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 effects of (-)isoproterenol (10(-6) M), dibutyryl cyclic AMP (10(-3) M), and the phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine (IBMX) (10(-4) M) on in vitro [3H]dopamine ([3H]DA) efflux and synthesis were studied in rat striatal slices continuously superfused with [3H]tyrosine. The beta-adrenoceptor agonist (-)isoproterenol induced an immediate and significant facilitation of [3H]DA efflux but did not alter [3H]DA synthesis as measured by [3H]H2O formation. In contrast, both dibutyryl cyclic AMP and IBMX enhanced [3H]DA synthesis as well as efflux. The presence of IBMX in the superfusing medium did not potentiate the augmentation of [3H]DA efflux caused by (-)isoproterenol. Additionally, the blockade of [3H]DA synthesis by alpha-methyl-p-tyrosine (10(-4) M) completely prevented the action of dibutyryl cyclic AMP on [3H]DA efflux. However, under similar conditions, (-)isoproterenol was still able to increase [3H]DA efflux. The results suggest that (-)isoproterenol can modify striatal DA release through a mechanism not involving cyclic AMP.
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PMID:Striatal dopamine release in vitro: a beta-adrenoceptor-regulated response not mediated through cyclic AMP. 618 Nov 95

We have previously shown that administration of 3-isobutyl-1-methylxanthine (IBMX) to rats causes an increase in levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) by a clonidine-reversible mechanism (J. Neurochem. 40: 246-251, 1983). Further investigations have revealed that IBMX administration (100 mumol/kg i.p.) stimulates noradrenergic tyrosine hydroxylation in vivo (measured after decarboxylase inhibition), an effect also reversed by the alpha-2 agonist clonidine. Consistent with previous electrophysiological data, IBMX also accelerates the disappearance of NE after inhibition of tyrosine-3-monooxygenase. When axons of the NE-dorsal bundle are mechanically severed, the effect of IBMX on MHPG is not attenuated, in contrast to the effects of the alpha-2 antagonist yohimbine which are blocked by axotomy. Administration of the adenosine agonist, 2-chloroadenosine (8 or 17 mumol/kg i.p.) or diazepam (35 mumol/kg) did not prevent the increase in MHPG caused by IBMX. The data, discussed in terms of enhanced noradrenergic activity, adenosine antagonism and phosphodiesterase inhibition, show that administration of methylxanthines (compounds known to produce anxiety and opiate withdrawal-like behaviors) results in increased biochemical activity of noradrenergic neurons in the rat.
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PMID:Neuropharmacology of 3-isobutylmethylxanthine: effects on central noradrenergic systems in vivo. 619 83

1. A comparison has been made of the ability of seven calmodulin derivatives to displace 125I-labeled calmodulin and to activate adenylate cyclase in a brain particulate fraction. The activation of brain-soluble cyclic-nucleotide phosphodiesterase by the same calmodulin derivatives was examined in parallel. 2. In general, the dose for half-maximal inhibition of 125I-labeled calmodulin binding and the apparent Km of adenylate cyclase activation were comparable in brain membranes. These concentrations were 20--40-times higher than the corresponding apparent Km values of activation of cyclic-nucleotide phosphodiesterase. 3. Modifying the single histidine residue or both tyrosine residues exerted no influence on the biological properties of calmodulin. The carboxymethylation of two methionine residues or the amidation of several carboxyl groups reduced the activation properties of calmodulin on adenylate cyclase and cyclic-nucleotide phosphodiesterase. Altering seven lysine or four arginine residues resulted in two proteins whose activation properties on adenylate cyclase and phosphodiesterase had been modified in a way suggesting that lysine and arginine residues play distinct roles in the interaction of native calmodulin with each enzyme.
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PMID:The activation of brain adenylate cyclase and brain cyclic-nucleotide phosphodiesterase by seven calmodulin derivatives. 624 45

