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 effect of diazepam on the adenylate cyclase system was studied in rat synaptosomal membranes. Micromolar concentrations of diazepam inhibited the cyclase activities in the presence or absence of guanylyl-5'-imidodiphosphate (GppNHp). The inhibitory effect of diazepam was greater on the cyclase activity in the presence of GppNHp than on that in the basal state. This effect of diazepam was not antagonized by Ro15-1788, an antagonist of a high affinity benzodiazepine receptor in the central nervous system. Furthermore, micromolar concentrations of Ro15-1788 had no inhibitory effect on cyclase activities in the presence or absence of GppNHp. In addition, the bromide ion enhanced the inhibition by diazepam of the cyclase activity in the presence of GppNHp, but not the basal activity, although the bromide ion had no effect on both activities in the absence of diazepam. On the other hand, the pretreatment of synaptosomal membranes with GppNHp increased the KD value for [3H]diazepam binding from 98 microM to 198 microM. These data led us to conclude that diazepam inhibits rat brain adenylate cyclase through the effects on both a low affinity benzodiazepine receptor coupled with the inhibitory GTP-binding regulatory protein (Gi) and the catalytic protein.
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PMID:Involvement of the inhibitory GTP-binding regulatory protein and a low-affinity benzodiazepine receptor in the inhibitory effect of diazepam on rat brain adenylate cyclase system. 284 31

New alkylating ligands derived from indole with high affinity for beta-adrenoceptors were synthesized and their properties examined. N8-(Bromoacetyl)-N1-[3-(4-indolyloxy)-2-hydroxypropyl]-(Z)-1,8-dia mino-p- menthane (8) and its N1,N8 isomer (9) were prepared by the reaction of bromoacetyl bromide with a product of the condensation of 4-indolyl glycidyl ether with (Z)-1,8-diamino-p-menthane. A similar reaction employing 2-cyano-4-indolyl glycidyl ether yielded the respective cyano derivatives 10 and 11. Apparent affinities (Ki, M) for beta-adrenoceptors on membrane preparations from rat heart and lung were 4.6 X 10(-10) and 1.34 X 10(-9) for 8, 2.3 X 10(-8) and 4.5 X 10(-9) for 9, 6.1 X 10(-10) and 1.49 X 10(-9) for 10, and 1.83 X 10(-9) and 2.78 X 10(-9) for 11, respectively. When membranes were preincubated with the above ligands (1 X 10(-8) M, 30 min, 30 degrees C) and then washed extensively, reduction in the concentration of specific binding sites of [3H]dihydroalprenolol ranged from 7% to 76% and there was no change in KD of the remaining binding sites. (+/-)-Alprenolol and (-)-isoproterenol, but not (+)-isoproterenol, when included with the alkylating ligands in the preincubation mixtures, prevented the reduction in concentration of [3H]dihydroalprenolol binding sites. Compounds 8-11 alone did not stimulate adenylate cyclase activity in rat heart homogenates. However, these compounds inhibited (-)-isoproterenol-stimulated adenylate cyclase activity with Ki values ranging between 5 X 10(-9) and 60 X 10(-9) M. These results suggest that high-affinity irreversible beta-adrenergic antagonists were obtained that may be useful for in vivo studies of beta-adrenoceptors.
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PMID:Affinity labels for beta-adrenoceptors: preparation and properties of alkylating beta-blockers derived from indole. 288 25

The release of prolactin (PRL) from a clonal cell-line of anterior pituitary cells (GH4C1) was inhibited by somatostatin (SRIH) in a dose-dependent manner (ED50 nM). The inhibition (20% of control levels) was detectable within 50 s and maximal within 90 s. Thyroliberin (TRH) enhancement of PRL secretion was biphasic. SRIH inhibited both phases equally. Ionomycin in combination with the phorbol ester, TPA, mimics the TRH-elicited PRL release, and SRIH partly inhibited this effect. SRIH had no effect on TRH-stimulated formation of inositol trisphosphate, and only small effects on TRH-activated adenylate cyclase. Vasoactive intestinal peptide (VIP) and forskolin stimulated cAMP formation and PRL release potently. SRIH inhibited both effects of VIP and forskolin, and there was a close correlation between the inhibition of PRL secretion and cAMP accumulation. 8-Bromo-cAMP enhanced PRL release, an effect that was also partly reduced by SRIH. The Ca2+ channel activator, BAY-K-8644 and high extracellular K+ increased PRL release, and SRIH caused a partial reduction in the release response to both secretagogues. SRIH lowered [Ca2+]i, and markedly reduced the rise in [Ca2+]i elicited by TRH, VIP and K+. SRIH did not influence the Ca2+ spikes recorded in Na+-free solution, and had no effect on the TRH-induced membrane potential changes. Our results demonstrate that SRIH may inhibit PRL release from GH4C1 cells by (1) inhibiting hormone-sensitive adenylate cyclase, (2) blocking the effect of cAMP and (3) lowering [Ca2+]i. None of these effects is, however, sufficient to explain all the effects of SRIH, suggesting that SRIH also exerts a major action at a step subsequent to cAMP accumulation and [Ca2+]i elevation. Since the GH4C1 cells possess one single class of binding sites, this implies that the same SRIH receptor is coupled to several cellular signalling systems.
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PMID:Somatostatin inhibits prolactin secretion by multiple mechanisms involving a site of action distal to increased cyclic adenosine 3',5'-monophosphate and elevated cytosolic Ca2+ in rat lactotrophs. 290 8

