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 demonstration of Ca2+ control of the cAMP level in heart cells and the localization of the Ca2+ activator protein of cAMP phosphodiesterase on the sarcoplasmic reticulum (SR) have led us to postulate a model whereby the Ca2+ flux is related to the cAMP flux. The model suggests that the increase in cytosol Ca2+ automatically results in an increase in SR Ca2+ and a subsequent decrease in cAMP to allow for the periodic flux of Ca2+ and cAMP in the contraction cycle.
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PMID:The effect of the reciprocal relationship of Ca2+ and cAMP on the control of beating in cultured rat heart cells. 20 2

The Ca2+-dependent regulation of smooth muscle actomyosin involves a myosin light chain kinase (ATP: myosin light chain phosphotransferase). It has been shown (Dabrowska, R., Aromatorio, D., Sherry, J.M.F., and Hartshorne, D.J. 1977, Biochem. Biophys. Res. Commun. 78, 1263) that the kinase is composed of two proteins of approximate molecular weights 105 000 and 17 000. In this communication it is demonstrated that the 17 000 component is the modulator protein. This conclusion is based on: (1) the identical behavior of the 17 000 kinase component and modulator protein in assays of actomyosin Mg2+-ATPase activity, phosphorylation of myosin, and phosphodiesterase activity, and, (2) the similarity of the 17 000 kinase component and the modulator protein with respect to amino acid composition, absorption spectrum, and electrophoresis in urea-polyacrylamide gels. It is shown also that the modulator protein from smooth muscle and troponin C are distinct proteins.
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PMID:Modulator protein as a component of the myosin light chain kinase from chicken gizzard. 20

In the presence of 10 micrometer Ca2+ and 5 mM Mg2+ (or 0.25 mM Mg2+), the addition of 100 micrometer Zn2+, Ni2+, Co2+, Fe2+, Cu2+ or 1 mM Mn2+ resulted in varying degrees of stimulation or inhibition of 10(-6) M cyclic GMP and cyclic AMP hydrolysis by the activator-dependent cyclic nucleotide phosphodiesterase from bovine heart in the absence or presence of phosphodiesterase activator. The substrate specificity of the enzyme was altered under several conditions. The addition of Zn2+ in the presence of 5 mM Mg2+ and the absence of activator resulted in the stimulation of cyclic GMP hydrolysis over a narrow substrate range while reducing the V 65% due to a shift in the kinetics from non-linear with Mg2+ alone to linear in the presence of Zn2+ and Mg2+. Zn2+ inhibited the hydrolysis of cyclic GMP and cyclic AMP in the presence of activator with Ki values of 70 and 100 micrometer, respectively. Zn2+ inhibition was non-competitive with substrate, activator and Ca2+ but was competitive with Mg2+. In the presence of 10 micrometer Ca2+ and activator, a Ki of 15 micrometer for Zn2+ vs. Mg2+ was noted in the hydrolysis of 10(-6) M cyclic GMP. Several effects of Zn2+ are discussed which have been noted in other studies and might be due in part to changes in cyclic nucleotide levels following phosphodiesterase inhibition.
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PMID:Effects of zinc chloride on the hydrolysis of cyclic GMP and cyclic AMP by the activator-dependent cyclic nucleotide phosphodiesterase from bovine heart. 20 21

Rats were injected daily with 1.3 mumol/kg of haloperidol s.c. for 10 days. From the second to the ninth day after haloperidol withdrawal the rats developed supersensitivity to the behavioral affects of apomorphine. Concomitantly, the Ka of dopamine for the activation of striatal adenylate cyclase was lowered and the striatal content of the Ca2+ dependent protein that activates cAMP phosphodiesterase was increased. This activator protein is stored in striatal membranes and can be released by membrane phosphorylation in cytosol. This protein increases the activity of the high Km phosphodiesterase (Uzunov et al., 1976) but when it is bound to striatal membranes it facilitates the activation of striatal adenylate cyclase by dopamine (Gnegy et al., 1976b). The increase in protein activator content of striatal membranes caused by haloperidol could be a primary factor in causing supersensitivity to the biochemical and behavioral effects of dopamine receptor agonists.
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PMID:Correlation between drug-induced supersensitivity of dopamine dependent striatal mechanisms and the increase in striatal content of the Ca2+ regulated protein activator of cAMP phosphodiesterase. 20 83

