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)

Forskolin caused a concentration-dependent relaxation and increase in cyclic AMP levels in rabbit detrusor muscle. Propranolol, a beta-adrenoceptor antagonist, did not affect the relaxation induced by forskolin. 3-isobutyl-1-metylxanthine (IBMX), a cyclic nucleotide phosphodiesterase inhibitor, potentiated the relaxation induced by forskolin. These data suggest that the relaxation of rabbit detrusor muscle induced by forskolin is mediated by cyclic AMP accumulation resulting from activation of adenylate cyclase.
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PMID:Effects of forskolin on contractility and cyclic AMP levels in rabbit detrusor muscle. 242 1

Activation of cAMP-dependent protein kinase II by static and dynamic steady-state cAMP levels was studied by reconstituting an in vitro model system composed of hormone-sensitive adenylate cyclase, cyclic nucleotide phosphodiesterase, and cAMP-dependent protein kinase II. The rates of cAMP synthesis were regulated by incubating isolated membranes from AtT20 cells with various concentrations of forskolin. In the presence of 3-methylisobutylxanthine, the rate of protein kinase activation was proportional to the rate at which cAMP was synthesized, and there was a direct relationship between the degree of activation and the level of cAMP produced. The activation profiles of protein kinase generated in the presence of exogenous cAMP or cAMP produced by activation of adenylate cyclase in the absence of cAMP degradation were indistinguishable. Dynamic steady-state levels of cAMP were achieved by incubating the membranes with forskolin in the presence of purified cyclic nucleotide phosphodiesterase. Under these conditions, the apparent activation constant of protein kinase II for cAMP was reduced by 65-75%. This increased sensitivity to activation by cAMP was seen when phosphotransferase activity was measured directly in reaction mixtures containing membranes, protein kinase, and histone H2B or when regulatory and catalytic subunits were first separated by immunoprecipitation of holoenzyme and regulatory subunits with specific anti-serum. Our results are consistent with the hypothesis that rapid cAMP turnover may function as a mechanism for amplifying hormonal signals which use the cAMP-dependent protein kinase system.
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PMID:Enhanced activation of cAMP-dependent protein kinase by rapid synthesis and degradation of cAMP. 243 Sep 60

On isolated electrically stimulated left and spontaneously beating right guinea-pig atria the interaction between PDE-inhibitors and the positive inotropic and chronotropic action of orciprenaline, forskolin and histamine in dose-response curve was examined. The experiments led to the following results: triamterene (20-120 mumol/l) and papaverine (10-100 mumol/l) inhibit the positive inotropic and chronotropic action of orciprenaline, whereas theophylline (10-100 mumol/l) and isobutyl-methyl-xanthine (0.1-10 mumol/l) only inhibit the inotropic action of orciprenaline. Amrinone (100-316 mumol/l) increases the positive inotropic and chronotropic action of orciprenaline; the positive inotropic and chronotropic action of forskolin is inhibited by triamterene but not by theophylline and IBMX. The positive chronotropic action of forskolin and histamine is inhibited by triamterene, whereas the positive inotropic action of histamine is not influenced; our experimental results suggest that triamterene and papaverine antagonize orciprenaline action by inhibition of adenylate cyclase. For this there is further evidence in the antagonism between triamterene and the inotropic action of forskolin and the tachycardic action of histamine. As theophylline and IBMX inhibit only the inotropic action of orciprenaline, there might be a different mechanism for their interaction regarding the chronotropic action of orciprenaline compared to triamterene and papaverine. The amrinone mechanism differs from that of the other PDE-inhibitors as it increases the positive inotropic and chronotropic action of orciprenaline.
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PMID:Interaction of phosphodiesterase inhibitors triamterene, papaverine, theophylline, IBMX and amrinone with other positive inotropic acting substances on isolated guinea-pig atria. 244 95

