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)

1 The vascular relaxant effects of histamine, adenosine, isoprenaline nitroglycerine, papaverine and 3-isobutyl-l-methylxanthine (IBMX) were assessed individually, in strips of rabbit renal artery moderately contracted with noradrenaline (NA) in the absence or presence of phosphodiesterase inhibitors (papaverine and IBMX) or verapamil, a Ca(2+) antagonist.2 The vasodilator effect of histamine was potentiated by papaverine (6.1 x 10(-7) M) and IBMX (4.4 x 10(-5) M) but inhibited dose-dependently by verapamil (5.1 and 51.0 x 10(-7) M).3 Adenosine-induced vascular relaxations were greatly increased in the presence of papaverine (6.1 x 10(-7) M) but significantly reduced in the presence of IBMX (4.4 x 10(-5) M) or verapamil (5.1 and 51.0 x 10(-7) M).4 The vasodilatation produced by isoprenaline was increased in the presence of IBMX (4.4 x 10(-5) M) or papaverine (6.1 x 10(-7) M), but inhibited by verapamil (5.1 and 51.0 x 10(-7) M).5 The vascular relaxant effects of nitroglycerine and papaverine were inhibited in the presence of IBMX (4.4 x 10(-5) M) or verapamil (5.1 and 51.0 x 10(-7) M). Papaverine (6.1 x 10(-7) M) also antagonized nitroglycerine-induced vascular relaxation.6 The vasodilator effect of IBMX was greatly reduced in the presence of papaverine (6.1 x 10(-7) M) or verapamil (5.1 and 51.0 x 10(-7) M).7 The vascular relaxant effect of verapamil was reduced proportionally by raising the extracellular Ca(2+) concentration from 1.25 to 5.0 mM while those elicited by histamine, adenosine, isoprenaline, nitroglycerine, papaverine and IBMX were not modified by this procedure.8 These results were taken as an indication that several vasodilators (e.g. histamine, adenosine, isoprenaline, nitroglycerine, papaverine and IBMX), but not a Ca(2+) antagonist such as verapamil, produce a fraction of their vasodilator effects by promoting Ca(2+) extrusion from and/or Ca(2+) sequestration into the vascular smooth muscle cells, via a cyclic adenosine 3',5'-monophosphate-dependent mechanism.
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PMID:Studies on the mechanism of action of various vasodilators. 615 29

Protein I is a neuronal phosphoprotein associated primarily with synaptic vesicles. Regulation of its state of phosphorylation has been investigated in slices of rat facial nucleus. This brainstem motor nucleus has a facilitatory serotonergic input and contains no interneurons. Serotonin (5-hydroxytryptamine, 5-HT, 10(-4) M), in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX, 4 x 10(-5) M), converted approximately 26% of Protein I in these slices from the dephospho-form to the phospho-form. This effect was partially inhibited using two classical 5-HT antagonists, mianserin added to the slices during in vitro incubation and metergoline administered in vivo. The effect of 5-HT appeared to be Ca2+-dependent, unlike that of IBMX (10(-3) M). Adenosine, its analog 2-chloroadenosine, and ATP also increased the phosphorylation of Protein I in facial nucleus slices. 2-Chloroadenosine (5 x 10(-4) M) caused a 29% phosphorylation of Protein I, and this effect was not dependent on extracellular Ca2+. The phosphorylation of Protein I caused both by 2-chloroadenosine and by ATP was inhibited by the adenosine antagonist 2'-deoxyadenosine. Results of additional experiments suggest that the great majority of the Protein I in the facial nucleus is present in presynaptic terminals other than the serotonergic afferents. It is concluded that the stimulation by 5-HT and adenosine of Protein I phosphorylation results largely from a direct action of these compounds on those Protein I-containing terminals.
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PMID:Neurotransmitter- and neuromodulator-dependent alterations in phosphorylation of protein I in slices of rat facial nucleus. 616 92

