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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A quasi-morphine withdrawal syndrome (QMWS) is a pattern of behavior closely resembling the true withdrawal syndrome in the opiate-dependent animal, which can be elicited acutely by a nonopiate drug in an opiate-naive animal. The main criteria proposed for the QMWS, in addition to its resembling the true withdrawal syndrome, are that the effects of opiates and of opiate antagonists on the QMWS should parallel those on true opiate withdrawal. Drugs that wholly or largely fulfill these criteria are 3-isobutyl-1-methylxanthine (IBMX), theophylline, caffeine, ICI 63197, and RO 201724. From the evidence given, it is concluded that these drugs act by inhibiting brain cyclic AMP phosphodiesterase, thus raising the level of cyclic AMP in appropriate neurons. These findings are consistent with the view that the molecular mechanisms of opiate dependence is the hypertrophy of a neuronal cyclic AMP system in compensation for the inhibition by opiate of an adenylate cyclase. Our studies and those of others suggest that: a) very rapid tests for opiate activity and for addictive liability can be devised by use of IBMX; b) opiates may be used clinically to counter poisoning by caffeine or theophylline; and c) a relationship may exist between caffeine consumption and opiate addiction.
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PMID:Character and meaning of quasi-morphine withdrawal phenomena elicited by methylxanthines. 616 62

Capillaries isolated by collagenase digestion of hamster epididymal fat pads were used to examine the properties of endothelial adenylate cyclase and cyclic nucleotide phosphodiesterase. Adenylate cyclase activity in capillary homogenates was increased by 10 microM GTP or 100 microM isoproterenol. Lower concentrations of the catecholamine and 5.7 microM prostaglandin E1 did not stimulate endothelial adenylate cyclase activity unless GTP was included in the assay system. The effects of isoproterenol on capillary adenylate cyclase activity were blocked by propranolol, but were not affected by phentolamine. Phosphodiesterase activity in endothelial homogenates showed anomalous kinetic behavior with either cyclic AMP or cyclic GMP as the enzyme substrate. At substrate concentrations below 1 microM, capillary phosphodiesterase activity hydrolyzed cyclic GMP 2-6 times faster than cyclic AMP. However, at high substrate levels, e.g., 100 microM, cyclic AMP and cyclic GMP were degraded at similar rates. Hydrolysis of 1 microM cyclic AMP by capillary homogenates was stimulated by 0.1 and 1 microM cyclic GMP. Caffeine, 1-methyl-3-isobutylxanthine, papaverine and dipyridamole SQ 20009 were effective inhibitors of capillary phosphodiesterase activity. In contrast, imidazole enhanced the activity of the enzyme. The presence of adenylate cyclase and phosphodiesterase activities in hamster isolated capillaries is consistent with a role for cyclic AMP in the regulation of endothelial function. Moreover, the experiments described here indicate that hamster isolated capillaries are useful model systems for studying the metabolism of vascular endothelium.
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PMID:Properties of adenylate cyclase and cyclic nucleotide phosphodiesterase in hamster isolated capillary preparations. 624 1

Exposure of chicken erythrocytes to epinephrine results in the appearance of considerable amounts of the nucleotide in the incubation medium. The release of cAMP from the cells to the surrounding medium is dependent upon its overproduction by adenyl cyclase. However, the efflux of cAMP was found not to be directly related to the total intracellular level of the nucleotide. The rate of cAMP release also remains unchanged under conditions of inhibited intracellular degradation of the nucleotide. The data presented suggest that cAMP release is not likely to serve as a regulatory mechanism which participates in the control of intracellular level of the nucleotide. The transport of cAMP from the cells to the surrounding medium was found to be reduced by the presence of NaF, iodoacetate and caffeine.
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PMID:Release of cyclic AMP from chicken erythrocytes. 624 99