A Ca2+-binding protein which is capable of activating mammalian Ca2+-activatable cyclic nucleotide phosphodiesterase has been purified from Lumbricus terrestris and characterized. This protein and the Ca2+-dependent protein modulator from bovine tissues have many similar properties. Both proteins have molecular weights of approximately 18,000, isoelectric points of about pH 4, similar and characteristic ultraviolet spectra, and similar amino acid compositions. Both proteins bind calcium ions with high affinity. However, the protein from Lumbricus terrestris binds 2 mol of calcium ions with equal affinity, Kdiss = 6 X 10(-6) M, whereas the Ca2+-dependent protein modulator from bovine tissues binds 4 mol of calcium ions with differing affinities. Although the Ca2+-binding protein of Lumbricus terrestris activates the Ca2+-activatable cyclic nucleotide phosphodiesterase from mammalian tissues, we have failed to detect the existence of a Ca2+-activatable phosphodiesterase activity in Lumbricus terrestris. The activation of phosphodiesterase by the Ca2+-binding protein from Lumbricus terrestris is inhibited by the recently discovered bovine brain modulator binding protein (Wang, J. H., and Desai, R. (1977) J. Biol. Chem. 252, 4175-4184). Since the modulator binding protein has been shown to associate with the mammalian protein modulator to result in phosphodiesterase inhibition, it can be concluded that the Lumbricus terrestris Ca2+-binding protein also associates with the bovine brain modulator binding protein. Attempts to demonstrate the existence of a similar modulator binding protein in Lumbricus terrestris have been unsuccessful.
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PMID:Purification and characterization of a Ca2+-binding protein in Lumbricus terrestris. 20 81

1. Stimulation of fluid secretion from fly salivary glands by 5-hydroxytryptamine (5-HT) is known to involve calcium and cyclic AMP. Isolated salivary glands were used to investigate the role of these second messengers in the control of enzyme (sucrase) secretion.2. The protein component of secretion from isolated glands treated with 5-HT appears to be identical to that of saliva secreted by flies during feeding.3. Stimulation of fluid secretion by 5-HT follows a definite dose-response curve, but there is no consistent relationship between the rate of enzyme secretion and the stimulating concentration of 5-HT.4. Exogenous cyclic AMP causes secretion of enzymes as well as of fluid, thus mimicking the action of 5-HT. The phosphodiesterase inhibitor theophylline enhances the rate of 5-HT-stimulated enzyme secretion.5. Removal of calcium from the bathing medium enhances enzyme secretion in response to 5 or 10 nM-5-HT but has no effect on enzyme secretion stimulated by 100 nM-5-HT or by cyclic AMP.6. Addition of 0.1 mM-lanthanum to medium containing 2 mM-calcium mimics the effect of calcium-free solution on 5-HT-stimulated enzyme secretion.7. The ionophore A 23187 causes secretion of both fluid and enzyme. The secretory rate is initially high but soon declines and ceases after about 40 min.8. Enzyme secretion in response to 5-HT or to cyclic AMP is progressively inhibited as the concentration of potassium is increased from 10 to 80 mM. Secretion in response to A 23187 is initially inhibited by 80 mM-potassium but then partially recovers.9. The rate of enzyme secretion appears to be affected by the intracellular concentrations of both calcium and cyclic AMP. It is possible that the rate of enzyme secretion increases as the intracellular calcium concentration rises, until the optimal calcium concentration is reached when further increase in the level of calcium progressively inhibits secretion. The optimal calcium concentration for enzyme secretion is lower than that for fluid secretion, and 5-HT normally causes maximal fluid secretion and submaximal enzyme secretion.
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PMID:The control of enzyme secretion from fly salivary glands. 20 76

Part of the soluble cyclic nucleotide phosphodiesterase activity of crude human lung tissue can be attributed to a thermosensitive (37 degrees) enzyme with a high apparent affinity for both adenosine 3':5'-monophosphate (cyclic AMP) and guanosine 3':5'-monophosphate (cyclic GMP). The enzyme can be partially purified by DEAE-Sephadex chromatography. In the presence of 0.1 mM EDTA or ethylene glycol bis(beta-aminoethyl ether)N,N'-tetraacetic acid (EGTA), it is eluted from the column immediately before a cyclic GMP-specific phosphodiesterase, but in the presence of 0.2 mM Ca2+, the elution follows that of the cyclic GMP-specific enzyme. The two forms of the nonspecific phosphodiesterase activity are referred to as DEAD-Sephadex Fractions Ia and Ic, respectively. Their apparent molecular weights, recorded at gel filtration, vary with different preparations from 230,000 to 150,000. Occasionally, corresponding recordings for main peaks of activity also cluster round the values 120,000, 105,000, and 78,000. The enzymatic properties of Fractions Ia and Ic closely resemble each other. The enzyme activity is blocked by EDTA, partially inhibited in the presence of 1,10-phenanthroline, but only slightly affected by EGTA. The inhibitory effect of EDTA can be overcome by Mg2+ and Mn2+ and that of 1,10-phenanthroline, in part, by Zn2+; this cation in itself is inhibitory at millimolar concentrations. With submicromolar substrate concentrations, the activity of either fraction obeys linear kinetics displaying an apparent Km of approximately 0.4 micron for both substrates. Reciprocal inhibition experiments suggest that hydrolysis of both cyclic AMP and cyclic GMP is performed by the same active site. Examination of the activity using extended substrate concentration ranges indicates nonlinear kinetics; Hill plots of such data also show nonlinear curvature. The activity is inhibited by micromolar concentrations of inosine 3':5'-monophosphate (cyclic IMP), 3-isobutyl-1-methylxanthine, papervine, and some antiallergic agents. Theophylline and disodium cromoglycate are less potent inhibitors. Inhibition of activity by Lubrol PX follows a biphasic dose response curve. The activity of Fraction Ia can be enhanced 2- to 3-fold by a Ca2+-dependent activator prepared from lung tissue, whose action is counteracted by chlorpromazine, and by lysophosphatidylcholine. It is initially enhanced but subsequently decreased at exposure to trypsin. Fraction Ic is less prone to activation by these agents. The results indicate that the present activity represents an enzyme form that differs from three previously described phosphodiesterases of human lung tissue. It is apparently related to, but also shows distinct differences from the Ca2+-dependent enzyme(s) of brain and heart tissue.
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PMID:Cyclic nucleotide phosphodiesterase. Partial purification and characterization of a high affinity enzyme activity from human lung tissue. 20 35

