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 nicotinic acetylcholine receptor (AChR) is a substrate for at least three different protein kinases, and phosphorylation of the receptor has been shown to increase its rate of desensitization. However, the first messengers that regulate AChR phosphorylation have not yet been identified. This study demonstrates that calcitonin gene-related peptide (CGRP), a neuropeptide present in the axon terminals of the neuromuscular junction, regulates phosphorylation of the AChR in primary rat myotube cultures. CGRP, in the presence of the phosphodiesterase inhibitor Ro 20-1724, increased phosphorylation of the alpha and delta subunits of the AChR. CGRP-induced phosphorylation of the AChR had the same subunit specificity and temporal sequence as previously observed using forskolin or cAMP analogs. Phosphorylation of the AChR in the presence of CGRP appears to be mediated by CGRP-stimulated increases in cAMP levels leading to activation of cAMP-dependent protein kinase. The present results, taken together with the recent demonstration that CGRP increases the rate of AChR desensitization in mouse myotubes, suggest that CGRP may play a physiological role as a regulator of AChR desensitization by modulating AChR phosphorylation at the neuromuscular junction.
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PMID:Calcitonin gene-related peptide regulates phosphorylation of the nicotinic acetylcholine receptor in rat myotubes. 256 Jun 47

In recent years several agents have been developed as selective inhibitors of the low Michaelis constant cyclic adenosine monophosphate (cAMP) phosphodiesterase (peak III), a fraction of the cyclic nucleotide phosphodiesterases that is specific for the metabolic breakdown of cAMP. These agents are often referred to as PDE III inhibitors and share similar pharmacologic profiles. The principal interest in these agents--the therapy of congestive heart failure--is based on the cardiovascular effects that result from sequential elevation of intracellular cAMP, cAMP-dependent protein kinase activation, phosphorylation of cellular proteins and change in cellular function. The selective PDE III inhibitors have a triad of cardiovascular activities that provide hemodynamic benefit to patients with congestive heart failure. As a representative drug from this class of compounds, milrinone increases myocardial contractility, increases the rate of ventricular relaxation, and unloads the heart by way of a peripheral vasodilator action. The selective PDE III inhibitors offer a new modality for oral therapy of congestive heart failure.
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PMID:Overview of cardiovascular physiologic and pharmacologic aspects of selective phosphodiesterase peak III inhibitors. 264 30

cAMP is a mediator of inter- and intracellular events in Dictyostelium discoideum and is thought to act through specific receptors. Eight forms of cAMP-binding proteins have been described in this organism: four forms of a cell surface receptor, a cell surface and extracellular phosphodiesterase, an intracellular cAMP-dependent protein kinase (CAK), and a recently identified cAMP-binding protein (CABP1) that is present on the cell surface, in the cytoplasm, and in the nucleus. In this study we have analyzed the cyclic nucleotide specificity of these cAMP-binding proteins using 13 derivatives of cAMP with modifications in the adenine, ribose, and phosphate moiety. The results suggest that the cAMP-binding proteins belong to three groups: (i) four forms of the cell surface receptor, (ii) two forms of an intracellular receptor (CABP1 and CAK), and (iii) cell surface and extracellular phosphodiesterase. cAMP is probably bound to the surface receptors in the anti conformation in a hydrophobic cleft of the receptor with essential interactions at N6H2' and O3'. In contrast, cAMP is probably bound to CAK and CABP1 in the syn conformation with essential interactions at O2', O3', O5', and exocyclic oxygen. Finally, binding of cAMP to phosphodiesterase involves only O3' and exocyclic oxygen. The cyclic nucleotide specificity of cAMP-induced processes in D. discoideum indicates that the cell surface receptors participate in the transduction of the cAMP signal during chemotaxis and cell differentiation. Functions for CABP1 and CAK in these processes are presently elusive.
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PMID:The cyclic nucleotide specificity of eight cAMP-binding proteins in Dictyostelium discoideum is correlated into three groups. 272 97

Using computer simulation we have modeled the kinetics of cAMP-dependent protein kinase, type II, following transient pulses of cAMP. We show that under the appropriate physiological conditions, the kinase can remain activated 20 min or longer after the cessation of adenylate cyclase activation, in a process we term long-term activation. Long-term activation depends in part on the state of phosphorylation of the regulatory subunit, because phosphorylation of the regulatory subunit regulates the affinity of this subunit for the catalytic subunit. We have used our model to simulate experiments that have been performed on the kinetic and steady state activities of cAMP-dependent protein kinase and have found good agreement between the simulations and the experimental data. The effects of the activity of phosphodiesterase, adenylate cyclase, and protein phosphatase on the kinetics of cAMP-dependent protein kinase have been modeled, as have the effects of different ratios of regulatory subunit to catalytic subunit. We have also simulated the activation of the cAMP-dependent protein kinase in Drosophila learning and memory mutants having primary or secondary defects in the cAMP cascade. We make predictions regarding the behavior of different mutants, which are in line with the experimental data. The model corroborates the assumption that the cAMP cascade may play a role in learning and short-term memory.
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PMID:A quantitative model for the kinetics of cAMP-dependent protein kinase (type II) activity. Long-term activation of the kinase and its possible relevance to learning and memory. 272 37