The present investigation was designed to study the histamine release and pharmacologic characteristics of dispersed human lung mast cells, particularly in comparison with parenchymal tissue fragments. Dispersed human lung mast cells were prepared by enzymatic treatment (yield, 0.5 to 2 x 10(6) mast cells/g tissue). Purity was 1 to 8% (mean, 3.6% +/- 0.7%), and histamine content varied from 2 to 6 pg/cell (mean, 3.6 +/- 0.5 pg/cell). Release, studied using anti-IgE as the stimulus, was relatively rapid, being essentially complete within 15 min when high concentrations of anti-IgE (greater than or equal to 0.3 microgram/ml) were used and was not enhanced by phosphatidyl serine. The concentration of drug required to inhibit histamine release by 50% in dispersed cells for a series of pharmacologic agents, including the beta-adrenergic agent fenoterol, the prostaglandin E2, and the phosphodiesterase inhibitor isobutylmethylxanthine, were 0.1 to 1 microM, 50 microM, and 0.5 mM, respectively; similar results were obtained in simultaneous experiments performed using tissue fragments. Adenosine enhanced release (19 +/- 3.4%) at low concentrations (10 microM) and inhibited release (61 +/- 5.1%) at high concentrations (1mM). The H2 agonist, dimaprit (at 10(-5) to 10(-7) M) and prostaglandin D2 (at 10(-4) to 10(-6) M) had no effect on histamine release, whereas deuterium oxide potentiated histamine release. This study serves to quantitate the pharmacologic effects of several agents on anti-IgE-mediated histamine release from dispersed human lung mast cells and has further suggested that the dispersed cell system is similar to the standard chopped lung system in dose-response relationships, kinetics, and pharmacologic modulation. It also indicates that the enzymatic treatment of the cells does not affect the release characteristics or functional capacity of several different receptors, and that this preparation, therefore, appears suitable as an in vitro human model of mediator release that can be used for the evaluation of pharmacologic agents and for further mast cell purification.
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PMID:Dispersed human lung mast cells. Pharmacologic aspects and comparison with human lung tissue fragments. 618 23

To investigate the possibility that purines modulate the response of testicular cells to gonadotropin, binding of adenosine analogs and biological responses to adenosine were evaluated in Sertoli cell-enriched cultures. The adenosine analog cyclohexyladenosine bound specifically to a crude particulate fraction prepared from such cultures. Binding was saturable, and steady state studies showed the presence of a high affinity binding site (Kd = 2.1 +/- 0.3 nM; n = 4) and a receptor density of 200-300 fmol/mg protein. The bound radioactive ligand was displaced by N6-phenylisopropyladenosine (PIA), adenosine, and methylisobutylxanthine. In addition to the presence of a specific binding site, purines modulated the biological function of the Sertoli cell. The adenosine analog PIA inhibited both the FSH-dependent cAMP response and the FSH-stimulated androgen aromatization. Under all experimental conditions, the IC50 of PIA was 1-3 nM, and maximal effects were observed at 10-100 nM PIA. Adenosine itself inhibited the FSH-dependent response of the Sertoli cell, but was less potent than PIA. In addition, purine inhibition of the FSH response was antagonized by methylisobutylxanthine, while the nonxanthine phosphodiesterase inhibitor Ro 20-1724 [4-(3-butoxy-4-methoxybenzyl)2-imidazolidinone] was without effect. Purine modulation was evident not only when cells were stimulated with FSH, but also when the androgen aromatization was augmented by the beta-adrenergic agonist isoproterenol, cholera toxin, and forskolin. On the contrary, the purines had no effect when cells were stimulated with (Bu)2cAMP. The data reported are consistent with the presence of purine inhibitory receptors in Sertoli cell-enriched cultures and show that purines can regulate the response of the immature Sertoli cell in vitro.
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PMID:Purine modulation of the hormonal response of the rat Sertoli cell in culture. 620 14

The effect of cyclic AMP and related compounds on both in vivo and in vitro epidermal cell migration during wound closure in the adult newt was examined. Cyclic AMP (cAMP) and N6,O2'-dibutyryl cyclic AMP (db-cAMP) inhibited migration both in vivo and in vitro when used with equimolar concentrations of theophylline, an inhibitor of 3',5'-cyclic nucleotide phosphodiesterase. Neither db-cAMP nor theophylline alone inhibited migration in vivo. Adenosine 5' monophosphate (AMP), cyclic guanosine 3',5' monophosphate (cGMP) and imidazole, a potentiator of phosphodiesterase were tested in vivo and had no effect on migration. Isoproterenol and epinephrine, which are known to stimulate adenylate cyclase, inhibited migration in vitro. Experiments using the protein synthesis inhibitor, cycloheximide, suggest that cAMP could be acting partially through regulation of protein synthesis but that other factors are involved. Dibutyryl cyclic AMP and theophylline had no effect on the incorporation of 3H-leucine into protein. The inhibition of migration both in vivo and in vitro provides further evidence for a role of cAMP in the regulation of cell motility.
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PMID:Effect of cAMP and related compounds on newt epidermal cell migration both in vivo and in vitro. 625 Nov 54