A phosphodiesterase activity that preferentially hydrolyzed cytidine 3':5'-monophosphate was partially purified from rat liver extract. The enzyme was best activated by Fe2+ (5 to 10 mM). Mn2+ and Mg2+ were less effective, whereas Zn2+, Co2+, and Ca2+ were ineffective. It exhibited kinetics typical of a high Km phosphodiesterase, with a Km for cycli CMP of 2.4 mM. The enzyme, inhibited by theophylline and 1-methyl-3-isobutyl xanthine to much less extents than cyclic AMP and cyclic GMP phosphodiesterases, was found in all rat tissues examined, with highest levels seen in the liver, kidney, and intestine, and lowest levels found in the skeletal muscle, cerebellum, aorta, and blood cells. The enzyme levels in the regenerating liver were found to be about 40% lower than the control liver of rats; they were also 3 to 10 times lower in the fetal liver, lung, and heart than the corresponding adult tissues of guinea pigs. These findings suggest that depressed cyclic CMP phosphodiesterase may be in part related to cell proliferation, in line with reports that the regenerating liver has higher levels of cyclic CMP (Bloch, A. (1975) Adv. Cycli Nucleotide Res. 5, 331-338) and cytidylate cyclase (Cech, S. Y., and Ignarro, L.J. (1977) Science 198, 1063-1065).
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PMID:Cytidine 3':5'-monophosphate phosphodiesterase in mammalian tissues. Occurrence and biological involvement. 20 53

Haemoglobin-free human erythrocyte ghosts that were prepared in the presence of EDTA and were then exposed to Ca2+ showed a substantial loss of phosphatidylinositol phosphate and phosphatidylinositol diphosphate, measured either chemically or by loss of 32P from the lipids of prelabelled membranes. At the same time there was, as reported previously (Allan, D. and Michell, R.H., (1976) Biochim. Biophys. Acta 455, 824--830), and approximately equivalent rise in the diacylglycerol content of the membranes. Analysis of the 32P-labelled water-soluble material released during this process showed that the major products were inositol diphosphate and inositol triphosphate. No change was seen in the phosphatidylinositol or phosphatidate content of the membranes, and there was no Ca2+-activated loss of 32P from the phosphatidate of prelabelled membranes: this suggests that Ca2+ did not activate phosphoinositide phosphomonoesterases or phosphatidate phosphomonoesterase in human erythrocyte membranes. It is concluded that human erythrocyte membranes contain at their cytoplasmic surface a Ca2+-activated phosphodiesterase that is active against both phosphatidylinositol phosphate and phosphatidylinositol diphosphate. Rabbit erythrocytes also contained this enzyme, but in these cells there was also evidence for the presence of a Ca2+-activated phosphatidate phosphomonoesterase.
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PMID:A calcium-activated polyphosphoinositide phosphodiesterase in the plasma membrane of human and rabbit erythrocytes. 20 46

The calcium-dependent regulatory protein (CDR) purified from bovine brain was iodinated with Na[125I]I using the lactoperoxidase-glucose oxidase system. The iodinated protein retained its ability to stimulate the Ca2+-sensitive CDR-depleted cyclic nucleotide phosphodiesterase from bovine heart. Stimulation of the phosphodiesterase by 125I-CDR was Ca2+-dependent and the labeled protein had a Ka for activation of cyclic nucleotide phosphodiesterase that was 4 times greater than unmodified CDR. 125I-CDR formed a Ca2+-dependent complex with the partially purified cyclic nucleotide phosphodiesterase which was detectable by autorradiography following electrophoresis of the complex on nondenaturing gels. This technique was used to detect CDR binding components in crude homogenates prepared from bovine heart and brain.
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PMID:Detection of calcium-dependent regulatory protein binding components using 125I-labeled calcium-dependent regulatory protein. 20 39


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