The cloning sequencing and analysis of an important antigenic component of Bordetella pertussis is described. The gene for P.69, in common with a variety of other so called "virulence" genes, (e.g., adenylate cyclase (AC), pertussis toxin (PT) and filamentous haemagglutinin (FHA)), is under control of the vir locus. The protein P.69 is externally localised on cells and protein preparations are protective as judged by the mouse intra-cerebral challenge test. The gene encoding the P.69 antigen was isolated by hybridization of mixed oligonucleotide probes against B. pertussis genomic DNA. These oligonucleotides were designed from the protein sequence data obtained from a cyanogen bromide digest of the P.69 protein. DNA sequence analysis reveals a G:C rich gene capable of encoding a protein of 910 amino acids and Mr of 93478, whose likely promoter and ribosome binding sites show little homology to their E.coli counterpart. In common with some of the genes in the PT operon the sequence 5'-CCTGG-3' was found 5' to the ATG initiation codon. At the 3', end 29 bases after the TAA stop codon, the sequence 5'GTTTTTCCT-3' was found in an equivalent position to the same sequence in the PT operon. Examination of the protein sequence reveals two regions with directly repeated elements (GGAVP)3(GGFGP)2 and (PQP)5.
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PMID:Molecular cloning and analysis of P. 69, a vir-controlled protein from Bordetella pertussis. 290 24

The relationship between Fc receptor specific for IgG2b (Fc gamma 2bR) and membrane adenylate cyclase was investigated. The specific binding of IgG2b immune complexes to P388D1 cell surface Fc gamma 2bR was found to inhibit the basal, forskolin-stimulated, and NaF-stimulated activities of membrane adenylate cyclase by 53%, 57%, and 31%, respectively. On the other hand, the binding of IgG2a immune complexes to cell surface Fc gamma 2aR increased the basal activity about 2.5-fold and the forskolin- and NaF-stimulated activities slightly. The fusion of liposomes containing Fc gamma 2bR, which was obtained as phosphatidylcholine (PC) binding protein as previously described, with the cyc- membrane preparations resulted in the marked suppression of membrane adenylate cyclase, whereas the fusion of liposomes containing Fc gamma 2a, which was obtained as IgG-binding protein, led to about a 2.7-fold increase. The Fc gamma 2bR-mediated inhibition of adenylate cyclase may be due to the temporary change of the lipid environment caused by the action of phospholipase A2, which was previously shown to be associated with Fc gamma 2bR, since (1) addition of snake venom phospholipase A2 or cholate-solubilized PC-binding protein to P388D1 membrane was found to inhibit adenylate cyclase in a dose-dependent manner, (2) prior treatment of snake venom phospholipase A2 or PC-binding protein with a specific inhibitor, p-bromophenacyl bromide, significantly reduced their inhibitory action, and (3) a product of phospholipase A2 action, arachidonic acid, was found to be an effective inhibitor of membrane adenylate cyclase, whereas the other product, lysophosphatidylcholine, was much less inhibitory than arachidonic acid. Arachidonic acid appeared to interfere with the functions of both guanine nucleotide-binding stimulatory (Gs) protein and the catalytic subunit of adenylate cyclase, since exogenously added arachidonic acid significantly suppressed the GTPase activity of P388D1 membrane and the forskolin response of the adenylate cyclase activity of Gs protein deficient cyc- membrane. The primary site of action of lysophosphatidylcholine is not clear but may be other than Gs protein and/or the catalytic subunit, since it did not change either GTPase activity of P388D1 membrane or the response to forskolin of adenylate cyclase of cyc- membrane. The Fc gamma 2bR/phospholipase A2 mediated inhibition of adenylate cyclase would be a transient event in viable cells, since phospholipase A2 did not inhibit adenylate cyclase in the presence of microsomal fraction, mitochondria, and coenzyme A, suggesting the occurrence of rapid acylation of CoA and reacylation of lysolecithin.
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PMID:Relationship between Fc gamma 2b receptor and adenylate cyclase of a murine macrophagelike cell line, P388D1. 295 16

