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)

The aim of the present study was to investigate the regulation of cAMP by tamoxifen in quail oviduct. A single injection of tamoxifen to immature female quails induced a transient activation of adenylate cyclase. Enzyme activity began to increase 3 h after the injection, peaked at 6 h and then dropped to control level at 12 h. The same time-response curves were observed following the injection of estradiol benzoate or estradiol benzoate + tamoxifen. Moreover, adenylcyclase exhibited the same sensitivity to exogenous activators (guanylylimidodiphosphate and forskolin) in the different treated groups. Phosphodiesterase activity was left unchanged during the prereplicative period and cAMP concentration was significantly increased at 6 h (+ 44.3%). Then, cAMP concentration continued to increase (+ 73.8% at 24 h) while cAMP phosphodiesterase and adenylcyclase activities remained at control levels. Injected concurrently with estradiol benzoate, tamoxifen completely inhibited the growth promoting effect of estradiol. Tamoxifen also inhibited the activation of adenylcyclase and cAMP phosphodiesterase induced by the hormone alone during the proliferative phase of the tissue. Moreover, the combined treatment led to a sustained elevation of cAMP in the oviduct, whereas estradiol benzoate alone decreased the level of cAMP. These results and those of our previous studies showing a significant correlation between the growth inhibitory potency of triphenylethylene derivatives in vivo and their efficiency to inhibit calmodulin-dependent cAMP phosphodiesterase in vitro, strongly suggest that the differential regulation of cAMP levels by estradiol and tamoxifen is essential for the growth promoting or growth inhibiting activities of these molecules.
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PMID:Growth inhibition and the regulation of cyclic AMP by the triphenylethylene anti-estrogen tamoxifen in the quail oviduct. 166 31

The cyclic adenosine-3',5'-monophosphate (cAMP) elevation caused by exposure of human neutrophils to the Ca2+ ionophore A23187 was prevented when endogenously produced adenosine was either removed by preincubation with adenosine deaminase or blocked from binding to the adenosine receptor by antagonists [theophylline or (E)-4-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-9H-purin-8-yl)cinnamic acid]. In the absence of endogenous adenosine, A23187 potentiated the neutrophil cAMP response to 2-chloroadenosine, prostaglandin E1, and isoproterenol. When neutrophil suspensions were preincubated with concentrations of Ro 20-1724, which appeared to maximally inhibit cAMP phosphodiesterase, A23187 was still able to substantially elevate cAMP levels, suggesting that A23187 increases cAMP by amplifying adenylate cyclase responsiveness to the agonist rather than by inhibiting cAMP phosphodiesterase. The ability of A23187 to augment the cAMP elevation caused by 2-chloroadenosine was persistent over a 10-min period. The neutrophil cAMP elevations caused by chemoattractants leukotriene B4, C5a, and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) were all prevented when endogenously produced adenosine was eliminated from the cell suspensions by the addition of adenosine deaminase. The A23187-induced cAMP elevation was inhibited completely by the calmodulin inhibitors chlorpromazine, trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, whereas cAMP levels induced by FMLP, leukotriene B4 and C5a were less affected. It appears that A23187 raises cAMP in human neutrophils by a calmodulin-dependent potentiation of adenylate cyclase responsiveness to endogenously produced adenosine while the chemoattractant-induced cAMP elevations (FMLP), leukotriene B4, and C5a), although possibly Ca2+ dependent, are less sensitive to calmodulin inhibitors and may involve additional biochemical events.
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PMID:Ca2+ ionophore-induced cyclic adenosine-3',5'-monophosphate elevation in human neutrophils. A calmodulin-dependent potentiation of adenylate cyclase response to endogenously produced adenosine: comparison to chemotactic agents. 166 48

The ginseng polysaccharides GH1 (100, 200 mg.kg-1) iv reduced liver glycogen and increased adenosine-3',5'-cyclic monophosphate (cAMP) level and adenyl cyclase (AC) activity in mice. The action of GH1 was completely antagonized by propranolol, inhibitor of adrenergic beta receptor. The stimulating effect of GH1 on AC activity was significant 2 and 4 h after iv GH1. However, GH1 at concentration of 20-120 mumol.L-1 in vitro showed no manifest effect on AC activity. GH1 stimulated the activities of 3',5'-cyclic-GMP phosphodiesterases (PDE) and calmodulin (CaM) in a dose-dependent manner. It is suggested that the reduction of liver glycogen induced by GH1 resulted from its obvious increase of cAMP which promoted glycogenolysis and decreased glycogenesis.
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PMID:[Effects of the ginseng polysaccharides on reducing liver glycogen]. 166 70