In this study we investigated the mechanism of inhibition of NK activity by monomeric IgG (mIgG) and the enhancement of inhibition induced by 3-isobutyl-1-methylxanthine (IBMX) or theophylline (TP) as inhibitors of cyclic nucleotide phosphodiesterase, or by prostaglandin E2 (PGE2) as an activator of adenyl cyclase. Human peripheral blood mononuclear cells (PBMN) and nonadherent lymphocytes (NAL) were treated with various concentrations of mIgG, IBMX, TP, PGE2, either alone, or in combination. The treatments were done before and/or during the cytotoxicity assay against 51chromium-labeled K562 target cells. Combined pretreatment with mIgG and treatment during the assay with IBMX or TP induced much more inhibition than that induced by either treatment alone. At some concentrations of each agent, additive inhibition was observed, whereas at other concentrations, synergistic effects were seen. With the combination of PGE2 and mIgG, an additive inhibitory effect could be seen only at very low concentrations of PGE2, due to its strong inhibitory potency. Although endogenous PGE2 released during preincubation at 37 degrees C by adherent PBMN led to some reduction of NK activity, experiments with indomethacin indicated that mIgG-induced inhibition of spontaneous cytotoxicity was not dependent on its presence. The intracellular levels of cyclic AMP in highly purified NK cells were increased after pretreatment with mIgG and even higher levels were measured when IBMX was also added to the effector cells. Taken together, our data provide evidence that mIgG-induced inhibition of NK cells is mediated at least partially by cyclic AMP.
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PMID:Regulation of human natural cytotoxicity by IgG. II. Cyclic AMP as a mediator of monomeric IgG-induced inhibition of natural killer cell activity. 245 4

Psoriatic involved epidermis reveals variously altered receptor-adenylate cyclase responses; among them the most prominent is defective beta-adrenergic adenylate cyclase response, which is normally the major receptor-adenylate cyclase system of human epidermis. It is known that activation of hormone-stimulated adenylate cyclase, a membrane-bound enzyme complex, requires functional coupling of at least 3 distinct subunits: 1) receptor subunit (R), 2) guanine nucleotide binding protein (G), and 3) catalytic subunit (C). The precise nature of the beta-adrenergic defect in the psoriatic epidermis, however, remains to be determined, especially in terms of G and C function. Using the involved and uninvolved skin from psoriatic patients, we investigated effects of cholera toxin (which monitors G-C interaction) and forskolin (which monitors C function) on the adenylate cyclase system of epidermis, which were compared with those of normal human epidermis. Both agents increased cyclic AMP levels of involved, uninvolved, and normal human epidermis. Marked accumulations were observed in the presence of cyclic nucleotide phosphodiesterase inhibitor, isobutyl-methylxanthine (IBMX); without the phosphodiesterase inhibitor, the effect of each agent was minimal. Comparison of the effects of cholera toxin revealed that the psoriatic involved epidermis accumulates much more cyclic AMP than the uninvolved epidermis (involved: 193 +/- 65; uninvolved: 117 +/- 54 pmoles/mg protein/5 h). Similarly forskolin-induced cyclic AMP accumulations of the involved epidermis were much more than those of uninvolved epidermis (involved: 374 +/- 152; uninvolved: 101 +/- 41 pmoles/mg protein/2 h). Those of normal human epidermis were not significantly different from those of uninvolved epidermis (cholera toxin: 99 +/- 36 pmoles/mg protein/5 h; forskolin: 84 +/- 22 pmoles/mg protein/2 h). Our results indicate that G and C function and their interaction is not defective (but rather increased) in the psoriatic involved epidermis. This suggests that the defective beta-adrenergic response of psoriatic involved epidermis reflects defective R or R-G interaction of the epidermal adenylate cyclase system.
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PMID:Increased cholera toxin-, and forskolin-induced cyclic AMP accumulations in psoriatic involved versus uninvolved or normal human epidermis. 245 58