We studied the effects of cyclic AMP (cAMP) on HCO-3 transport by rabbit cortical collecting tubules perfused in vitro. Net HCO-3 secretion was observed in tubules from NaHCO3- loaded rabbits. 8-Bromo-cAMP-stimulated net HCO-3 secretion, whereas secretion fell with time in control tubules. Both isoproterenol and vasopressin (ADH) are known to stimulate adenylate cyclase in this epithelium; however, only isoproterenol stimulated net HCO-3 secretion. The mechanism of cAMP-stimulated HCO-3 secretion was examined. If both HCO-3 and H+ secretion were to occur simultaneously in tubules exhibiting net HCO-3 secretion, cAMP might increase the net HCO-3 secretory rate by inhibiting H+ secretion, by stimulating HCO-3 secretion, or both. These possibilities were examined using basolateral addition of the disulfonic stilbene (4,4'-diisothiocyanostilbene-2,2'-disulfonate (DIDS). In acidifying tubules from NH4Cl-loaded rabbits, DIDS eliminated HCO-3 reabsorption, a result consistent with known effects of DIDS as an inhibitor of H+ secretion. In contrast, cAMP left acidification (H+ secretion) intact. DIDS applied to HCO-3 secretory tubules failed to increase the HCO-3 secretory rate, indicating minimal H+ secretion in HCO-3 secreting tubules. Thus, inhibition of H+ secretion by cAMP could not account for the cAMP-induced stimulation of net HCO-3 secretion. cAMP-stimulated HCO-3 secretion was reversibly eliminated by 0 Cl perfusate, whereas luminal DIDS had no effect. Bath amiloride (1 mM) failed to eliminate cAMP-stimulated HCO-3 secretion when bath [Na+] was 145 mM or 5 mM. cAMP depolarized the transepithelial voltage. The collected fluid [HCO-3] after cAMP could be accounted for by electrical driving forces, suggesting that cAMP stimulates passive HCO-3 secretion. However, cAMP did not alter HCO-3 permeability measured under conditions expected to inhibit transcellular HCO-3 movement (0 Cl- solutions and bath DIDS). This measured HCO-3 permeability was not high enough to account, by passive diffusion, for the HCO-3 fluxes observed in Cl-containing solutions. We conclude the following: cAMP increased net HCO3- secretion by stimulating HCO3- secretion and not by inhibiting H+ secretion; this HCO3- secretion may have occurred by Cl-HCO3- exchange; Na+-H+ exchange appeared not to play a role in basolateral H+ extrusion under these conditions; and the stimulation of HCO3- secretion by isoproterenol, but not ADH, suggests the existence of separate cell cAMP pools or cellular heterogeneity in this cAMP response.
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PMID:Cyclic adenosine monophosphate-stimulated bicarbonate secretion in rabbit cortical collecting tubules. 298 40

The effects of drugs known to enhance intracellular cyclic AMP levels on depolarization-induced [3H]norepinephrine release from superfused rat neocortical slices and synaptosomes were investigated. The adenylate cyclase activator forskolin, the membrane-permeating cyclic AMP analogues 8-bromo-cyclic AMP and dibutyryl cyclic AMP, as well as the phosphodiesterase inhibitors isobutylmethylxanthine and 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrolidone (ZK 62771) enhanced the electrically evoked release of [3H]norepinephrine from superfused rat brain neocortex slices. 8-Bromo-cyclic GMP was without effect on the electrically evoked release. When [3H]norepinephrine release was enhanced by prolonging the electrical pulse duration from 2 msec to 10 msec, the relative inhibitory effect of the Ca2+ channel blocker Cd2+ and the relative facilitatory effect of the K+ channel blocker 4-aminopyridine remained unaffected. In striking contrast, the relative facilitatory effects of forskolin and 8-bromo-cyclic AMP were strongly reduced, whereas the effect of ZK 62771 was almost doubled. When veratrine-induced release of [3H]norepinephrine from cortex synaptosomes was examined, the facilitatory effects of forskolin, 8-bromo-cyclic AMP, and ZK 62771 were even more pronounced than in brain slices. The data strongly support the hypothesis that a presynaptic adenylate cyclase system plays a facilitatory role in the stimulus-secretion coupling process in central noradrenergic nerve terminals.
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PMID:Evidence for a presynaptic adenylate cyclase system facilitating [3H]norepinephrine release from rat brain neocortex slices and synaptosomes. 299 6