In noncontracting mouse hemidiaphragms incubated in modified Krebs-Ringer--bicarbonate buffer with 10 mM Ca++, isoproterenol-stimulated phosphorylase a formation, conversion of phosphorylase kinase to the activated form, elevation of cyclic AMP-dependent protein kinase activity ratios and increase in cyclic AMP concentrations were reduced 35 to 50% over the responses in buffer with 2.5 mM Ca++. In buffer with 10 mM Ca++, the initial rate of isoproterenol-stimulated cyclic AMP accumulation was 59% of that in buffer with 2.5 mM Ca++. The inhibitory action of Ca++ on cyclic AMP accumulation was antagonized by verapamil, but not by inhibitors of cyclic nucleotide phosphodiesterase activity. In buffer with 2.5 mM Ca++, isoproterenol-stimulated cyclic AMP accumulation was inhibited by A23187 and caffeine, agents that can increase intracellular Ca++ concentrations. In addition to Ca++, high concentrations of Co++, Ni++, Mn++ and, to a lesser extent, Sr++ inhibited the isoproterenol response. The results of these studies indicate that high buffer Ca++ concentrations inhibit the response of the glycogenolytic pathway to isoproterenol by an action on cyclic AMP formation. We propose that the site of the inhibitory action of Ca++ is the divalent metal activator site associated with hormone-stimulated adenylate cyclase activity.
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PMID:Ca++ inhibition of isoproterenol responses in mammalian skeletal muscle. 626 81

The cyclic nucleotide effect on junction was studied in C1-1D cells, a mouse cancer cell type that fails to make permeable junctions in ordinary confluent culture. Upon administration of cyclic AMP, dibutyryl cyclic AMP, dibutyryl cyclic AMP plus caffeine (db-cAMP-caffeine), or cholera toxin (an adenylate cyclase activator), the cells acquired permeable junctions; they became electrically coupled and transferred fluorescent tracer molecules among each other - a transfer exhibiting the molecular size limit of permeation of normal cell-to-cell channels. The effect took several hours to develop. With the db-cAMP-caffeine treatment, junctional permeability emerged within two hours in one-fifth of the cell population, and within the next few hours in the entire population. This development was not prevented by the cytokinesis inhibitor cytochalasin B. Permeable junctions formed also in two other conditions where the cell-endogenous cyclic AMP level may be expected to increase: serum starvation and low cell density. After three weeks of starving, the cells of serum, a junctional permeability arose in confluent cultures, which on feeding with serum disappeared within two to three days. At low cell density, namely below confluency, the cells made permeable junctions, unstarved. In cultures of rather uniform density, the frequency of permeable junctions was inversely related to the average density, over the subconfluent range; at densities of about 1 X 10(4) cells/cm2, where the cells had few mutual contacts, 80% of the pairs presumed to be in contact were electrically coupled. In cultures with adjoining territories of high (confluent) and low cell density, there was coupling only in the last, and in this low-density state the cells were also capable of coupling with other mammalian cell types (mouse 3T3-BalbC and human Lesch-Nyhan cells).
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PMID:Cell junction and cycle AMP: III. Promotion of junctional membrane permeability and junctional membrane particles in a junction-deficient cell type. 627 68

The effects of cyclic adenosine monophosphate (cAMP), MnCl2, caffeine, and theophylline at concentrations of 10 mM on human sperm motility and forward migration in vitro were tested. cAMP was effective in activating human spermatozoal motility and forward migration after incubation with the spermatozoa for 3 hr or more and 5 hr, respectively, whereas caffeine and theophylline were effective in activating sperm motility after incubation with the spermatozoa for 1 hr or more. Caffeine and theophylline significantly activated sperm forward migration only after incubation with the sperm for 5 hr. MnCl2, a potent sperm adenylate cyclase activator, had no significant effect in improving human sperm motility and forward migration.
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PMID:Effect of cAMP, Mn2+, and phosphodiesterase inhibitors on human sperm motility. 627 63

Cyclic AMP phosphodiesterase in Klebsiella aerogenes is a soluble cytoplasmic enzyme with an apparent Km of 0.9 mM and a pH optimum of 7.0. It was inhibited by EDTA, Mg2+ and other metal ions. The enzyme activity was inhibited or activated by some nucleotides but not by any metabolite except pyruvate. It was inhibited by the methylxanthines, caffeine, theophylline and methylisobutylxanthine. During starvation or substrate-accelerated death, the enzyme activity remained essentially constant. It is postulated that during substrate-accelerated death the enzyme acts as a drain on the cellular cyclic AMP levels. The cyclic nucleotide concentrations during substrate-accelerated death are proposed to be controlled directly by adenylate cyclase.
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PMID:Characterization of 3': 5' -cyclic AMP phosphodiesterase in Klebsiella aerogenes and its role in substrate-accelerated death. 627 1