Release of [14C]glucosamine-labelled mucins was studied in vitro using well-characterised preparations of rat submandibular acini. Mucin release was stimulated by forskolin, an activator of the catalytic subunit of adenylate cyclase, and 3-isobutyl-1-methylxanthine (IBMX), a cyclic nucleotide phosphodiesterase inhibitor. Both stimulated in a dose-dependent manner to the same maximum as that seen with isoproterenol. Neither forskolin nor IBMX added in the presence of isoproterenol increased secretion above the maximum in response to isoproterenol alone, suggesting a similar mechanism of action, mediated by cyclic AMP. Prior exposure of acini to isoproterenol (10 microM) for 45 min, followed by washout resulted in (a) persistent increase in basal secretion which was abolished by propranolol and (b) reduced stimulation of mucin secretion in response to either a second isoproterenol challenge, noradrenaline or forskolin. Thus, exposure of rat submandibular acini in vitro desensitizes the cells to subsequent stimulation. Although this mimics the decreased beta-adrenergic secretory responses seen in submandibular cells from cystic fibrosis patients, results suggest that the isoproterenol-induced desensitization is at the level of beta-receptor and adenylate cyclase, rather than distal to cyclic AMP.
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PMID:Isoproterenol-induced desensitization of mucin release in isolated rat submandibular acini. 245 89

1. Secretion of [3H]acetylcholine was studied in the guinea-pig ileum longitudinal muscle-myenteric plexus preparation. The transmitter stores of the cholinergic nerves were labelled by pre-incubation with [3H]choline. The preparation was mounted in an organ bath and superfused with Tyrode solution containing hemicholinium-3 and eserine. [3H]Acetylcholine secretion was evoked by electrical stimulation (0.5 Hz, 150 shocks). 2. 8-Bromo cyclic AMP, the adenylate cyclase activator forskolin, and the cyclic nucleotide phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine enhanced the [3H]acetylcholine secretion in a concentration-dependent manner. The values of 'maximal enhancement' calculated were similar, viz. 200-300% of control. 3. 8-Bromo cyclic GMP reduced the [3H]acetylcholine secretion. 4. The 'maximal enhancement' of 3-isobutyl-1-methylxanthine was not altered by the presence of forskolin (25 mumol/l) suggesting a common mechanism of action, i.e. elevation of endogenous cyclic AMP levels. 5. The muscarinic acetylcholine receptor antagonist atropine enhanced the [3H]acetylcholine secretion with a 'maximal enhancement' of 506% of control. Presence of neither forskolin (25 mumol/l) nor 3-isobutyl-1-methylxanthine (5 mmol/l) altered the 'maximal enhancement' for atropine. 6. In contrast, atropine (1 mumol/l) and 4-aminopyridine (0.5 mmol/l) additively enhanced the [3H]acetylcholine secretion. 7. The results suggest that neuronal cyclic AMP may be involved in muscarinic acetylcholine receptor-mediated control of [3H]acetylcholine secretion in guinea-pig ileum myenteric plexus.
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PMID:Interaction of forskolin with the effect of atropine on [3H]acetylcholine secretion in guinea-pig ileum myenteric plexus. 245 81

1. The effects of adibendan (BM 14.478; 7,7-dimethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f] benzimidazole-6-one) on force of contraction and beating frequency were analysed in guinea-pig electrically driven papillary muscles and spontaneously beating right auricles, respectively. The effects of 3-isobutyl-1-methylxanthine (IBMX) and milrinone were studied for comparison. 2. Adibendan exerted a concentration-dependent (0.03-300 mumol/l) positive inotropic effect in papillary muscles (EC50 = 1.3 mumol/l) which was only partially reversible. The efficiency of adibendan was less than that of milrinone, but adibendan was about two orders of magnitude more potent and had only slight positive chronotropic effects (113% of pre-drug values) at most. Milrinone increased the frequency of beating maximally to 140% of pre-drug values. The positive inotropic effect of adibendan is probably at least partially mediated by cAMP since carbachol reduced the increase in force of contraction by about 75%. 3. To elucidate the mechanism of action of adibendan we investigated its effects on phosphodiesterase I-III and adenylate cyclase activity in isolated preparations from guinea-pig hearts. 4. Adibendan selectively inhibited phosphodiesterase III (PDE III) activity concentration-dependently (IC50 = 2.0 mumol/l). The IC50 values for the inhibition of PDE I or II were more than 60-fold higher. Since adibendan did not affect adenylate cyclase activity a stimulation of the cAMP synthesis as a mechanism of action can be ruled out. 5. The results provide evidence that the positive inotropic action of adibendan is at least in part due to an inhibition of cAMP-PDE III.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of action and cardiotonic activity of a new phosphodiesterase inhibitor, the benzimidazole derivative adibendan (BM 14.478), in guinea-pig hearts. 245 16