Treatments that increased intracellular cyclic 3',5' adenosine monophosphate (cAMP) levels following catecholamine depletion caused by alpha-methyl-p-tyrosine (AMPT) provided a prophylactic effect against AMPT-induced amnesia. This effect gives evidence that cAMP mediated the formation of memory. In Experiment I, the phosphodiesterase inhibitor papaverine (50 mg/kg), immediately after a one-trial acquisition task, functionally increased cAMP levels and prevented amnesia 3 h after treatment with AMPT (200 mg/kg) for New Zealand A strain (NZ/A) mice tested in a step-through passive avoidance apparatus. Retention test latencies 72 h later were significantly higher for animals that received only saline and for animals that received AMPT and papaverine than for animals that received AMPT and saline (the amnesic group). In a similar task (Experiment II), mice that received an intracerebroventricular injection of either 5 or 10 microgram dibutyryl cAMP immediately after acquisition and 3 h after AMPT administration showed significantly higher retention test latencies than animals that received AMPT and saline. The AMP plus 10 microgram dibutyryl cAMP group showed facilitated performance even compared to the saline plus saline group.
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PMID:Testing cyclic AMP mediation of memory: reversal of alpha-methyl-p-tyrosine-induced amnesia. 626 44

Terbium, a trivalent lanthanide, effectively substituted for Ca2+ in calmodulin as judged by several criteria: intrinsic fluorescence spectra, altered mobilities on polyacrylamide gel electrophoresis, formation of a stable complex with troponin I or calcineurin, and stimulation of phosphodiesterase. Calmodulin harbors four Ca2+ binding domains; domains I and II contain no tyrosine, whereas domains III and IV each have one tyrosine. The binding of Tb3+ to calmodulin was followed by the increase of Tb3+ fluorescence at 545 nm upon binding to calmodulin. This fluorescence was elicited either by exciting Tb3+ directly at 222 nm or by exciting the calmodulin tyrosine at 280 nm with resulting energy transfer from tyrosine to Tb3+. Fluorescence generated by direct excitation measures binding of Tb3+ to any of the Ca2+ binding domains, whereas energy transfer through indirect excitation is effective only when Tb3+ is within 5 A of tyrosine, indicating that Tb3+ necessarily occupies a Ca2+ binding domain that contains tyrosine. A judicious use of the direct and indirect excitation could reveal the sequence of fill of the binding domains. Our results suggest these domains are filled in the following sequence: 1) domain I or II; 2) domains III and IV; and 3) domain II or I that has not been filled initially.
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PMID:Calcium binding domains of calmodulin. Sequence of fill as determined with terbium luminescence. 627

A series of Benzo [b]-promazines and analino-N, N-dimethylpropylamine analogs and the free radical of chlorpromazine were compared to chlorpromazine and promazine in the rat striatum for their ability to inhibit either dopamine activated adenylate cyclase or calmodulin stimulation of a partially purified high Km cyclic AMP phosphodiesterase. Chlorpromazine and the corresponding free radical were generally the most potent inhibitors of the two enzyme preparations, however, Piperazino-Benzo [b]-promazine, 1-Oxo-Benzo [b]-promazine, N-38-76-3A and Benzo [b]-promazine were relatively effective inhibitors. To a lesser extent, tyrosine, N-57-77, Piperidino-Benzo [b]-promazine, Diethyl-Benzo [b]-promazine, promazine and 1-Oxo-Diethyl-Benzo [b]-promazine exerted varying degrees of antagonism of the two enzymes. In all instances the compounds inhibited dopamine-sensitive adenylate cyclase to a greater extent than the calmodulin activated phosphodiesterase.
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PMID:Benzo [b]-promazines, chlorpromazine free radical and analino-N, N-dimethylpropylamine analogs influence rat striatal DA-adenylate cyclase and calmodulin-phosphodiesterase. 628 52

Troponin I inhibited, concentration-dependently, [3H]-N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and [3H]-trifluoperazine (TFP) binding to purified bovine brain calmodulin (CaM). Selective oxidation of methionine residues of CaM by N-chlorosuccinimide resulted in a rapid decrease in [3H]-W-7, [3H]-TFP and [14C]-chlorpromazine binding concomitant with the loss of CaM activity. Carbethoxylation of histidine residues, nitration of tyrosine residues and chemical modification of arginine residues with 1,2-cyclohexanedione produced no significant changes either in [3H]-W-7 binding to CaM or in the ability of CaM to stimulate phosphodiesterase. Our results suggest that the binding sites of these CaM antagonists on CaM may be located between the second and third Ca2+-binding loops.
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PMID:Calmodulin antagonists' binding sites on calmodulin. 630 89

