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 participation of the adenylate cyclase system in the short-lived changes in the efficiency of synaptic transmission of a functionally identified synapse of the edible snail has been investigated. It was established that imidazole (a phosphodiesterase activator) in a concentration of 5 mM and tolbutamide (an inhibitor of cAMP-dependent phosphorylation) in a concentration of 2 mM do not alter the rate of the depression of EPSPs which is elicited by rhythmic stimulation at a frequency of 0.1 Hz, and do not block heterosynaptic facilitation. At the same time, both of these substances decrease the amplitude of EPSPs. The possibility of the modulation of the efficiency of synaptic transmission through the adenylate cyclase system is discussed.
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PMID:Role of cyclic adenosine monophosphate in simple forms of plasticity in the edible snail. 217 Aug 58

(Rp)-Adenosine 3',5'-monophosphorothioate ((Rp)-cAMPS) is a highly specific antagonist of the cAMP-dependent protein kinase from eukaryotic cells and is a very poor substrate for phosphodiesterases. It is therefore a useful tool for investigating the role of cAMP as a second messenger in a variety of biological systems. Taking advantage of stereospecific inversion of configuration around the alpha-phosphate during the adenylate cyclase reaction, we have developed a method for the preparative enzymatic synthesis of the Rp diastereomer of adenosine 3',5'-monophosphorothioate ((Rp)-cAMPS) from the Sp diastereomer of adenosine 5'-O-(1-thiotriphosphate) ((Sp)-ATP alpha S). The adenylate cyclase from Bordetella pertussis, partially purified by calmodulin affinity chromatography, cyclizes (Sp)-ATP alpha S approximately 40-fold more slowly than ATP, but binds (Sp)-ATP alpha S with about 10-fold higher affinity than ATP. The triethylammonium salt of the reaction product can be purified by elution from a gravity flow reversed-phase C18 column with a linear gradient of increasing concentrations of methanol. Yields of the pure (Rp)-cAMPS product of a synthesis with 2 mg of substrate are about 75%.
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PMID:Enzymatic synthesis of the cAMP antagonist (Rp)-adenosine 3',5'-monophosphorothioate on a preparative scale. 217 77

Infusion of forskolin, an adenylate cyclase activator, in concentrations (2 microM) that do not alter basal prostaglandin (PG) synthesis inhibit synthesis of PG elicited by isoproterenol in rabbit heart. This inhibitory action of forskolin appears to be dependent on cyclic AMP (cAMP). Bolus injection of forskolin (75 nmol), however, was found to stimulate PG synthesis in rabbit heart. The purpose of this study was to elucidate the mechanism of the stimulatory action of forskolin on PG synthesis (prostaglandin I2 measured as 6-ketoprostaglandin F1 alpha [6-keto-PGF1 alpha]) in isolated perfused rabbit heart. Forskolin enhanced PG production in a dose-dependent manner. 1,9-Dideoxyforskolin, a forskolin analogue devoid of adenylate cyclase-stimulating activity, also enhanced PG synthesis. The cAMP analogue chlorophenylthio-cAMP failed to stimulate output of 6-keto-PGF1 alpha, although this agent produced dose-related changes in mechanical function in rabbit heart. Furthermore, the adenylate cyclase inhibitor (-)-N6-(R-phenylisopropyl)adenosine potentiated, whereas the phosphodiesterase inhibitor cilostamide attenuated, forskolin-stimulated PG production. (-)-N6-(R-Phenylisopropyl)adenosine and cilostamide had no effect on the mechanical actions of chlorophenylthio-cAMP, suggesting selectivity of these agents for adenylate cyclase and phosphodiesterase, respectively. 6-Keto-PGF1 alpha output elicited by forskolin was abolished by reduction of calcium in the perfusion fluid as well as by the calcium channel blocker diltiazem. The intracellular calcium antagonists TMB-8 and ryanodine also abolished forskolin-stimulated PG synthesis in rabbit heart. PG synthesis stimulated by 1,9-dideoxyforskolin was also prevented by reduced extracellular calcium, diltiazem, and ryanodine. The calmodulin antagonists trifluoperazine, W-7, and calmidazolium failed to significantly alter PG production in response to forskolin. These results indicate that forskolin-stimulated PG synthesis in rabbit heart is independent of cAMP and requires calcium from both extracellular and intracellular sources.
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PMID:Forskolin stimulates prostaglandin synthesis in rabbit heart by a mechanism that requires calcium and is independent of cyclic AMP. 217 6

