins. It functions as a ligand for receptor-mediated uptake of lipoproteins. Granulosa cells from ovaries of diethylstilbestrol-stimulated hypophysectomized immature rats cultured in serum-free medium with [35S]methionine secretes a 34-kDa protein which reacts with a monospecific anti-rat apo-E antibody and represents 0.2% of total secreted protein. Protease mapping confirms that this protein is apoprotein E. The secreted apoprotein E may be complexed with lipid since it floats in the ultracentrifuge at density less than 1.21 micrograms/ml. Freshly isolated granulosa cells contain receptors for follicle stimulating hormone (FSH) but not for human chorionic gonadotropin (hCG) or prolactin. Apoprotein E secretion is stimulated 2-fold by FSH, but hCG and prolactin have no effect. When granulosa cells develop hCG and prolactin receptors after 48 h of culture with FSH, apoprotein E secretion is not stimulated by addition of FSH, hCG, or prolactin although steroidogenesis is induced. The addition of 10(-7) M androgen plus FSH stimulates a marked increase in progestin synthesis over FSH alone, but androgen has little added effect on apoprotein E secretion. Cholera toxin (1.25 micrograms/ml) and dibutyryl cAMP (5 mg/ml), both of which increase intracellular cAMP, stimulate apo-E secretion 9-fold and 12-fold, respectively. The dibutyryl cAMP effect is dependent on both dose (greater than or equal to 0.5 mg/ml required) and time (onset at 24 h, maximum at 48 h, and back to near baseline at 96 h). Isobutylmethylxanthine, a phosphodiesterase inhibitor, augments FSH-stimulated apoprotein E synthesis 2.5-fold, supporting a role for cAMP in mediating the FSH effect. This is the first demonstration of the hormonal regulation of apoprotein E synthesis in an extrahepatic tissue.
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PMID:Regulation of apolipoprotein E synthesis in rat ovarian granulosa cells. 241 Apr 6

Papaverine, an inhibitor of cAMP phosphodiesterase, reduced yields of infectious vesicular stomatitis virus in HEp-2 cells approximately 100-fold if added to cultures at a concentration of 30 microM before and after virus infection. The extent of papaverine-induced suppression of viral growth was dependent on drug dose and treatment regimen. Cells progressively recovered their viral permissive state after removal of drug. The cyclic nucleotide, cGMP, nullified the inhibitory effect of papaverine if added to cells during drug treatment. Pulse labeling experiments with [35S]methionine showed that papaverine compromises production of all virus-specific proteins in infected cells without adversely affecting host cell protein synthesis. Treatment of cells with papaverine strongly inhibited the production of viral RNA and both cellular RNA and DNA. It was found that VSV causes an immediate but transient stimulation of DNA synthesis in HEp-2 cells which is prevented by papaverine treatment. This drug also selectively blocked primary transcription of VSV in vivo and to a lesser extent in vitro RNA polymerase activity of the virion-bound transcriptase. The finding that papaverine has a strong inhibitory effect on viral biosynthesis including early transcription suggests that VSV replication may depend on host factors that regulate intracellular levels of cyclic nucleotides such as cAMP.
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PMID:Inhibitory effect of papaverine on RNA and protein synthesis of vesicular stomatitis virus. 241 Oct 62

The cDNA nucleotide and corresponding amino acid sequences of the gamma-subunit of cyclic-GMP phosphodiesterase (cGMP-PDE gamma) from mouse retina have been determined. The cDNA translated region was found to be 91.5% homologous to the cDNA coding region for the enzyme from bovine retina [(1986) FEBS Lett. 204, 288-292]. On Northern blots of normal mouse retinal RNAs this cDNA hybridized the cGMP-PDE gamma mRNA which is 900 bp long. The mouse gamma-subunit contains 87 amino acid residues which share 97.7% homology with the bovine polypeptide [(1986) FEBS Lett. 204, 288-292]. Only two amino acids have been changed, Ala 8 to Gly and Met 17 to Ile.
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PMID:Gamma-subunit of mouse retinal cyclic-GMP phosphodiesterase: cDNA and corresponding amino acid sequence. 283 67