We have isolated two Ca2+-binding proteins from squid optic lobes, each of which is also able to bind phenothiazines in a Ca2+-dependent manner. These proteins have each been purified and partly characterized. One of the proteins corresponds to calmodulin, in that it has a similar amino acid content to bovine brain calmodulin, including a single residue of trimethyl-lysine, it co-migrates with bovine calmodulin both on alkaline-urea- and on sodium dodecyl sulphate (SDS)/polyacrylamide-gel electrophoresis, and will activate calmodulin-dependent phosphodiesterase. The second protein has the same subunit molecular weight as calmodulin, as determined by SDS/polyacrylamide-gel electrophoresis, Mr 17 000, but migrates more slowly than this protein on alkaline-urea-gel electrophoresis. It has an amino acid composition distinct from calmodulin, containing no trimethyl-lysine, its CNBr fragments migrate on alkaline gels in a pattern distinct from those of calmodulin and it shows little ability to activate phosphodiesterase. The u.v.-absorption spectra of the proteins indicate the absence of tryptophan and the presence of a high phenylalanine/tyrosine ratio in each. Both proteins also bind 3-4 calcium ions/mol at 0.1 mM-free Ca2+ and each binds chlorpromazine in a Ca2+-dependent manner.
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PMID:Two low-molecular-weight Ca2+-binding proteins isolated from squid optic lobe by phenothiazine--Sepharose affinity chromatography. 630 66

Ophiobolin A, a fungal metabolite and a phytotoxin which can stimulate the net leakage of electrolytes and glucose from maize seedling roots (Tipton, C. L., Paulsen, P. V., and Betts, R. E. (1977) Plant Physiol. 59, 907-910) was found to be a potent inhibitor of calmodulin-activated cyclic nucleotide phosphodiesterase. The physiologically less active analogue, 3-anhydro-ophiobolin A, was found to be less inhibitory than ophiobolin A in the phosphodiesterase assay. The direct interaction between ophiobolin A and calmodulin has been demonstrated by changes in fluorescence of the protein and by the effect of ophiobolin A on calmodulin activity upon preincubation. Addition of ophiobolin A to calmodulin solutions resulted in an instantaneous quenching of the intrinsic tyrosine fluorescence followed by a time-dependent quenching. The instantaneous quenching is probably due to the inner filtering effect of ophiobolin A. The time-dependent fluorescence quenching was correlated with a time-dependent inhibition of calmodulin upon preincubation with ophiobolin A. The inhibition of calmodulin by ophiobolin A could not be reversed by dialysis, dilution, nor denaturation by urea in the presence of methanol followed by renaturation, and was much more pronounced in solutions containing Ca2+ than in those containing EGTA. Ophiobolin A also was shown to inhibit spinach calmodulin. The results of the present study suggest that calmodulin may be one of the target proteins of the phytotoxic action of ophiobolin A and that the interaction of ophiobolin A with calmodulin may involve a covalent modification of the protein by the fungal metabolite.
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PMID:Ophiobolin A. A natural product inhibitor of calmodulin. 632 79

The effect of theophylline, an inhibitor of phosphodiesterase, on tyrosine (Tyr) transport across cell membrane was studied using cultured B-16 mouse melanoma cells. 1.5 mM Theophylline in culture medium increased Tyr uptake velocity in linear fashion up to 36 h, after which it reached a plateau at which the cells showed about a 60% increase in Tyr transport velocity. This increase was independent of extracellular Na, essentially unaffected by cell density, and partially inhibited by concomitantly added cycloheximide. These results suggested that biosynthesis of macromolecules, probably acting as System L transporter, was induced by theophylline treatment.
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PMID:Effect of theophylline on the transport of tyrosine in cultured B-16 mouse melanoma cells. 643 10


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