Bordetella pertussis produces extracytoplasmic adenylate cyclase toxin (AC toxin) which penetrates target cells and, upon activation by host calmodulin, generates high levels of intracellular cyclic AMP (cAMP). As a result, bactericidal functions of immune effector cells are impaired. Since a considerable amount of AC toxin is associated with the bacterium, it was proposed that the toxin may be delivered by direct interaction of the organism with the target cells (E. L. Hewlett, M. C. Gray, and R. D. Pearson, Clin. Res. 35:477A, 1987). Incubation of CHO cells with intact B. pertussis led to formation of intracellular cAMP at levels comparable to those produced in CHO cells by equivalent activities of isolated AC toxin. cAMP accumulation induced by the whole bacteria appeared after a lag of 40 to 60 min and reached high levels within 2 to 3 h, whereas adherence of the bacteria proceeded rapidly and reached a maximal level within 80 min. Sera of pertussis patients completely blocked cAMP accumulation induced by the whole bacteria without having a major effect on either bacterial adherence or cAMP production by the AC toxin. Cytochalasins B and D, inhibitors of bacterial invasion, abrogated the cAMP response to the whole bacteria but not the response to the AC toxin. These agents did not affect bacterial adherence. Transmission electron micrographs revealed that B. pertussis, within the time course of cAMP induction, invaded CHO cells. We suggest that cAMP induction by B. pertussis is caused by the entry of the whole bacteria into CHO cells rather than by delivery of AC toxin during bacterial adherence. This route of cell intoxication may be relevant to the pathogenesis of whooping cough.
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PMID:Bordetella pertussis adenylate cyclase toxin: intoxication of host cells by bacterial invasion. 217 67

3'-Anthraniloyl-2'-deoxyadenosine 5'-triphosphate (Ant-dATP), a fluorescent analogue of ATP, was tested as a probe for the nucleotide-binding site of calmodulin (CaM)-activated adenylate cyclases from Bordetella pertussis (BPCYA47) and Bacillus anthracis (BACYA62). Ant-dATP competitively inhibited both bacterial enzymes expressed in Escherichia coli (ki approximately 10 microM). Binding of the analogue to adenylate cyclase was monitored by equilibrium dialysis and by an increase in its fluorescence emission at 420 nm upon excitation at 330 nm. Whereas the fluorescence of Ant-dATP was little influenced by divalent cations, CaM, or adenylate cyclase alone, the Ca2+.CaM.cyclase complex increased up to 4 times the quantum yield of Ant-dATP. Binding of the analogue to the catalytic site of BPCYA47 and BACYA62 was specific as shown by its displacement with ATP or 3'-dATP. Our results substantiate the role of CaM in favoring substrate binding to CaM-activated enzymes.
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PMID:Binding of 3'-anthraniloyl-2'-deoxy-ATP to calmodulin-activated adenylate cyclase from Bordetella pertussis and Bacillus anthracis. 217 37

Rolipram (4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone) represents a new class of specific low Km cAMP phosphodiesterase (PDE) inhibitors. This compound enhances basal, hormone- and forskolin-elicited cAMP accumulation in prolactin (PRL) producing rat pituitary adenoma (GH4C1) cells in culture (ED50 = 5.10(-8) M). This effect is due to a selective inhibition of the low Km cAMP PDE (type III), since neither basal nor hormone-stimulated adenylate cyclase (AC) nor the Ca2+/calmodulin-dependent PDE were affected by rolipram. The drug enhanced vasoactive intestinal polypeptide (VIP)-stimulated PRL-secretion, while thyroliberin (TRH)- and 12-0-tetradecanoyl phorbol-13-acetate (TPA)-elicited PRL egress were slightly reduced indicating a cAMP-mediated reduction of protein kinase C (PK-C) mediated PRL release. Interestingly, inhibition of PRL secretion by somatostatin (SRIH) was completely suppressed suggesting cAMP-mediated inactivation of some GTP-binding protein(s) of the alpha i family (G alpha i2 or Gk). Rolipram did not affect phosphoinositide metabolism (i.e. IP3 accumulation), neither acutely nor after long term administration. Rolipram, like the cAMP PDE inhibitor Ro 20-1724, did not influence AC and PDE I, but dose-dependently inhibited PDE III activity. Long term incubation of GH4C1 cells with rolipram in the presence of noradrenaline (NA) exerted a marginal decrease of beta-receptor number, AC activation and cAMP accumulation, while Ro 20-1724 brought about a marked down-regulation and desensitization of the AC complex. In summary, rolipram selectively interacts with PDE III in rat pituitary adenoma cells in culture and does not result in beta-adrenoceptor AC downregulation. These features are not shared by the other drugs tested.
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PMID:The pharmacodynamic action of the cyclic AMP phosphodiesterase inhibitor rolipram on prolactin producing rat pituitary adenoma (GH4C1) cells. 217 76

The effect of cooling of animals on phosphorylation of proteins in hypothalamus, pituitary gland and adrenals, was studied in white mice. The regulation of protein phosphorylation in cells during hypothermia was carried out via the adenylate cyclase system in all these structures. The calcium-calmodulin system took part in this process in hypothalamus and adrenals.
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PMID:[The regulation of protein phosphorylation in the hypothalamus, hypophysis and adrenals during deep hypothermia]. 217 87