The results presented here demonstrate that an elevation in the cellular levels of cyclic AMP (cAMP) increases the phosphorylation of an Mr = 58,000 cellular protein in quiescent cultures of Swiss 3T3 cells. The enhancement of 32Pi incorporation into the Mr 58,000 cellular protein was detected as early as 1 min and reached a maximum after 20 min of treatment. The role of cAMP in the phosphorylation of Mr = 58,000 protein is substantiated by the following lines of evidence: a) a variety of agents that cause cAMP accumulation in 3T3 cells, including cholera toxin, 5'-N-ethylcarboxamideadenosine (NECA), PGE1, and 3-isobutyl-1-methyl-xanthine (IBMX) increased the phosphorylation of the same Mr 58,000 cellular protein as demonstrated by peptide mapping; b) inhibitors of cyclic nucleotide phosphodiesterase potentiated the ability of low concentrations of the adenylate cyclase activators NECA, PGE1, and forskolin to increase Mr 58,000 phosphorylation; and c) permeable derivatives of cAMP such as 8BrcAMP were also effective and specific in promoting Mr 58,000 phosphorylation. Detergent extraction, immunoblotting, and immunoprecipitation identified the Mr = 58,000 phosphoprotein as vimentin, the main protein subunit of the intermediate filaments of mesenchymal cells including Swiss 3T3 cells. Studies with intact 3T3 cells revealed that an increase in the intracellular level of cAMP induced a marked redistribution and collapse of the intermediate filaments. These results raise the possibility that an intact intermediate filament network may restrict the reinitiation of DNA synthesis.
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PMID:Cyclic AMP increasing agents rapidly stimulate vimentin phosphorylation in quiescent cultures of Swiss 3T3 cells. 246 73

Our previous studies with fluoride have indicated that G-proteins may mediate the gating of Ca++ channels in vascular smooth muscle (VSM). We now present further studies on the relationship between G-proteins and Ca++ channels in VSM using guanosine-5'-(gamma-thio)triphosphate (GTP gamma S), a hydrolysis-resistant analog of GTP. Rat tail artery helical strips pretreated with GTP gamma S in a cytosol-like solution contracted in a Ca++-dependent manner in the absence of a depolarizing concentration of K+, hormones or any other Ca++ agonists. Contraction was dependent on the concentrations of applied GTP gamma S. The ability of strips pretreated with GTP gamma S to contract in response to Ca++ was not reversed by repeated washing. Incubation with 1 mM GTP applied extracellularly did not induce tension development. Treatment with a subthreshold concentration of GTP gamma S shifted the K+ concentration-related tension curve to the left but did not alter the maximum response. The contractions induced by GTP gamma S pretreatment and by submaximal (60 mM) KCI were additive at all levels of Ca++ tested. Extra tension development could be evoked from tissue maximally contracted with GTP gamma S by adding maximal K+ and norepinephrine. The relaxing sensitivity of the GTP gamma S-related contraction to reversal by nifedipine was between those for K+ depolarization and norepinephrine, and the GTP gamma S-induced rise in tension was partially inhibited by the Ca++ channel blocker nifedipine. Ca++-elicited contraction of the GTP gamma S-pretreated strips was relaxed by forskolin, an adenylate cyclase activator, 3-isobutyl-l-methyl-xanthanine, a cyclic nucleotide phosphodiesterase inhibitor, and dibutyryl cyclic AMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Guanine nucleotide binding proteins may modulate gating of calcium channels in vascular smooth muscle. II. Studies with guanosine 5'-(gamma)triphosphate. 247 91


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