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)

Gonad-stimulating substance (GSS) secreted from radial nerves induces meiotic maturation of starfish oocytes by stimulating production of 1-methyladenine (1-MeAde) in ovarian follicle cells. We have previously shown that cAMP mediates the action of GSS on 1-MeAde synthesis by starfish ovarian follicle cells. The present study examines the possible involvement of guanine nucleotide-binding regulatory proteins (G-proteins) and adenylate cyclase in the action of GSS on 1-MeAde production by starfish (Asterina pectinifera) follicle cells. GSS slightly stimulated adenylate cyclase activity in crude membrane preparations of follicle cells. GTP markedly enhanced this action of GSS in a dose-dependent manner. Nonhydrolyzable GTP analogs such as guanosine 5'-O-(3-thiotriphosphate) and 5'-guanylylimidodiphosphate, NaF, and forskolin also stimulated adenylate cyclase activity. In addition, chorela toxin (CT) stimulated adenylate cyclase activity in membrane preparations in the presence of NAD and GTP. Unlike adenylate cyclase, phosphodiesterase activity was not influenced by GSS. When crude membranes of follicle cells were incubated with [alpha-32P]NAD in the presence of CT and pertussis toxin, 45-kDa and 41-kDa proteins were ADP-ribosylated, respectively, suggesting the presence of two types (stimulatory and inhibitory) of G-proteins. It is concluded that G-proteins and adenylate cyclase play an important role in the action of GSS on 1-MeAde production by starfish ovarian follicle cells.
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PMID:Involvement of G-proteins and adenylate cyclase in the action of gonad-stimulating substance on starfish ovarian follicle cells. 184 1

When the homogenate prepared from immature rat testes was incubated with [32P]NAD, several proteins (90, 39 and 20 kDa) were ADP-ribosylated in the absence of bacterial toxins. This observation suggested the existence of an endogenous ADP-ribosyltransferase and substrates. The data that the digested product by phosphodiesterase of ADP-ribosylated 20 kDa protein was 5'-AMP suggested that 20 kDa protein was mono(ADP-ribosyl)ated. In addition, the mono(ADP-ribosyl)ation of 20 kDa protein was enhanced by guanine nucleotides such as GTP, GDP and GTP[gamma S], and decreased by the concentrations of 10 mM Mg2+. In contrast, the incorporation of ADP-ribose moiety from NAD to both 90 and 39 kDa proteins was not changed by guanine nucleotides. On the other hand, mono(ADP-ribosyl)ation of 20 kDa protein was not observed in the homogenate prepared from other tissues of the same rats. Furthermore, we found that mono(ADP-ribosyl)ation of 20 kDa protein was decreased with the maturation of the rats and that an endogenous mono(ADP-ribosyl)transferase and 20 kDa protein were located in the nuclei.
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PMID:Reduction of mono(ADP-ribosyl)ation of 20 kDa protein with maturation in rat testis: involvement of guanine nucleotides. 189 5

We used pertussis toxin to study the mechanism(s) by which divalent cations lower cellular cAMP content in bovine parathyroid cells. In cultured parathyroid cells, high extracellular Ca2+ (5 mM) or Mg2+ (5-10 mM) lowers dopamine-stimulated cAMP content by 70-90%. Pertussis toxin (0.5 microgram/ml) totally blocks the inhibitory effects of Ca2+ and Mg2+ on cAMP content. Ba2+ and Sr2+ (5 mM) also lower cAMP content by 80-90%, and this effect is, likewise, blocked by pertussis toxin. Pretreatment with pertussis toxin had no effect on the release of cAMP into the extracellular fluid. The toxin also did not modify phosphodiesterase activity in sonicates of parathyroid cells (42.68 +/- 3.26 vs. 47.00 +/- 2.82 pmol cAMP hydrolyzed/10(6) cells.20 min in control and toxin-treated cells, respectively). Moreover, addition of the phosphodiesterase inhibitor isobutyl-methylxanthine did not modify the inhibition of dopamine-stimulated cAMP accumulation by 5 mM Ca2+ in control cells (85% vs. 86% inhibition, respectively, with and without isobutylmethylxanthine). Pertussis toxin-catalyzed ADP ribosylation in homogenates of control cells demonstrated the presence of two substrates with mol wt of 40K and 41K. Preexposure of cells to pertussis toxin overnight resulted in the complete loss of both substrates on subsequent ADP ribosylation with [32P]NAD. Pertussis toxin pretreatment did not enhance adenylate cyclase activity indirectly via reducing the extracellular Ca2+-induced rise in cytosolic Ca2+, since the cytosolic Ca2+ level at 5 mM Ca2+ was about 60% higher in pertussis toxin-treated than in control cells (531 +/- 85 vs. 326 +/- 35 nM; P less than 0.05). In addition, ionomycin had no significant effect on cellular cAMP levels in control cells despite increasing the cytosolic Ca2+ concentration to levels as high as 1700 nM at 10(-5) M. Thus, changes in cytosolic Ca2+ phosphodiesterase activity, or efflux of cAMP from the cell cannot explain the inhibition of cAMP accumulation by divalent cations or the reversal of this effect by pertussis toxin. Instead, the present data suggest that extracellular divalent cations modulate the formation of cellular cAMP in parathyroid cells by a process involving a pertussis toxin-sensitive guanine nucleotide regulatory protein, presumably inhibition of adenylate cyclase by Gi via a receptor-like mechanism.
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PMID:Divalent cations suppress 3',5'-adenosine monophosphate accumulation by stimulating a pertussis toxin-sensitive guanine nucleotide-binding protein in cultured bovine parathyroid cells. 246 88