The nicotinic acetylcholine receptor (AcChoR) from rat myotubes prelabeled in culture with [32P]orthophosphate was isolated by acetylcholine affinity chromatography followed by immunoaffinity chromatography. Under basal conditions, the nicotinic AcChoR was shown to be phosphorylated in situ on the beta and delta subunits. Regulation of AcChoR phosphorylation by cAMP-dependent protein kinase was explored by the addition of forskolin or cAMP analogues to prelabeled cell cultures. Forskolin, an activator of adenylate cyclase, stimulated the phosphorylation of the delta subunit 20-fold over basal phosphorylation and induced phosphorylation of the alpha subunit. The effect of forskolin was dose dependent with a half-maximal response at 8 microM in the presence of 35 microM Ro 20-1724, a phosphodiesterase inhibitor. Stimulation of delta subunit phosphorylation was almost maximal within 5 min, whereas stimulation of alpha subunit phosphorylation was not maximal until 45 min after forskolin treatment. Stimulation of AcChoR phosphorylation by 8-benzylthioadenosine 3',5'-cyclic monophosphate was identical to that obtained by forskolin. Two-dimensional thermolytic phosphopeptide maps of the delta subunit revealed a single major phosphopeptide. These results correlate closely with the observed effects of forskolin on AcChoR desensitization in muscle and suggest that cAMP-dependent phosphorylation of the delta subunit increases the rate of AcChoR desensitization in rat myotubes.
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PMID:Regulation of nicotinic acetylcholine receptor phosphorylation in rat myotubes by forskolin and cAMP. 281 83

Anagrelide (BL-4162A, 6,7-dichloro-1,5-dihydroimidazo[2, 1-6] quinazolin-2[3H]one monohydrochloride hydrate) is a potent and broad spectrum inhibitor of platelet aggregation. Prior studies showed that anagrelide inhibited platelet cyclic AMP (cAMP) phosphodiesterase activity but did not appreciably elevate platelet cAMP levels. We examined the effects of anagrelide on washed human platelets and found that anagrelide caused significant elevation of cAMP levels. Anagrelide treatment also resulted in activation of the platelet cAMP-dependent protein kinase at anagrelide concentrations of 0.1 to 1 microgram/ml, which inhibited platelet aggregation but caused only small increases in platelet cAMP content. When whole platelets were incubated with radiolabeled phosphate, anagrelide increased phosphorylation of platelet proteins with relative molecular weights of 22, 26, 50 and 80 kilodaltons. The pattern of protein phosphorylation stimulated by anagrelide treatment was similar to that observed when the platelets were treated with forskolin. Anagrelide also inhibited the rise in intracellular Ca++ caused by thrombin, as measured using Fura-2-loaded platelets. The inhibition of increased intracellular Ca++ resulted from block of thrombin-induced mobilization of intracellular Ca++, as well as prevention of Ca++ influx through the plasma membrane. Anagrelide itself had no influence on inositol 1,4,5-trisphosphate-induced Caz5++ release from isolated platelet membrane vesicles. These studies suggest that anagrelide inhibits platelet phosphodiesterase activity in intact platelets resulting in an elevation in cAMP levels sufficient to activate the cAMP-dependent protein kinase and inhibit agonist-activated Ca++ fluxes.
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PMID:Effects of anagrelide on platelet cAMP levels, cAMP-dependent protein kinase and thrombin-induced Ca++ fluxes. 282 59

When demembranated axonemes of Chlamydomonas were reactivated with Mg-ATP, the proportion of motile axonemes was significantly increased by the presence of either phosphodiesterase (PDE) or protein inhibitor of cAMP-dependent kinase (PKI). The effect of PDE was cancelled by the addition of cAMP. These findings strongly suggest that the axoneme samples have endogenous cAMP, which can reduce the proportion of motile axonemes via phosphorylation. This inhibitory effect of cAMP on Chlamydomonas axonemes is opposite to its stimulatory effect on the axonemal motility in other organisms so far reported. PKI or PDE activated the motility either in the absence of Ca2+, when the axonemes beat with an asymmetric waveform, or in 10(-5) M Ca2+, when the axonemes beat with a symmetric waveform. This cAMP-dependent regulation of motility was observed with the axonemes from which detergent-soluble material had been removed, indicating that the proteins responsible for the regulation still remained in the axonemes. Preliminary in vitro phosphorylation studies have implicated two polypeptides as candidates for the target protein of cAMP-dependent protein kinase: one with a molecular weight of 270 kD and the other with a much larger molecular weight.
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PMID:Stimulation of in vitro motility of Chlamydomonas axonemes by inhibition of cAMP-dependent phosphorylation. 282 19