Bovine calmodulin analogues, spin-labeled at methionine and tyrosine residues, have been utilized in electron paramagnetic resonance (EPR) studies designed to investigate calmodulin interactions with the antipsychotic drug trifluoperazine and the calmodulin-binding protein 3',5'-cyclic nucleotide phosphodiesterase. Trifluoperazine titrations of spin-labeled calmodulin analogues were carried out in the presence of Ca(II), Cd(II), and Tb(III). Similar experiments were performed with the phosphodiesterase in the presence of Ca(II), Cd(II), La(III), Tb(III), and Lu(III). EPR signals from the methionine-directed probe proved to be more sensitive to the binding of target molecules than signals from the tyrosine-directed probe, perhaps indicating that the spin-labeled methionine is at a site close to the target molecule binding site. While the binding of TFP, as monitored by EPR spectral changes in the methionine spin-labeled calmodulin, was in evidence with Ca(II), Cd(II), and all the lanthanides examined, no binding of phosphodiesterase to calmodulin could be detected in the presence of the lanthanide ions, perhaps due to inactivation of the phosphodiesterase by lanthanide ion binding. The abilities of the spin-labeled calmodulins to activate phosphodiesterase were also investigated. The spin-labeled tyrosine calmodulin was able to activate phosphodiesterase as well as native calmodulin, while a lower degree of activation was found when the spin-labeled methionine analogue was used.
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PMID:Interactions of spin-labeled calmodulin with trifluoperazine and phosphodiesterase in the presence of Ca(II), Cd(II), La(III), Tb(III), and Lu(III). 284 52

The secretory response of cytochalasin B-treated human polymorphonuclear neutrophils to the peptide chemoattractant f-Met-Leu-Phe (FMLP), the calcium ionophore A23187 and other secretagogues was measured by assaying neutrophil supernatants for the granular enzymes beta-glucuronidase and lysozyme. The dose-dependent enzyme secretion in response to 10(-8)-10(-4) M FMLP and A23187 was unaffected by pretreatment with 10-75 microM forskolin (an activator of adenylate cyclase), but inhibited by high concentrations of prostaglandins E1 and E2. The phosphodiesterase inhibitors isobutyl-methyl-xanthine (IBMX), papaverine and Ro 20-1724 dose dependently inhibited enzyme secretion from FMLP- or A23187-treated cells, and this effect was augmented in the presence of 50-75 microM forskolin. Similar results for PGE1, forskolin and forskolin/IBMX combinations were also obtained using leukotriene B4, platelet activating factor and C5a des-Arg as secretagogues. We conclude that the adenylate cyclase system of human neutrophils is activatable by forskolin, but that the regulatory effects of adenylate cyclase stimulants in these cells are greatly attenuated unless cyclic AMP-phosphodiesterases are inhibited. Thus the phosphodiesterase activity of neutrophils may be of functional importance and is relevant to the modulation of neutrophil activity in inflammation.
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PMID:Inhibition of human neutrophil degranulation by forskolin in the presence of phosphodiesterase inhibitors. 301 41

The cyclic nucleotide phosphodiesterase (phosphodiesterase) of Dictyostelium discoideum is one of a group of developmentally regulated proteins which enable cells to aggregate by chemotaxis during the early stages of development. We report the identification and DNA sequence of a cDNA clone encoding the amino-terminal region of the phosphodiesterase. The clone, pPD-3, was selected from a cDNA library created by priming first strand synthesis using a set of oligonucleotides with sequences predicted from the amino-terminal amino acid sequence of purified phosphodiesterase. The DNA sequence of pPD-3 encodes perfectly the available phosphodiesterase amino acid sequence, and pPD-3 selects an mRNA which can be translated into material recognized by phosphodiesterase antisera. The nucleotide sequence of pPD-3 indicates there are 49 amino acids, which contain a segment possessing the characteristics of a signal peptide, that separate the amino-terminal residue identified in the purified protein from the methionine codon at which translation originates. DNA blot analysis demonstrates that the phosphodiesterase gene exists as a single copy in the nuclear genome. Analysis of RNA indicates that the phosphodiesterase transcript is 2.1 kb long, which is approximately 0.8 kb more than the minimum required to encode this protein.
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PMID:Isolation of a cDNA encoding a portion of the cyclic nucleotide phosphodiesterase of Dictyostelium discoideum. 302 Jan 55

Studies with the pyrimido-pyrimidine analogue RA 233 (Rapenton) suggest that its antimetastatic action may not be mediated entirely by inhibition of platelet function. Little is known about its direct effects on tumor cells. We investigated the in vitro effects of RA 233 on clones MTLn3 and MTC of differing metastatic potentials, isolated from the 13762NF rat mammary adenocarcinoma. The results indicated that RA 233 is cytostatic (EC50 of approximately 140 microM and approximately 180 microM for MTLn3 and MTC cells, respectively) rather than cytotoxic by determining changes in viable cell number, thymidine uptake, and incorporation of thymidine and methionine. In both clones RA 233 inhibited cAMP-dependent phosphodiesterase activity and affected cAMP accumulation in intact cells. In contrast, clonal heterogeneity in drug-induced morphological changes, such as vacuole formation and altered organization of cytoskeletal structures, as well as increased tumor cell growth at 50 microM RA 233 was observed between clones MTLn3 and MTC. These data could explain the conflicting results obtained with RA 233 when evaluated as an antimetastatic agent.
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PMID:Direct effects of the pyrimido-pyrimidine derivative RA 233 (Rapenton) on rat 13762NF mammary tumor cell clones in vitro. 302 16


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