Previous work in our laboratory led us to postulate that N2a cells release adenosine into growth medium, where it acts at the extracellular adenosine receptors to modulate the sensitivity of the cells to the cyclic AMP-elevating effect of adenosine [Green, RD, J Pharmacol Exp Ther 201:610, 1977]. We have now devised a high-performance liquid chromatographic (HPLC) procedure capable of quantitating the concentrations of adenosine in cells and tissue culture media. Growth media of N2a cells and a variant of N2a cells deficient in hypoxanthine-guanine phosphoribosyltransferase (HGPRT-) contain 10-20 nM adenosine, while that of a variant deficient in adenosine kinase (AK-) is elevated severalfold. It appears that the concentration of adenosine in growth media is determined by both the rate at which it is released by cells into the medium and the rate at which it is metabolized by adenosine deaminase present in the serum in the growth medium. Both N2a and AK- cells release considerable amounts of adenosine into serum-free medium (SFM) over a short period. Adenosine release is greater from AK- cells and is accelerated by erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), a potent adenosine deaminase inhibitor. This accelerated release is retarded by dipyridamole and homocysteine. Surprisingly, dipyridamole and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20 1724), a potent phosphodiesterase inhibitor, stimulate basal adenosine release from N2a but not from AK- cells. It remains to be determined if this is due to an effect of these compounds on adenosine kinase. These results give further support for the hypothesis that adenosine in growth medium modulates the sensitivity of the cells to the cyclic AMP-elevating affect of adenosine, and furthermore they suggest that adenosine in growth media may tonically stimulate adenylate cyclase and affect processes controlled by the cyclic AMP:cyclic AMP-dependent protein kinase system.
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PMID:Release of adenosine by C1300 neuroblastoma cells in tissue culture. 626 30

Adenosine stimulates the formation of cyclic 3',5'-adenosine monophosphate (cyclic AMP) in rat spinal cord tissue slices in a concentration-dependent manner with maximal accumulation (30 pmol/mg of protein) at a concentration of 1 mM (Ec50 50 microM). 2-Chloroadenosine (EC50 1 microM) produced a maximal accumulation to 50 pmol/mg of protein. The adenosine antagonists, theophylline and isobutylmethylxanthine, block the increase, and the phosphodiesterase inhibitor, RO 20-1724, potentiates the increase in cyclic AMP accumulation. Adenosine deaminase eliminated the adenosine-dependent increase. Cyclic AMP accumulation was also enhanced by ATP, ADP and 5'-AMP. However, the stimulation due to these nucleotides was dependent upon conversion to adenosine. The increase in cyclic AMP accumulation was more than additive when adenosine was combined with norepinephrine. This potentiation effect is blocked by theophylline, isobutylmethylxanthine and alpha adrenergic antagonists. Additional experiments revealed that only postsynaptic alpha adrenergic agonists were capable of potentiating the response to adenosine. The interaction is concentration-dependent, is also observed with phosphorylated nucleotides of adenosine and is blocked specifically by alpha receptor antagonists. Receptor binding assays revealed that adenosine does not alter the number of alpha adrenergic receptors. Both the alpha receptor and adenosine-stimulated cyclic AMP accumulation were Ca++-dependent. These results suggest that adenosine-dependent cyclic AMP formation in rat spinal cord is mediated through two types of receptors, one of which is independent, and the other coupled to the alpha adrenergic receptor.
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PMID:Adenosine regulation of cyclic 3',5'-adenosine monophosphate formation in rat spinal cord. 627 Mar 5