The multiple functions of calmodulin in brain bring to light an apparent paradox in the mechanism of action of this multifunctional regulatory protein: How can the simultaneous calmodulin stimulation of enzymes with opposing functions, such as cyclic nucleotide phosphodiesterases and adenylate cyclase, which are responsible for the degradation and synthesis of cAMP, respectively, be physiologically significant? The same question applies to the simultaneous activation of protein kinases (in particular calmodulin kinase II) and a protein phosphatase (calcineurin). One could propose that the protein kinase(s) and the phosphatase may be located in different cells or in different cellular compartments, and are therefore not antagonizing each other. The same result could be achieved if the specific substrates of these enzymes have different cellular localizations. This does not seem to be the case. In many areas of the brain the two enzymes and their substrates coexist in the same cell. For example, the hippocampus is rich in calmodulin kinase II, calcineurin and substrates for the two enzymes. A more general scheme is presented here, based on different mechanisms of the calmodulin regulation of the two classes of enzyme, which helps to solve this apparent inconsistency in the mechanism of action of calmodulin.
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PMID:Concerted regulation of protein phosphorylation and dephosphorylation by calmodulin. 166 95

1. The effects of selective inhibitors of adenosine 3':5'-cyclic monophosphate (cyclic AMP) and guanosine 3':5'-cyclic monophosphate (cyclic GMP) phosphodiesterases (PDEs) were investigated on PDEs isolated from the rat aorta and on relaxation of noradrenaline (1 microM) precontracted rat aortic rings, with and without functional endothelium. 2. Four PDE forms were isolated by DEAE-sephacel chromatography from endothelium-denuded rat aorta: a calmodulin-activated PDE (PDE I) which hydrolyzed preferentially cyclic GMP, two cyclic AMP PDEs (PDE III and PDE IV) and one cyclic GMP-specific PDE (PDE V). The latter was selectively and potently inhibited by zaprinast. The two cyclic AMP PDEs were discriminated by specific inhibitors: one was inhibited by cyclic GMP (PDE III) and by new cardiotonic agents (milrinone, CI 930, LY 195115 and SK&F 94120); the other was inhibited by denbufylline and rolipram (PDE IV). None of these drugs significantly inhibited PDE I. 3. The PDE III inhibitors caused endothelium-independent relaxations of rat aortic rings with the following EC50 values (microM concentration producing 50% relaxation): LY 195115: 3.4, milrinone: 5.7, CI 930; 7.8, SK&F 94120: 14.7. Neither NG-monomethyl-L-arginine (L-NMMA, 300 microM), an inhibitor of the L-arginine-NO pathway, nor L-arginine (1 mM) modified the effect of PDE III inhibitors. However, methylene blue (10 microM) an inhibitor of soluble guanylate cyclase abolished relaxation induced by PDE III inhibitors except in the case of compound CI 930. 4. The specific PDE IV and PDE V inhibitors both produced endothelium-dependent relaxations which were inhibited by L-NMMA and by methylene blue (10 microM). In the presence of L-NMMA, relaxation was restored by subsequent addition of L-arginine. 5. The relaxant effects of denbufylline and rolipram were studied in the presence of drugs stimulating either adenylate cyclase (forskolin and isoprenaline) or soluble guanylate cyclase (sodium nitroprusside, SNP), or inhibiting PDE III (milrinone). In endothelium-denuded rings, a relaxing effect of both denbufylline and rolipram was found in the presence of milrinone (EC5o values 1.7 and 12 microM, respectively) or SNP (EC50 values 12.3 and 124 microM, respectively), but not in the presence of forskolin or isoprenaline. However in the presence of functional endothelium, relaxations produced by PDE IV inhibitors were significantly potentiated by forskolin, isoprenaline, milrinone and SNP (respective EC50 values for denbufylline: 2, 2, 0.4 and 0.7 microM and for rolipram: 7, 13, 7 and 1.2 microM). 6. These results indicate that the relaxant effects of inhibitors of the cyclic AMP-specific PDE IV are markedly enhanced by cyclic GMP elevating agents and by the PDE III inhibitor milrinone. They support the hypothesis that cyclic GMP enhances cyclic AMP-mediated relaxation, possibly through the inhibition of the cyclic GMP-inhibited PDE III.
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PMID:Endothelium-dependent and independent relaxation of the rat aorta by cyclic nucleotide phosphodiesterase inhibitors. 166 41