The role of the second messengers cAMP and Ca++ in the control of proopiomelanocortin (POMC) gene expression was investigated with the use of hybridization with cloned complementary DNA probes. The effects of cAMP-related drugs on POMC messenger RNA (mRNA) levels were assessed in primary cultures of intermediate (IL) and anterior rat pituitary cells maintained in serum-free medium. 8-Bromo-cAMP (1 mM), but not 8-bromo-cGMP (1 mM), induced a 2-fold increase in IL and anterior lobe cell after 2 days of treatment. A similar increase was obtained with the adenylate cyclase-activating drugs forskolin (1 microM) and cholera toxin (100 ng/ml) or the phosphodiesterase inhibitor RO 20-1724 (100 microM). At 48 h, all these treatments had increased beta-endorphin accumulation in the medium and transiently decreased the cellular beta-endorphin content in IL cells, suggesting a parallel effect of cAMP-related drugs on secretion and biosynthesis. Incubating the cells with the Ca++ channel antagonists D600 (50 microM), verapamil (50 microM), and the dihydropyridine nifedipine (0.1 microM) decreased basal POMC mRNA levels, whereas the dihydropyridine BAYK 8644 (0.1 microM), which activates the Ca++ channel, increased POMC mRNA levels after 2 days. In addition, nifedipine decreased the stimulatory effect of forskolin, whereas BAYK 8644 further stimulated the forskolin-increased POMC mRNA levels in IL cells. We conclude that both Ca++ and cAMP may regulate the gene expression of POMC.
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PMID:Calcium ion and cyclic adenosine 3',5'-monophosphate regulate proopiomelanocortin messenger ribonucleic acid levels in rat intermediate and anterior pituitary lobes. 302 21

The ADP-ribosylation factor (ARF) is a 21-kDa GTP-binding protein cofactor in the cholera toxin-catalyzed ADP-ribosylation of the stimulatory regulatory subunit of adenylate cyclase. Purified bovine brain ARF was digested with cyanogen bromide, and peptides were purified and sequenced. Approximately 25-30% of the protein was sequenced in this manner. Peptides contained consensus sequences for GTP-binding proteins but were distinct from any of the previously published GTP-binding proteins. Antibodies were raised in rabbits against both protein and synthetic peptide fragments of ARF. Specific ARF immunoreactivity was detected in every eukaryotic tissue or cell examined, including yeast, slime mold, and man. No ARF immunoreactivity was observed when Escherichia coli proteins were tested. Immunoblotting revealed the majority of ARF to be present in the 100,000 x g supernatant. Immunological cross-reactivity with the cytosolic factor indicate that it and ARF are likely to be the same protein. ARF is shown to be myristylated at the amino terminus. The potential role of myristylation in cellular localization is discussed.
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PMID:Chemical and immunological characterization of the 21-kDa ADP-ribosylation factor of adenylate cyclase. 313 41

1 In mouse isolated atria previously incubated with [3H]-noradrenaline, 8-bromo-cyclic AMP (3-270 microM) produced a concentration-dependent increase in the fractional stimulation-induced outflow of radioactivity. 8-Bromo-cyclic GMP induced a lesser increase in the stimulation-induced outflow. 2 The phosphodiesterase inhibitors: M&B 22948 (90 microM); ICI 63197 (30 and 90 microM) and 3-isobutyl-1-methylxanthine (90 microM) increased the fractional stimulation-induced outflow. Together these results indicate that cyclic AMP may have a modulatory effect on noradrenaline release. 3 The inhibition of the stimulation-induced outflow produced by clonidine (0.03 microM) and its facilitation produced by phentolamine (1 microM) were unaltered in the presence of 8-bromo-cyclic AMP (90 microM). However, in the presence of 8-bromo-cyclic AMP (270 microM), the facilitatory effect of phentolamine was enhanced, but the inhibitory effect of clonidine (0.03 microM) was unaltered. In the presence of ICI 63197 (30 microM) the inhibitory effect of clonidine (0.03 microM) was unaltered, but the facilitatory effect of phentolamine (1 microM) was slightly enhanced. 4 Isoprenaline (0.003-0.1 microM) enhanced the fractional stimulation-induced outflow, an effect blocked by propranolol (0.1 microM). In the presence of 8-bromo-cyclic AMP (90 microM), the facilitatory effect of isoprenaline (0.01 microM) was blocked. In the presence of ICI 63197 (30 microM) the facilitatory effect of isoprenaline (0.003 microM) was potentiated. 5 These results suggest that whereas beta-adrenoceptor-mediated enhancement of noradrenaline release is linked to the stimulation of adenylate cyclase and enhanced formation of cyclic AMP, alpha-adrenoceptor-mediated inhibition of noradrenaline release is not linked to inhibition of adenylate cyclase activity.
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PMID:Involvement of cyclic nucleotides in prejunctional modulation of noradrenaline release in mouse atria. 366 78


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