A monoclonal antibody (CGI-5) directed against the cGMP-inhibited phosphodiesterase isolated from bovine heart was used to examine the phosphorylation of this isozyme in human platelets. PGE1 promoted the phosphorylation of this isozyme, identified as a 110 kDa peptide following SDS-gel electrophoresis. Phosphorylation resulted in approximately a 40% increase in the cGMP-inhibited phosphodiesterase activity. Cell-free experiments demonstrated that cAMP-dependent protein kinase phosphorylated the cGMP-inhibited phosphodiesterase, and that this could be blocked by the heat stable inhibitor peptide (PKI). Phosphorylation of the cGMP-inhibited phosphodiesterase increases the Vmax for cAMP hydrolysis approximately 50%, but does not affect the Km for cAMP (0.12 microM).
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PMID:Intact cell and cell-free phosphorylation and concomitant activation of a low Km, cAMP phosphodiesterase found in human platelets. 283 Dec 58

Rabbit ventricular myocardium contains distinct cytosolic and particulate cyclic AMP (cAMP) phosphodiesterase activities that exhibit characteristics ascribed to a high-affinity type IV cAMP phosphodiesterase activity found in several tissues. The particulate activity associated with sarcoplasmic reticulum vesicles has an apparent Km for cAMP of about 0.3 microM and a Vmax of 2.45 +/- 0.55 nmol/min/mg. Cyclic GMP (cGMP) inhibits hydrolysis measured at 0.25 microM cAMP with an IC50 value of 0.28 microM. In comparison, a ventricular cytosolic high-affinity cAMP phosphodiesterase activity obtained by anion exchange chromatography (Peak III) has an apparent Km of 0.93 microM and a Vmax of 17 +/- 1 nmol/min/mg. Hydrolysis of 0.25 microM cAMP by this cytosolic activity is weakly inhibited by cGMP with an IC50 value of 142 microM. Particulate enzyme activity is 60-fold more sensitive to inhibition by milrinone than is the cytosolic form (Ki = 0.18 versus 11 microM, respectively); the pyridazinone imazodan is a 12-fold more potent inhibitor of the particulate activity than of the cytosolic form (Ki = 1.5 versus 18 microM, respectively). Inhibition of both cytosolic and particulate enzyme activities appears competitive in nature. Solubilization of particulate activity did not significantly alter its affinity for substrate or sensitivity to inhibition by cGMP. In the presence of a submaximally activating concentration of forskolin (0.4 microM), selective phosphodiesterase inhibitors potentiated the activation of protein kinase in isolated ventricular septal slices. Under these conditions, changes in cAMP-dependent protein kinase activity ratios correlated more closely with contractile responses than did changes in intracellular content of cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Subcellular distribution of high-affinity type IV cyclic AMP phosphodiesterase activity in rabbit ventricular myocardium: relations to the effects of cardiotonic drugs. 283 97

We observed the effects of milrinone, an inotropic agent prescribed to treat congestive heart failure, on cyclic nucleotide messenger systems in various human tissues in vivo. Cyclic nucleotide phosphodiesterases (PDEs) from the human heart were separated into three isoforms, FI, FII and FIII, by DEAE-cellulose chromatography. Milrinone proved to be a potent and selective inhibitor of human cardiac FIII PDE, a "low Km" enzyme for cyclic AMP (cAMP-PDE). The IC50 value for the inhibition of FIII PDE was 0.42 microM, while those of FI and FII PDEs, "high Km" enzymes, were 38 and 19 microM, respectively. Kinetic studies showed that milrinone inhibited the activity of FIII PDE, competitively with respect to cAMP, and the Ki was 0.15 microM. Milrinone in doses to 100 microM had no effect on human cardiac cAMP-dependent protein kinase and adenylate cyclase. The activity of cAMP-PDEs from human platelets and the aorta, as well as that from heart, were potently inhibited by milrinone, with much the same IC50 values. Cyclic AMP-PDEs from human kidney, liver and lung were not readily inhibited by milrinone, and the IC50 values of cAMP-PDEs from these tissues were about 7-30-fold higher than that from heart. On the other hand, papaverine had a relatively lesser selectivity for any of the cAMP-PDEs. All these results suggest that milrinone exerts inotropic effects by inhibiting cAMP-PDE selectively in the human heart tissues and that this compound can be used to evaluate different forms of cAMP-PDEs present in human tissues.
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PMID:Selective inhibition of cyclic AMP phosphodiesterase from various human tissues by milrinone, a potent cardiac bipyridine. 283 22


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