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)

In Dictyostelium discoideum, binding of cAMP to high affinity surface receptors leads to a rapid activation of adenylate cyclase followed by subsequent adaptation within several minutes. The rate of secretion of [ 3H ]cAMP, which reflects the state of activation of the enzyme, was measured. Caffeine noncompetitively inhibited the response to cAMP. Inhibition was rapidly reversible and pretreatment of cells with caffeine for up to 22 min had little effect on the subsequent responsiveness to cAMP. However, cells pretreated with caffeine plus cAMP for greater than or equal to 8 min did not respond when caffeine was removed and the same concentration of cAMP was applied. The following observations indicate that both adaptation and deadaptation to cAMP occurred to the same extent and at the same rate whether or not cAMP synthesis was inhibited. First, when cells were pretreated with 10(-9)-10(-6) M cAMP in the presence or absence of caffeine and the stimulus was switched to a saturating dose of cAMP, the response to the increment was the same whether or not the initial response was blocked. Second, cells progressively lost responsiveness to 10(-6) M cAMP as pretreatment with 10(-6) M cAMP plus caffeine was extended from 0 to 8 min with the same time course as for those pretreated with 10(-6) M cAMP alone. Third, cells which were adapted in the presence of caffeine and cAMP deadapted within the same time period as controls when cAMP was removed. These observations demonstrate that while some part of the activation process is inhibited by caffeine the adaptation process is unaffected. Our conclusion is that adaptation does not depend on the activation of adenylate cyclase.
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PMID:Cyclic 3', 5'-AMP relay in Dictyostelium discoideum: adaptation is independent of activation of adenylate cyclase. 630 13

A variety of nitrogen heterocycles structurally related to caffeine and theophylline have been tested for activity as adenosine receptor antagonists. Preliminary screening, utilizing displacement of [3H]N6-phenylisopropyladenosine binding to rat brain membrane A1-adenosine receptors, identified several pyrazolo[3,4-d]pyrimidines with potential antagonist activity. These were then tested for their ability to antagonize the adenosine-stimulated adenylate cyclase system of guinea-pig brain slices. One of these, 4,6-bis-alpha-carbamoylethylthio-1-phenylpyrazolo[3,4-d]pyrimidine (DJB-KK), was over an order of magnitude more potent than theophylline in blocking adenosine-stimulated increases in cyclic AMP levels.
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PMID:Pyrazolo [3,4-d] pyrimidines, a new class of adenosine antagonists. 631 16

Cyclic AMP (cAMP) appears to play multiple roles in the development of the social ameba Dictyostelium discoideum, serving as the chemoattractant mediating aggregation, and perhaps also regulating gene transcription in both early and late stages of differentiation. Progress in understanding the mechanism of activation of the adenylate cyclase in D. discoideum has been frustrated by the inability to obtain its activation in vitro. Also, the lack of defined cAMP-defective mutants has prevented a causal relationship from being established between cAMP levels and gene expression. As an alternative approach to studying the role of cAMP in D. discoideum development, we have sought a compound which inhibits cAMP synthesis in a reasonably specific manner. Here we identify caffeine as a compound which rapidly and reversibly inhibits cAMP-dependent activation of the adenylate cyclase without affecting either cell viability or intracellular levels of ATP or GTP. Using this drug, we show that cAMP synthesis is not required for the cAMP-stimulated decrease in lightscattering, the increase in cyclic GMP synthesis, or for chemotaxis toward cAMP. Studies of the mechanism of action of caffeine show that the drug does not act by inhibiting a cAMP phosphodiesterase, by inhibiting binding of cAMP to its receptor, by itself binding to a physiological adenosine receptor, or by directly inhibiting the adenylate cyclase. Instead, caffeine blocks the cAMP-dependent activation of the adenylate cyclase. Since similar effects are obtained with the cation ionophore A23187, it is possible that caffeine exerts its effect by altering intracellular calcium distribution.
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PMID:Caffeine blocks activation of cyclic AMP synthesis in Dictyostelium discoideum. 631 7