The effects of cAMP phosphodiesterase inhibitors on ADP-induced shape change and cAMP concentrations have been studied. Caffeine (10 mM), theophylline (8 mM), dipyridamole (0.2 mM), or papaverine (0,05 mM) prevented the shape change of washed rabbit platelets induced by 0.4 microM ADP. At these concentrations, none of these cAMP phosphodiesterase inhibitors increased 14C-cAMP in platelets in which the cytoplasmic adenine nucleotides had been labelled with 14C-adenine. By a protein binding assay, only papaverine by itself increased platelet cAMP above its basal level. These results indicate that two pools of cAMP may exist in platelets. Both methods showed that stimulation of platelet adenylate cyclase with PGE1 (1 microM) resulted in an increase in platelet cAMP and all these cAMP phosphodiesterase inhibitors potentiated this increase caused by PGE1. By themselves, some of these compounds may act through mechanisms that do not involve platelet cAMP. The effects of these cAMP phosphodiesterase inhibitors on platelet nucleoside diphosphokinase (NDK) activity were also investigated. At concentrations that prevented ADP-induced shape change, papaverine and dipyridamole had no effect on the formation of 14C-ATP from 14C-ADP by washed rabbit platelets. The methylxanthines partially inhibited NDK activity of washed rabbit platelets and of isolated platelet membranes, probably due to the structural similarity between the adenine ring of ADP and these substances. However, adenine (8 mM) inhibited ADP-induced shape change and platelet NDK activity but was a less effective inhibitor of ADP-induced platelet aggregation. Thus it seems unlikely that interference with platelet NDK or the ADP receptor is the major mechanism by which the methylxanthines inhibit platelet functions.
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PMID:Effect of cAMP phosphodiesterase inhibitors on ADP-induced shape change, cAMP and nucleoside diphosphokinase activity of rabbit platelets. 628 43

In sonicated human spermatozoa, phosphodiesterase hydrolyzed adenosine 3':5'-monophosphate (cAMP) at 20.80 +/- 3.23 nmoles/10(8)sperm/20 min at 37 degrees C (50 microM cAMP, initially). In human semen, about 60% of the phosphodiesterase activity was in the spermatozoa. Both polyacrylamide gel electrophoresis and DEAE-cellulose column chromatography indicated that there are at least 5 isozymes of phosphodiesterase. Various steroids were tested at a concentration of 2 micrograms/ml for their effects on phosphodiesterase activity in semen. None was found to have any significant effect. In sonicated human spermatozoa, adenylate cyclase synthesized cAMP at 0.02-2.11 nmoles/10(8)sperm/20 min at 37 degrees C (1 mM ATP, initially) depending on the availability of Mn2+ and caffeine in the assay mixture. Mn2+ was demonstrated to be a potent adenylate cyclase activator in human spermatozoa and its effect on human sperm adenylate cyclase was found to be dose-dependent. Cholera toxin, at a concentration of 20 micrograms/ml, had no effect on human sperm adenylate cyclase activity after it had been incubated with the intact spermatozoa for between 5 min and 5 h at 37 degrees C before the sperm were homogenized and the rate of cAMP formation assayed. In addition, human sperm adenylate cyclase decayed rapidly at 37 degrees C. Of various steroids tested at a concentration of 2 micrograms/ml for their effects on human sperm adenylate cyclase activity, only oestradiol-17 beta showed a significant effect, elevating the rate of cAMP formation by about 30%.
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PMID:Partial characterization of human spermatozoal phosphodiesterase and adenylate cyclase and the effect of steroids on their activities. 628 74

A study was made of the mechanism of action of ethimizole, a drug synthesized as central stimulant in terms of structural similarity to caffeine but possessing some antagonistic pharmacological effects as regards caffeine action. Experiments on rats given intraperitoneal injections of ethimizole demonstrated a considerable increase in adenylate cyclase activity of the brain and in the ATP level. Caffeine was found to prevent the stimulant action of ethimizole on energy metabolism and adenylate cyclase activity, while adenosine to potentiate this action. The possibility of ethimizole action on brain adenosine receptors is analyzed.
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PMID:[Purinergic effect of ethymisole]. 629 22


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