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. Analogues of GTP and GDP were introduced into isolated rod photoreceptors using the whole-cell patch clamp technique, while simultaneously recording the photocurrent with a suction pipette. After several minutes of whole-cell recording the patch pipette was disengaged, thus trapping the analogue inside the cell. 2. During the introduction of the hydrolysis-resistant GTP analogues guanosine-5'-O-(3-thio-triphosphate) (GTP-gamma-S) and guanylyl-imidodiphosphate (GMP-PNP) the dark current progressively declined, and the duration of responses to flashes of light which had previously been just-saturating increased slightly. The form of the rising phases of the responses to dim or bright flashes was little affected. 3. Following the incorporation of these GTP analogues the response to an intense flash was prolonged by a factor of up to 300, and the circulating current remained suppressed for up to 1 h. Ultimately the circulating current recovered and the duration of the flash response returned to near its control value. 4. Superfusion of the outer segment with the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX) during the extended period of saturation resulted in a rapid increase in the circulating current, suggesting that the analogues had their major effect on the duration of phosphodiesterase activation by light. 5. Introduction of the phosphorylation-resistant GDP analogue guanosine-5'-O-(2-thio-diphosphate) (GDP-beta-S) resulted in a decrease in light sensitivity and a reduction in the slope of the rising phase of the flash response. 6. The response to an intense flash was also prolonged in cells containing GDP-beta-S, recovery becoming progressively slower on successive presentations of the flash following the withdrawal of the patch pipette. This observation suggests that GDP-beta-S may be slowly converted within the cell to form a hydrolysis-resistant product. 7. These results indicate that the presence of a hydrolysis-resistant analogue of GTP within the cell causes light activation of the transduction mechanism for an extended period. Our interpretation of this finding is that hydrolysis of the bound guanosine nucleotide is necessary for the quenching of activated GTP-binding protein.
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PMID:Incorporation of analogues of GTP and GDP into rod photoreceptors isolated from the tiger salamander. 247 54

The effect of zinc deficiency on calmodulin function was investigated by assessing the in vivo activity of two calmodulin regulated enzymes, adenosine 3',5'-monophosphate (c-AMP) and guanosine 3',5'-monophosphate (c-GMP) phosphodiesterase (PDE) in several rat tissues. Enzymatic activities in brain, heart, and testis of rats fed a zinc deficient diet were compared with activities in these tissues from pair fed, zinc supplemented rats. In testis, a tissue in which zinc concentration decreased with zinc deficient diet, enzyme activities were significantly decreased over those in rats who were pair fed zinc supplemented diets. In brain and heart, tissues in which zinc concentrations did not change with either diet, enzymatic activities between the groups were not different. These results indicate that zinc deficiency influences the activity of calmodulin-regulated phosphodiesterases in vivo supporting the hypothesis that zinc plays a role in calmodulin function in vivo in zinc sensitive tissues.
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PMID:Zinc deficiency decreases the activity of calmodulin regulated cyclic nucleotide phosphodiesterases in vivo in selected rat tissues. 248 50

Although the total concentration of cGMP in rod outer segments is thought to be substantially greater than the free concentration, no quantitatively relevant site for the bound cGMP has been described in mammalian photoreceptors. We have found that preparations of purified bovine rod photoreceptor cyclic nucleotide phosphodiesterase (PDE) contain 1.8 +/- 0.3 mol of tightly bound cGMP per mol of PDE. When subunits of the purified PDE were separated by reverse-phase HPLC in 0.1% trifluoroacetic acid and acetonitrile, a peak of material having spectral properties characteristic of a guanine ring was seen. This material was identified as cGMP by comigration with authentic cGMP on HPLC, conversion to 5-GMP by trypsin-activated rod PDE, and conversion to guanosine by a combination of trypsin-activated PDE and 5'-nucleotidase-containing snake venom. When incubated with 1 microM [3H]cGMP, only 0.1 mol of [3H]cGMP bound per mol of purified PDE, presumably because nearly all binding sites were occupied by tightly bound endogenous cGMP carried through the purification. Scatchard plots of [3H]cGMP binding have indicated that two classes of binding sites are present on the rod PDE. The off-rate of cGMP from the slowly dissociating site is extremely slow; it has a t1/2 of approximately 4 hr at 37 degrees C. At lower temperatures, very little cGMP dissociates; the amount of [3H]cGMP bound to rod PDE after 2 hr at 4 degrees C was essentially the same as at the beginning of the incubation. The observation that stoichiometric amounts of cGMP are tightly bound to PDE accounts for the inability to purify the bovine rod PDE on cGMP affinity columns or to demonstrate stoichiometric high-affinity binding sites with [3H]cGMP. More significantly, the tightly bound cGMP may resolve the apparent discrepancy between the free and total cGMP concentrations of photoreceptor outer segments.
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PMID:cGMP is tightly bound to bovine retinal rod phosphodiesterase. 254 68