A large number of nitrogen heterocycles structurally related to caffeine and theophylline have been tested for activity as adenosine antagonists. Preliminary screening, utilizing displacement of [3H]N6-phenylisopropyladenosine (PIA) binding to rat brain membranes, identified several pyrazolo[3,4-d]pyrimidines with potential antagonist activity. These were then tested for their ability to antagonize adenosine-stimulated adenylate cyclase of guinea-pig slices and to block adenosine receptors which mediate presynaptic inhibition of transmitter release from cholinergic nerves in guinea-pig ileum. Of several compounds found to have antagonist activity, one of these, 4,6-bis-alpha- carbamoylethylthio -1-phenylpyrazolo[3,4-d]pyrimidine ( DJB -KK) was approximately an order of magnitude more potent than theophylline in both tests. GTP greatly reduces the potency of purine agonists, but not antagonists, as inhibitors of [3H] PIA binding; the potency of the pyrazolo[3,4-d]pyrimidine compounds was not altered by GTP. The compounds have no significant activity against [3H]adenosine uptake or on the binding of ligands to muscarinic cholinergic, beta-adrenergic, GABA or L-glutamate receptors.
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PMID:Pyrazolo[3,4-d]pyrimidines as adenosine antagonists. 632 56

Adenosine receptors in human platelet membranes have been characterized by radioligand binding and measurement of adenylate cyclase activity. Binding of 5'-N-ethylcarboxamido[3H]adenosine ([3H] NECA ) was rapid, reversible and dependent on protein concentration, pH and temperature. Due to a rapid rate of dissociation (t 1/2 approximately 20 s) binding was highest at 0 degree C. Adenosine deaminase and GTP alone did not influence [3H] NECA binding, whereas several divalent cations decreased binding. Saturation experiments revealed two different binding sites for [3H] NECA , with KD values of 0.16 and 2.9 mumol/l and Bmax values of 8.4 and 33.4 pmol/mg of protein. In competition experiments NECA was the most potent adenosine agonist (IC50 0.5 mumol/l), followed by 2-chloroadenosine (IC50 6.3 mumol/l) and adenosine (IC50 12 mumol/l). A similar rank order of potencies was observed for the stimulatory effect of adenosine analogues on platelet adenylate cyclase. NECA stimulated adenylate cyclase activity with an EC50 value of 0.5 mumol/l and was approximately 4-fold more potent than (-)N6-phenylisopropyladenosine [(-)PIA]. However, (-)PIA and N6-cyclohexyladenosine did not significantly affect [3H] NECA binding, an observation not consistent with the stimulatory effect on adenylate cyclase. The adenosine antagonists 3-isobutyl-1-methylxanthine, theophylline and caffeine showed IC50 values between 98 and 5,600 mumol/l. [3H]PIA bound to platelet membranes with very low affinity and was not displaced by NECA . The [3H] NECA binding to human platelet membranes satisfies essential criteria for Ra adenosine receptors and, with some limitations, should be of value for the characterization of adenosine receptors in Ra subtype selective cells.
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PMID:Ra adenosine receptors in human platelets. Characterization by 5'-N-ethylcarboxamido[3H]adenosine binding in relation to adenylate cyclase activity. 632 33

We have investigated the potential role of adenosine 3',5'-cyclic monophosphate (cAMP) in controlling levels of enzymes of energy metabolism in primary cultures of rat skeletal muscle cells. Incubating myotubes with cholera toxin or forskolin (2 persistent activators of adenylate cyclase) significantly increased the levels of two enzymes of oxidative metabolism, fumarase and malate dehydrogenase. These enzymes were also increased (1.5- to 2.0-fold) by phosphodiesterase inhibitors (caffeine, theophylline, theobromine, 3-isobutyl-1-methylxanthine, papaverine, MJ 1988, Ro 20-1724, or SQ 20009) and the cAMP derivatives: 8-bromo-cAMP or dibutyryl cAMP. In contrast two enzymes of glycolytic metabolism, lactate dehydrogenase and pyruvate kinase, were not consistently affected by these agents. The results presented provide strong evidence that an increase in cAMP can lead to an increase in certain enzymes of oxidative energy metabolism.
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PMID:Evidence that levels of malate dehydrogenase and fumarase are increased by cAMP in rat myotubes. 633 Nov 85