DPN 205-734 [5-(4-cyanophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-3-carbo nitrile] was investigated in vitro in Langendorff rabbit hearts, guinea pig and rabbit papillary muscles, and rat myocardium and in vivo in anesthetized and unanesthetized dogs, pithed open-chest cats, anesthetized rats, and cardiomyopathic hamsters. In vitro, this substance caused a concentration-dependent positive inotropic effect. Left ventricular dP/dtmax was increased in anesthetized dogs after intravenous injection of 0.02 and 0.2 mg/kg (35 +/- 10 and 130 +/- 13%, respectively) and in unanesthetized dogs after oral doses of 0.05-0.5 mg/kg (15 +/- 2 to 71 +/- 14%). DPN 205-734 lowered blood pressure and total peripheral resistance in several experimental models, indicating an afterload-reducing effect. It induced moderate tachycardia. The positive inotropic effect is not explainable by beta-stimulation as shown in pithed open-chest cats pretreated with propranolol. A phosphodiesterase-inhibiting activity (IC50 = 35.5 microM), measured in rat myocardium, may be primarily responsible for the positive inotropic action. In guinea pig papillary muscles partially depolarized with 22 mM K+, DPN 205-734 in a concentration of 1 microM restored slow action potentials, which were then blocked by carbachol. These actions can be explained by the increase in cardiac cyclic AMP level due to a phosphodiesterase-inhibiting effect. In rabbit papillary muscles the positive inotropic effect of DPN 205-734 (100 microM) was only moderately inhibited by carbachol (3 microM), suggesting an additional mechanism.
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PMID:Pharmacological actions of DPN 205-734, a novel cardiotonic agent. 246 46

Ventricular myocytes isolated from the hypertrophied hearts of thyrotoxic adult rats have an increase in mean protein content per myocyte (6.3 +/- 0.2 vs. 4.4 +/- 0.2 ng) compared with euthyroid cells. Viability and adenine nucleotide profiles are similar in both populations, but NAD content of the hyperthyroid myocytes is depressed (4.9 +/- 0.2 vs. 5.5 +/- 0.2 nmol/mg for controls) and UTP is higher (1.2 +/- 0.09 vs. 0.9 +/- 0.04 nmol/mg). Binding of (-)-[125I]iodocyanopindolol to intact hyperthyroid myocytes is increased by 42% compared with controls, with no change in the dissociation constant (Kd). This elevation in beta-receptor number is correlated to enhanced beta-agonist-induced adenosine 3',5'-cyclic monophosphate (cAMP) production. The half-maximal effective concentration (EC50) for the euthyroid isoproterenol dose-response curve is 2.14 x 10(-7) M but is decreased to 2.51 x 10(-8) M in hyperthyroid cardiac cells. Basal adenylate cyclase activity is apparently not affected by thyroid hormones, since basal cAMP levels for both groups are identical (5 pmol/mg) and both rise roughly twofold in the presence of a phosphodiesterase inhibitor. Forskolin-induced cAMP production and cAMP-specific phosphodiesterase activity are similar as well. In contrast to beta-adrenergic response, there are no significant differences in alpha 1-antagonist [3H]prazosin binding parameters between hyperthyroid and euthyroid cardiomyocytes.
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PMID:Hyperthyroid adult rat cardiomyocytes. I. Nucleotide content, beta- and alpha-adrenoreceptors, and cAMP production. 248 Jul 17