Light, in the presence of ATP, has been reported to stimulate cGMP binding to a 58 kDa protein in ROS (rod outer segments, Fesenko and Krapivinsky, 1986b, Photobiochem. Photobiophys. 13 345-58). This apparent light-related redistribution of ROS cGMP has been suggested to eliminate any requirement for phosphodiesterase-promoted hydrolysis of cGMP in the mechanism subserving phototransduction. Using conditions identical to those previously reported, this effect of light and ATP was examined further by characterizing the metabolic products that arise and the nucleotides that become liganded. The increased binding of radiolabeled guanine nucleotide upon illumination of ROS in the presence of ATP was confirmed, but the species of guanine nucleotide that were stimulated to bind under these conditions were identified as [32P]GDP and [32P]GTP rather than [32P]cGMP. The precautions to prevent enzymic hydrolysis of cGMP, which included conducting the reactions at 0 degrees and the addition of 3-isobutyl-l-methylxanthine (250 microM) to the reaction mixture did not prevent about a 20-fold increase in the rate of phosphodiesterase-catalyzed hydrolysis of radiolabeled cGMP by light when ATP was also present. This stimulation of phosphodiesterase activity is undoubtedly related to transphosphorylation by exogenous ATP of endogenous GMP and GDP involving catalytic actions of guanylate kinase and nucleoside diphosphate kinase in isolated ROS. These enzymes can also serve to generate [32P]GDP and [32P]GTP, which subsequently bind to ROS components. Such a mechanism involving ATP as phosphoryl donor was supported by observing that an analog of ATP (beta,gamma-methyleneadenosine 5'-triphosphate), which cannot serve as a phosphoryl donor, did not increase radiolabeled guanine nucleotide binding. Although several ROS proteins can form filter-retainable complexes with GDP and GTP, the properties of the 58 kDa protein found to be photoaffinity labeled with radioactive guanine nucleotide are most characteristic of those attributable to tubulin. The previous report that illumination in the presence of ATP stimulates the binding of cGMP to ROS components finds no support from the data obtained in the present studies.
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PMID:Non-identity of cGMP as the guanine nucleotide stimulated to bind to ROS by light and ATP. 254 44

The mechanism of activation of cGMP phosphodiesterase by the GTP-binding protein in the disc membrane of retinal rods has been investigated by measuring the light-induced phosphodiesterase activity in reconstituted systems where the concentration of either the GTP-binding protein or the phosphodiesterase is varied. The results are consistent with the existence of two activator sites per phosphodiesterase functional unit: binding of one G alpha GTP (alpha subunit of the G-protein with GTP bound) with high affinity (100 +/- 50 nM) partially activates the enzyme (Vmax1 approxmately 0.05 Vmax to 0.10V max to trypsin-activated phosphodiesterase); binding of a second G alpha GTP with lower affinity (600 +/- 100 nM) induces maximal activation (Vmax2 approximately Vmax of trypsin-activated phosphodiesterase). The two different states of activated phosphodiesterase have the same Km for cGMP and the same pH dependence; they differ in their sensitivity to GMP. Micromolar concentration of protamines increases the affinity of the two activator sites and slightly increases Vmax1. When G-protein is activated with GTP-gamma S instead of GTP, the affinities of the two activator sites are not significantly modified, while Vmax1 appears to be increased.
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PMID:Activation of cGMP phosphodiesterase in retinal rods: mechanism of interaction with the GTP-binding protein (transducin). 255 70