Activity-dependent facilitation is a mechanism of associative synaptic plasticity that contributes to classical conditioning in Aplysia. Previous studies of activity-dependent facilitation in the mechanosensory neurons of Aplysia suggested that the Ca2+ influx during paired spike activity enhances the transmitter-stimulated, cAMP-dependent, presynaptic facilitation in these cells. Moreover, paired activity was found to potentiate the activation of the adenylate cyclase by transmitter. It was therefore proposed that the Ca2+/calmodulin-sensitive cyclase may serve as a site of interaction between the inputs from the conditioned and unconditioned stimuli. These studies were carried out to test whether a Ca2+/calmodulin-sensitive adenylate cyclase in the Aplysia CNS has the properties necessary to mediate such an associative interaction. Three lines of evidence indicate that the same cyclase molecules that are sensitive to Ca2+/calmodulin are also stimulated by receptor to facilitatory transmitter via the stimulatory G-protein, Gs: First, calmodulin inhibitors reduced stimulation of the cyclase by facilitatory transmitter. When membranes had been preexposed to one of these inhibitors, trifluoperazine, the addition of exogenous calmodulin partially reversed the inhibition. Second, when Gs had been activated by GTP gamma S, so that it persistently activated the catalytic unit of the cyclase, stimulation of the cyclase by Ca2+ was greatly amplified, suggesting that the two inputs interact in activating a common population of the enzyme. Third, solubilized cyclase activity that bound to calmodulin-Sepharose in a Ca(2+)-dependent manner was stimulated by Gs, which had been partially purified from Aplysia CNS, as well as by Ca2+/calmodulin. Having demonstrated dual activation of the cyclase, we have explored the dependence of cyclase activation on the temporal pattern of Ca2+ and transmitter addition. Optimal activation required that a pulse of Ca2+ temporally overlap the addition of facilitatory transmitter. These several results suggested that the dually regulated adenylate cyclase might underlie the temporal requirements for effective classical conditioning in this system.
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PMID:Biochemical studies of stimulus convergence during classical conditioning in Aplysia: dual regulation of adenylate cyclase by Ca2+/calmodulin and transmitter. 167 20

Calmodulin is a protein with calcium-dependent binding sites. Binding of calcium ions induces changes in the conformation and activation of many enzymes such as adenylate cyclase, guanylate cyclase, ATPase. Neuroleptic drugs bind calmodulin. Trifluoperazine has a very high affinity for calmodulin. Tricyclic antidepressants and benzodiazepines also bind calmodulin. Binding of neuroleptics inhibits many biological phenomena such as lymphocyte endocytosis, platelets aggregation. When neuroleptics are administrated chronically, calmodulin could act in regulation of the receptors specially in the drug induced supersensitivity of striatum dopamine receptors. These experiments about the regulation of the receptors mediated by calmodulin have been performed ten years ago and their results were not confirmed later. Moreover, binding of calmodulin is not specific of neuroleptic drugs. The effects of neuroleptics on calmodulin, only observed in vitro or with animals, seem to be mainly related to structural properties of the drugs.
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PMID:Could the interaction of neuroleptics with calmodulin be an "explanation" of the psychotropic effects? 168 72