The possible role of adenosine 3',5'-cyclic monophosphate (cAMP) in the mechanism of the acute inhibitory effects of nicotinamide and analogues on brush-border membrane (BBM) phosphate transport was investigated. Compared with basal values, cAMP content of rat renal proximal tubule suspensions was elevated two- to fivefold when incubated at 37 degrees C for 1 h with nicotinamide, 5-methylnicotinamide, or picolinamide at 1-3 mM and in the presence of a phosphodiesterase inhibitor. Thymidine had no effect on cAMP content. There was significant and specific inhibition of BBM transport of phosphate when proximal tubules were incubated with either nicotinamide or picolinamide at concentrations that increased tubule cAMP content. Thymidine had no effect on BBM transport of phosphate. These findings were independent of the dietary Pi intake of the rats. The absence of any effect of thymidine on phosphate transport strongly suggests that inhibition of poly(adenosine diphosphate ribose) polymerase does not play a role in nicotinamide action on phosphate transport. The change in phosphate transport induced by nicotinamide occurred with no change in NAD content. These findings indicate that an increase in cAMP, rather than NAD, is the important change that may mediate the acute inhibition of Na(+)-dependent phosphate transport by nicotinamide.
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PMID:Increased cAMP in proximal tubules is acute effect of nicotinamide analogues. 255 65

Phosphodiesterase I [EC 3.1.4.1] was purified from normal human urine in a highly purified state free from phosphodiesterase II, RNase, DNase I, DNase II, and phosphatase by column chromatographies of DEAE-Toyopearl, butyl-Toyopearl, Affi-Gel blue, and Sephadex G-150. The molecular weight of the enzyme was 1.9 x 10(5) and the pH optimum around 9.0 with p-nitrophenyl deoxythymidine 5'-phosphate as the substrate. The enzyme hydrolyzed the 3'-5' linkage of various dinucleoside monophosphates at approximately the same rate and the phosphodiester bonds of cyclic 3',5'-mononucleotides to produce mononucleoside 5'-phosphate. The enzyme also hydrolyzed ADP to 5'-AMP and Pi, ATP to 5'-AMP and PPi, and NAD+ to 5'-AMP and NMN. The enzyme activity was abolished by removal of metal ions with EDTA, and the metal-free enzyme was reactivated on the addition of Zn2+. The enzyme activity was also abolished by some reducing agents and the inhibition was reversed by Zn2+. The metal-free enzyme was less stable than the native enzyme, and Zn2+ and Co2+ restored the stability of the metal-free enzyme to the level of the native enzyme. The enzyme degraded oligonucleotides and high molecular nucleotides stepwise from the 3'-termini to give 5'-mononucleotides. The enzyme hydrolyzed single-stranded DNA more preferentially than double-stranded DNA. The enzyme also nicked superhelical covalently closed circular phi X174 DNA to yield first open circular DNA and then linear DNA.
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PMID:Phosphodiesterase I in human urine: purification and characterization of the enzyme. 282 85