Extracts of Chlorella pyrenoidosa, Euglena gracilis var. bacillaris, spinach, barley, Dictyostelium discoideum and Escherichia coli form an unknown compound enzymically from adenosine 5'-phosphosulphate in the presence of ammonia. This unknown compound shares the following properties with adenosine 5'-phosphoramidate: molar proportions of constituent parts (1 adenine:1 ribose:1 phosphate:1 ammonia released at low pH), co-electrophoresis in all buffers tested including borate, formation of AMP at low pH through release of ammonia, mass and i.r. spectra and conversion into 5'-AMP by phosphodiesterase. This unknown compound therefore appears to be identical with adenosine 5'-phosphoramidate. The enzyme that catalyses the formation of adenosine 5'-phosphoramidate from ammonia and adenosine 5'-phosphosulphate was purified 1800-fold (to homogeneity) from Chlorella by using (NH(4))(2)SO(4) precipitation and DEAE-cellulose, Sephadex and Reactive Blue 2-agarose chromatography. The purified enzyme shows one band of protein, coincident with activity, at a position corresponding to 60000-65000 molecular weight, on polyacrylamide-gel electrophoresis, and yields three subunits on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis of 26000, 21000 and 17000 molecular weight, consistent with a molecular weight of 64000 for the native enzyme. Isoelectrofocusing yields one band of pI4.2. The pH optimum of the enzyme-catalysed reaction is 8.8. ATP, ADP or adenosine 3'-phosphate 5'-phosphosulphate will not replace adenosine 5'-phosphosulphate, and the apparent K(m) for the last-mentioned compound is 0.82mm. The apparent K(m) for ammonia (assuming NH(3) to be the active species) is about 10mm. A large variety of primary, secondary and tertiary amines or amides will not replace ammonia. One mol.prop. of adenosine 5'-phosphosulphate reacts with 1 mol.prop. of ammonia to yield 1 mol.prop. each of adenosine 5'-phosphoramidate and sulphate; no AMP is found. The highly purified enzyme does not catalyse any of the known reactions of adenosine 5'-phosphosulphate, including those catalysed by ATP sulphurylase, adenosine 5'-phosphosulphate kinase, adenosine 5'-phosphosulphate sulphotransferase or ADP sulphurylase. Adenosine 5'-phosphoramidate is found in old samples of the ammonium salt of adenosine 5'-phosphosulphate and can be formed non-enzymically if adenosine 5'-phosphosulphate and ammonia are boiled. In the non-enzymic reaction both adenosine 5'-phosphoramidate and AMP are formed. Thus the enzyme forms adenosine 5'-phosphoramidate by selectively speeding up an already favoured reaction.
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PMID:Purification and properties of adenylyl sulphate:ammonia adenylyltransferase from Chlorella catalysing the formation of adenosine 5' -phosphoramidate from adenosine 5' -phosphosulphate and ammonia. 627 7

Adenosine 5'-(S)-[16O,17O,18O]phosphate was pyrophosphorylated by the combined action of adenylate kinase and pyruvate kinase. The isotopomers of adenosine 5'-[alpha-16O,17O,18O]triphosphate were hydrolysed by venom 5'-nucleotide phosphodiesterase (Crotalus adamanteus) in H2(17)O. Analysis by 31P nuclear magnetic resonance spectroscopy of the resulting adenosine 5'-[16O,17O,18O]phosphate, after cyclization and esterification, showed that the hydrolysis occurs with retention of configuration at phosphorus. The most likely explanation of this observation is that the enzymic hydrolysis involves a double displacement at phosphorus with a covalent nucleotidyl--enzyme intermediate on the reaction pathway.
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PMID:The stereochemical course of hydrolysis catalysed by snake venom 5'-nucleotide phosphodiesterase. 628 Jun 70

In the isolated rat heart, changes in the ventricular fibrillation threshold (VFT) relate to the myocardial cyclic AMP content rather than to the high-energy phosphate content. After coronary ligation the reduction in VFT correlates with the increase in ischemic tissue cyclic AMP. Agents that reduce the myocardial cyclic AMP (propranolol, 16 microM in perfusate, or amiodarone, 42 microM/kg pretreatment) prevent the postligation fall of the VFT without altering high-energy phosphate depletion. Conversely, theophylline (500 microM), which increases cyclic AMP in ischemic myocardium, causes a greater reduction of VFT without increasing high-energy phosphate depletion. Spontaneous ventricular tachycardia and fibrillation are uncommon in coronary ligated hearts in the first 15 min after ligation (10-20%); these arrhythmias are greatly increased either by reducing the perfusate potassium from 5.9 to 3.0 mM or by pretreating hearts with 1-methyl-3-isobutyl xanthine (10 microM), a cyclic-AMP phosphodiesterase inhibitor. Adenosine (100 microM) antagonizes the increased arrhythmogenesis in both low perfusate potassium and cyclic-AMP phosphodiesterase-inhibited hearts, in the latter without reducing the ischemic tissue cyclic AMP levels. The antiarrhythmic action of adenosine in these hearts is independent of reducing tissue cyclic AMP. Adenosine generated in ischemic myocardium may serve as an endogenous antagonist to the arrhythmogenic action of cyclic AMP.
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PMID:Modulation of myocardial cyclic AMP and vulnerability to fibrillation in the rat heart. 630 87


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