In the porcine renal epithelial cell line, LLC-PK1, activation of the cAMP-dependent signal transduction pathway induces the urokinase-type plasminogen activator (uPA) gene. We show here that the cAMP response is enhanced when the intracellular calcium concentration is increased. When LLC-PK1 cells were treated with the calcium ionophore ionomycin alone, there was no uPA mRNA accumulation. However, in the presence of ionomycin the dose-response of 8-bromo-cAMP (Br-cAMP) with respect to uPA mRNA accumulation was shifted toward the lower concentrations of Br-cAMP. A Northern blot analysis after the inhibition of RNA synthesis and nuclear run-on assays showed that the synergistic effect of Ca2+ could be attributed to increases in uPA gene transcription and mRNA stability. In the presence of cycloheximide, a protein synthesis inhibitor, uPA mRNA was stabilized, but the effect of ionomycin on Br-cAMP-induced mRNA accumulation was still maintained. The result suggests that the Ca2+, at least on transcription, does not require new protein synthesis. Ionomycin treatment did not modify the activity of the cAMP-dependent protein kinase, suggesting that Ca2+ either affects a step in the pathway between the kinase and the uPA gene, or acts independently of the cAMP-dependent protein kinase pathway. The effect of ionomycin was not suppressed by protein kinase C down-regulation nor by inhibitors of calmodulin. Synergism was also observed when Br-cAMP was replaced with calcitonin, a peptide hormone which is coupled to adenylate cyclase, and when ionomycin was replaced with another ionophore A23187, suggesting that the synergism is due to an interaction between cAMP-dependent and Ca2(+)-dependent signal transduction pathways.
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PMID:Ca2+ potentiates cAMP-dependent expression of urokinase-type plasminogen activator gene through a calmodulin- and protein kinase C-independent mechanism. 170 Nov 76

Scatter factor (SF) is a cytokine that causes cohesive epithelial colonies to 'scatter' into isolated cells and stimulates epithelial cell migration. To investigate SF's mechanism(s), we screened agents that modulate various intracellular processes for effects on scattering of Madin-Darby canine kidney (MDCK) cells. Selected agents were studied in quantitative migration assays using microcarrier beads. Agents that activate the adenylate cyclase (AC) pathway caused mild to moderate inhibition of scattering and migration, while modulators of Ca2+/calmodulin pathways had little effect on scattering. In contrast, phorbol esters (PMA, PDD) and protein kinase C (PKC) inhibitors (staurosporine, H-7, 7,8-dihydroxychlorpromazine) markedly enhanced and accelerated scattering; PMA and staurosporine also stimulated migration. Diacylglycerol analogues (e.g. diC8), naphthalenesulfonamide PKC activators (SC-9, SC-10) and inactive phorbol esters (e.g. 4a-PDD) did not potentiate scattering, while PKC depletion by 48 h pre-incubation with PMA markedly stimulated scattering. Thus, PMA-enhanced scattering may be related to down-modulation of PKC. Scattering was blocked by inhibitors of protein and RNA but not DNA synthesis; SF- and agent-stimulated migration were ablated by cycloheximide. Scattering and migration were inhibited by an anti-microfilament (cytochalasin B) but not anti-microtubule (e.g. colcemid) agents. These findings suggest that SF-induced epithelial mobility may be mediated, in part, by protein synthesis, alterations in protein phosphorylation (?inhibition of PKC), and actin filament reorganization. They indicate directions for further studies.
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PMID:Studies on the mechanism of scatter factor. Effects of agents that modulate intracellular signal transduction, macromolecule synthesis and cytoskeleton assembly. 170 77

The cyclic AMP content of cat carotid bodies in vitro measured with a radioimmunoassay under control conditions (PO2: 230 torr) was 0.79 +/- 0.10 pmol/carotid body (n = 10). Lowering medium PO2 to 20 torr for 2 min significantly increased cyclic AMP content to 1.13 +/- 0.14 pmol/carotid body (n = 10). This increase was inhibited neither by propranolol (34 microM) nor by propranolol plus haloperidol (27 microM). Inhibition of the cyclic nucleotide phosphodiesterase with 1-methyl-3-isobutylxanthine (0.8 mM) provoked a fast and large increase in cyclic AMP during both control and hypoxic conditions. The cyclic AMP increase induced by hypoxia was still observed when extracellular Ca2+ was absent. Inhibition of the adenylate cyclase by N-(cis-2-phenylcyclopentyl)azacyclotridecan-2-imine hydrochloride (MDL 12330A; 20-1,000 microM) under zero-Ca2+ conditions irreversibly inhibited the cyclic AMP increase produced by hypoxia. Similarly, inhibition of the Ca2(+)-calmodulin complex by trifluoperazine (0.2 mM) or calmidazolium (R 24571; 50-200 microM) prevented the cyclic AMP response. These results suggest that cyclic AMP may be involved in the PO2-sensing mechanism of the carotid body. Hypoxia appears to activate adenylate cyclase directly and independent of any hormone-receptor interactions.
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PMID:Hypoxia increases the cyclic AMP content of the cat carotid body in vitro. 171 Oct 98


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