Effects of caffeine on single fibers of frog (Rana pipiens) toe muscle and rabbit atrial trabeculae were investigated by measuring action potential, tension and the E-C coupling-related birefringence signal. Caffeine in concentrations of 1.0 to 2.0 mmol/l potentiated the twitch, prolonged the action potential, delayed the onset and suppressed the rate of the birefringence signal in skeletal muscle fibers. In heart muscle, caffeine at concentrations of 2-10 mmol/l potentiated tension and suppressed the second component of the birefringence signal. Although theophylline also potentiated tension and suppressed the rate of rise of the birefringence signal, other diesterase inhibitors, Ro7-2956, or stimulators of adenylate cyclase system such as dibutyryl cAMP or adrenaline failed to alter the birefringence signal while potentiating tension. Since the second component of the birefringence signal has been associated with Ca2+-releasing activity of the sarcoplasmic reticulum, the suppression of this signal and the simultaneous potentiation of tension by caffeine suggests that either caffeine depresses the rate of Ca2+ release or that the birefringence signal is not associated directly with Ca2+ release, rather with Ca2+ uptake. In either case, the results suggest that potentiation of tension by caffeine may be mediated by suppression of the Ca2+ reuptake process.
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PMID:Effect of caffeine on the birefringence signal in single skeletal muscle fibers and mammalian heart. Possible mechanism of action. 660 8

Forskolin, a potent activator of adenylate cyclase, has been proposed to activate this enzyme by a direct interaction with the catalytic subunit. To test this hypothesis, we examined the effects of forskolin on sperm cyclic AMP content and sperm adenylate cyclase activity. Forskolin or cholera toxin did not increase cyclic AMP content in either bull or boar sperm, whereas the inhibitors of phosphodiesterase, caffeine and methylisobutylxanthine, significantly increased sperm cyclic AMP content. Forskolin, NaF, and guanylimidodiphosphate did not activate the adenylate cyclase of either sperm membranes or cytosol. When homogenates of rat, guinea pig, or bull testes were centrifuged at 100,000 X g, the supernatant was found to contain a forskolin-stimulated adenylate cyclase. Further centrifugation of this 100,000 X g supernatant fraction at 250,000 X g for 3 hr quantitatively sedimented the forskolin-sensitive enzyme activity. We conclude that forskolin does not activate either the cytosolic or membrane-bound adenylate cyclase of mammalian sperm.
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PMID:Forskolin does not activate sperm adenylate cyclase. 668 55

Prostaglandin (PG) E1, PGD2 and the unstable PGI2 are inhibitors of human platelet aggregation and increase the concentration on cAMP in human platelets, presumably by stimulation of the adenylate cyclase. Methylxanthines exert their antiaggregatory effect by inhibiting the platelet cAMP phosphodiesterase. We examined whether caffeine-indomethacin is able to block PGI2 release from gastric mucosa less than the administration of indomethacin alone. PGI2 production was determined on aliquots of incubated mucosal strips, tested for ADP-induced aggregation of human platelet rich plasma. The obtained data indicate that the PGI2 production found in rats treated with the association was higher than that observed in rats treated with indomethacin alone. The present preliminary findings suggest that caffeine when given together with indomethacin reduces the indomethacin-induced inhibition of PGI2 release from the gastric mucosa.
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PMID:[Effect of the association of caffeine-indomethacin on the production of prostacyclin in the rat stomach]. 676 86

Insulin release from pancreata of human fetuses aged 4 to 9 months and from adult pancreata were studied in monolayer cell culture by static incubation and perifusion technique. Fetal pancreata at the midterm of gestation (4 to 6 months) showed no response of insulin release to glucose. In a case of 9 months-old fetus, in which a small but significant increase of insulin release was observed with glucose (300 mg/ml). Tolbutamide (100 microgram/ml) had no effect on insulin release from all the pancreata of fetuses tested. Caffeine (5 and 10 mM), a phosphodiesterase inhibitor, potentiated insulin release by itself and also induced the glucose-stimulated insulin release from the fetal pancreata in the dose related manner. Glucagon (2 microgram/ml), L-isoproterenol (2 microgram/ml), L-arginine (10 mM) and L-leucine (10 mM) failed to induce any increase of insulin release from fetal pancreata. In the presence of caffeine, the significant increase of insulin release from fetal pancreata was observed with L-leucine, but not with L-arginine. There was no evidence of the maturation of B-cells during the culture periods (4 to 8 days), probably lacking the key steps of stimulus-secretion couplings in relation to adenylate cyclase-cyclic AMP system. By contrast, glucose (100 and 300 mg/100 ml), tolbutamide (100 microgram/ml), L-arginine (10 mM) and caffeine (5 mM) caused a significant increase of insulin release from adult pancreata. Thus, the development of human pancreatic B-cells seems to depend substantially on gestational age, being ready to equip most machinary of insulin release before delivery.
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PMID:Monolayer culture of human fetal and adult pancreas. Static and dynamic studies of insulin release in vitro. 699 62


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