Binding of polyvalent antigens to IgE present in Fc epsilon receptors on the surface of mast cells and the RBL-2H3 cell line triggers the exocytotic release of allergic mediators. Preincubation of RBL-2H3 cells with cholera toxin (CT) was found to potentiate greater than or equal to 2- to 3-fold the rate and final amount of antigen-induced secretion of [3H]serotonin and N-acetyl beta-D-glucosaminidase. This was accompanied by a more variable increase in the initial rate of antigen-triggered formation of inositol phosphates. The holotoxin was required for potentiation, as neither the A nor the B subunit was effective when added separately. Four observations indicate that cAMP was not the primary effector of the augmentation of secretion caused by CT: (i) culture conditions were found in which CT caused large increases in secretion but very modest (or no) increases in cAMP; (ii) under other conditions, progressive increase in [CT] caused a maximum 2.5- to 3-fold increase in cAMP followed by a return to basal levels, whereas the secretory response saturated and remained stable; (iii) permeant cAMP analogs consistently enhanced secretion at low doses and inhibited at higher doses, but the peak enhancement was always much less than that achieved by an optimal dose of CT; (iv) the selective phosphodiesterase inhibitor Ro 20-1724 exhibited similar biphasic dose-response curves, the maximum enhancement again being small compared to that caused by CT itself. Both in vitro and in vivo, CT catalyzed transfer of ADP-ribose from NAD to two membrane proteins that comigrated on NaDodSO4/polyacrylamide gel electrophoresis with two CT substrates in other cell types, and these were identified by immunoblotting as Gs alpha. These results suggest that ADP-ribosylation of a cholera toxin substrate potentiates IgE-mediated secretion from RBL-2H3 cells by a largely cAMP-independent route.
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PMID:Cholera toxin potentiates IgE-coupled inositol phospholipid hydrolysis and mediator secretion by RBL-2H3 cells. 284 4

In order to exert its antitumor effects, the C-nucleoside tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) is converted to the dinucleotide TAD (thiazole-4-carboxamide adenine dinucleotide), an inhibitor of IMP dehydrogenase (IMPD). With few exceptions, sensitive tumors (such as the P388 leukemia) have been found to accumulate substantially more of this inhibitory dinucleotide than resistant strains (exemplified by the colon 38 carcinoma). Previous studies have attributed this difference to a depressed capacity to synthesize TAD on the part of tumors refractory to tiazofurin. In the present study, a second contributory factor has been identified, viz. an enhanced ability to degrade preformed TAD. This degradation has been traced to a soluble phosphodiesterase present at high levels in tumors naturally resistant to tiazofurin. Using standard techniques, this TAD-phosphodiesterase has been purified 200-fold from the colon 38 carcinoma. The activity so purified readily hydrolyzed TAD and ADP-ribose, but exhibited a comparatively weak activity toward NAD and thymidine-5'-monophosphate-nitrophenyl ester. ADP-Ribose was also an excellent inhibitor of the hydrolysis of TAD. It is concluded, on the basis of these results, that TAD-phosphodiesterase plays an important role in the expression of the oncolytic activity of tiazofurin. The suggestion is also made that ADP-ribose may be the natural substrate for this enzyme.
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PMID:Studies on the mechanism of action of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide). VI. Biochemical and pharmacological studies on the degradation of thiazole-4-carboxamide adenine dinucleotide (TAD). 287 71

Activation of muscarinic cholinergic receptors of 1321N1 human astrocytoma cells attenuates cyclic AMP accumulation. This effect results from an activation of phosphodiesterase with no direct inhibition of adenylate cyclase activity. In spite of this lack of coupling of muscarinic receptors to adenylate cyclase, guanine nucleotides reduce the apparent binding affinity of the agonist carbachol in a washed membrane preparation of 1321N1 cells. The order of potency for this effect is guanosine 5'-O-(3-thiotriphosphate) greater than 5'-guanylyl-imidodiphosphate = GTP = GDP; ATP has no effect. The occurrence of a Mr = 41,000 protein labeled in the presence of [32P]NAD and pertussis toxin as well as the occurrence of guanine nucleotide-mediated inhibition of forskolin-stimulated adenylate cyclase activity indicate that the functional inhibitory guanine nucleotide regulatory component of adenylate cyclase (Ni) is present in 1321N1 cells. Pertussis toxin pretreatment of NG108-15 neuroblastoma X glioma cells, which express muscarinic receptors that link through Ni to inhibit adenylate cyclase, blocked the GTP-sensitive, high affinity binding of carbachol. In contrast, pretreatment of 1321N1 cells with a concentration of pertussis toxin that blocked [32P]ADP ribosylation of the Mr = 41,000 substrate and GTP-mediated inhibition of forskolin-stimulated adenylate cyclase activity had no effect on GTP-sensitive high affinity binding of carbachol. These results suggest that muscarinic cholinergic receptors of 1321N1 cells couple to a guanine nucleotide regulatory protein that is distinct from Ni.
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PMID:Guanine nucleotide-sensitive, high affinity binding of carbachol to muscarinic cholinergic receptors of 1321N1 astrocytoma cells is insensitive to pertussis toxin. 298


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