Cyclic AMP phosphodiesterase (PDE) partially purified from roots of Vigna mungo exhibited optimum activity at pH 5.5 to 6.0 and maximum enzyme activity at 50 degrees C. Levels of PDE activity in roots remained relatively constant from the first to the eleventh day after germination; on the twelfth day there was a 400% increase in PDE activity. The enzyme was stable for at least 48 hours at 28 degrees C, retaining 92% of its original activity. Plant growth hormones including gibberellic acid, indoleacetic acid and kinetin at 1.0 and 10.0 microM concentrations did not have any significant effect on enzyme activity. Nucleotides tested including cyclic 2'3' AMP, cyclic 2'3' GMP completely abolished enzyme activity at 1.0mM while cyclic 3'5' GMP, cyclic 3'5' GMP, 2'deoxy 5' ATP, 2'deoxy 5'GTP and 5'ADP were also inhibitory to the enzyme. The enzyme was stimulated by Mg2+, Fe2+ and NH4+ while Cu2+ and Fe3+ were inhibitory. Theophylline, caffeine, phosphate, pyrophosphate and EDTA were inhibitory to the enzyme.
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PMID:Properties of a cyclic 3'5'-nucleotide phosphodiesterase from Vigna mungo. 255 28

Mechanisms involved in the K+-induced rhythmic contraction were investigated in the isolated rat vas deferens. Isolated vas deferens is mechanically quiescent in normal Krebs-bicarbonate solution, but addition of KCl (10 to 35 mM) to the solution induces a rhythmic contraction. The K+-induced rhythmic contraction was not inhibited by tetrodotoxin, prazosin and indomethacin as well as by in vivo pretreatment with reserpine, but was abolished by verapamil or by Ca++ removal from the solution. TMB-8, a calcium release blocker, blocked the K+-induced rhythmic contraction and, instead, sustained tonic contractions developed. The rhythmic contraction was abolished by isoproterenol or by 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor. The action of isoproterenol was inhibited by propranolol and was potentiated by 3-isobutyl-1-methylxanthine. In addition, dibutyryl cyclic AMP, but not dibutyryl C-GMP, blocked the rhythmic contraction. After those drugs affecting intracellular C-AMP levels, addition of excess KCl to the solution induced a sustained contraction, but not the rhythmic contraction. These results suggest that K+-induced rhythmic contractions are myogenic in origin and are caused by Ca++ movements which are controlled by intracellular cyclic AMP levels.
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PMID:Involvement of calcium and cyclic AMP in the K+-induced rhythmic contraction of isolated rat vas deferens. 282 63

SIE AP mass spectra of tryptic peptides from the cyclo-GMP phosphodiesterase gamma-subunit and of chymotryptic peptides from the cyanogen bromide fragments of the same subunit exhibit MH+ ions for all theoretically possible smaller peptides. These facts show that SIE AP mass spectrometry can be successfully applied to peptide mapping using 1-2 nmoles of the compound.
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PMID:[Mass-spectrometry with ion extraction from solution at atmospheric pressure for peptide mapping]. 283 31

Phosphodiesterase of cyclic nucleotides from membranes of rat brain synaptosomes hydrolyzes cAMP and cGMP; the maximal rate of cAMP hydrolysis is 2.5 times higher than the values of the analogous index for GMP. The enzyme is found to be activated by calmodulin. A different direction of changes in the rate of cAMP and cGMP hydrolysis is observed 1 h after total X-ray irradiation. The process of cAMP hydrolysis by phosphodiesterase is characterized by positive cooperativity which is also shown after irradiation and for the process of cGMP hydrolysis. It is established that enzyme inhibition by the reaction product takes place both in control and after irradiation.
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PMID:[Properties of cyclic nucleotide phosphodiesterase from plasma membranes of rat synaptosomes at early stages of acute radiation injury]. 284 4

Cyclic GMP depresses Ba2+ current through high-voltage-activated Ca2+ channels (ICa) in acutely isolated hippocampal neurons. The effect is produced by intra-, but not extracellular, cGMP or by 5' GMP. The membrane-permeant derivative, 8-Br-cGMP, produces a reversible suppression. The effect of 8-Br-cGMP is similar to phorbol ester-induced ICa depression, except that ICa depression due to 8-Br-cGMP is not blocked by protein kinase inhibitors H-8 or H-7, whereas phorbol ester effects are. The data suggest that cGMP depresses ICa by a cGMP-kinase- and protein kinase C (PKC)-independent mechanism. Cyclic AMP, which enhances ICa, and the cyclic nucleotide phosphodiesterase inhibitor, IBMX, both antagonize ICa depression induced by 8-Br-cGMP, but not that due to phorbol esters. Cyclic IMP, a more potent activator of phosphodiesterase than of cGMP-dependent protein kinase, is also a powerful depressant of ICa. We conclude that cGMP-induced depression of ICa is mediated by activation of cyclic nucleotide phosphodiesterase with consequent reduction of intracellular cAMP.
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PMID:Cyclic GMP depresses hippocampal Ca2+ current through a mechanism independent of cGMP-dependent protein kinase. 285 1


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