Rapid in vivo effects of 1,25-dihydroxyvitamin D3 on muscle calcium metabolism have been reported. In vitro studies have shown that exposure of vitamin D-deficient chick soleus muscles to the sterol for 1-10 minutes causes a significant stimulation of tissue 45Ca uptake which can be suppressed by Ca channel blockers. A parallel increase in muscle membrane calmodulin content that could be mimicked by forskolin was observed. Experiments were carried out to obtain information about the mechanism underlying the fast action of 1,25-dihydroxyvitamin D3. Like the sterol, forskolin (10 microns) rapidly increased (+48% at 5 min) soleus muscle 45Ca uptake and its effect could be reversed by nifedipine (50 microns). In agreement with these observations, 1,25-dihydroxyvitamin D3 markedly elevated tissue cAMP levels within 45 seconds to 5 minutes of treatment in a dose-dependent manner (10(-11)-10(-7) M). Moreover, incubation of isolated muscle microsomes with 1,25-dihydroxyvitamin D3 increased adenylate cyclase activity and caused a similar profile of stimulation of protein phosphorylation with [gamma-32P]-ATP as forskolin. Major changes were detected in proteins whose calmodulin binding ability has been previously shown to be increased by 1,25-dihydroxyvitamin D3. In addition, the calmodulin antagonists fluphenazine and compound 48/80 abolished the increase in muscle Ca uptake and membrane calmodulin content produced by the sterol. The results suggest that 1,25-dihydroxyvitamin D3 activates muscle Ca channels through a direct membrane action which involves cAMP-dependent protein phosphorylation and calmodulin binding.
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PMID:Cyclic AMP-dependent membrane protein phosphorylation and calmodulin binding are involved in the rapid stimulation of muscle calcium uptake by 1,25-dihydroxyvitamin D3. 217 47

Endothelial cell incubated with IL-1 have been shown adhere more lymphocytes than nontreated endothelial cells. Here we demonstrate that IL-1 can also increase lymphocyte penetration through endothelial monolayers in vitro. IL-1 induced a transient increase in the number of lymphocytes penetrated through the endothelial monolayer into a filter in a time- and dose-dependent manner. This effect could be mimicked by increasing the cytosolic cAMP levels in the endothelial cells either by forskolin or dibutyryl-cAMP. Concomitantly we were able to show that IL-1 increased the cytosolic cAMP levels in endothelial cells. An inhibitor of adenylate cyclase, ddAdo, decreased both the IL-1-induced cAMP elevation and lymphocyte penetration. A protein kinase A inhibitor HA 1004 could inhibit the IL-1-induced lymphocyte penetration, where as protein kinase C (N-(2-guamidino-ethyl)-5-isoquinolinesyl foamide hydrocloride) and calcium-calmodulin (N-(6-aminohexyl)-5-chloro-1-naphthalensulfanamide) inhibitors had no effect. Adding dibutyryl-cGMP or calcium ionophore to the endothelial cells could not mimic IL-1-induced penetration and finally IL-1 did not induce PKC translocation in endothelial cells. These data support the view that IL-1 acts via cAMP as a second messenger in regard to lymphocyte penetration through endothelial cells. The above data demonstrate that IL-1-induced lymphocyte penetration through endothelial cells and that this IL-1-induced signal is transduced via cAMP in endothelial cells.
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PMID:cAMP mediates IL-1-induced lymphocyte penetration through endothelial monolayers. 217 25

Bordetella pertussis, the pathogen responsible for whooping cough, produces a calmodulin-sensitive adenylate cyclase. Several investigators have shown that the partially purified adenylate cyclase is capable of entering animal cells and elevating intracellular cAMP levels (Confer and Eaton: Science 217:948-950, 1982; Shattuck and Storm: Biochemistry 24:6323-6328, 1985). However, the mechanism for entry of the catalytic subunit of this adenylate cyclase into animal cells is unknown. It has been reported that the B. pertussis adenylate cyclase extracted from bacterial cells with urea does not enter animal cells by receptor-mediated endocytosis. There is, in addition to the cell associated form of the B. pertussis adenylate cyclase, a cell-invasive form of the enzyme secreted into the bacterial culture media. The properties of the cell-associated and secreted enzymes are significantly different (Masure and Storm: Biochemistry 28:438-442, 1989). In this study, we report evidence that the secreted form of the B. pertussis adenylate cyclase enters animal cells by a mechanism distinct from receptor-mediated endocytosis.
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PMID:Evidence that the adenylate cyclase secreted from Bordetella pertussis does not enter animal cells by receptor-mediated endocytosis. 217 58


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