Showing papers on "Cyclase published in 1984"
TL;DR: It is clear that detailed understanding of the mechanism of regulation of CAMP synthesis will soon be achieved from study of the interactions of purified components that have been reconstituted in lipid bilayers of defined composition.
1,645 citations
TL;DR: Islet-activating protein (IAP), pertussis toxin, catalyses the transfer of the ADP-ribose moiety of NAD to the active subunit of N u resulting in a complete loss of the N i functions, which will be useful as a tool for further studies of the transmembrane signal transduction mechanism.
583 citations
TL;DR: An X-linked recessive mutation in Drosophila that blocks associative learning is isolated and mapped, and it is postulated that there is at least one other type of adenylate cyclase activity that is unaffected by the mutation and insensitive to calcium/calmodulin.
567 citations
TL;DR: It is found that in bovine cerebral cortex there are three proteins of similar molecular weight which are modified by pertussis toxin which differ in two functions: susceptibility to ADP-ribosylation and GTPase activity.
518 citations
TL;DR: The physical characteristics of Gi are important determinants of its role as the inhibitory guanine nucleotide-binding regulatory component of adenylate cyclase.
478 citations
TL;DR: The apparent ability of ARF to bind to the alpha subunit of Gs suggests that it may play another, unknown role in the regulation of adenylate cyclase activity.
392 citations
TL;DR: Treatment of guinea pig neutrophils with pertussis toxin (islet-activating protein; IAP) results in inhibition of N-formyl peptide receptor-mediated release of arachidonic acid and granular enzymes, suggesting that this G protein is involved in receptor- mediated signal transduction in neutrophil by mechanisms that do not involve cyclic AMP.
382 citations
TL;DR: The data strongly suggest that the IAP substrate is another dimeric, guanine nucleotide-binding regulatory protein and that it is responsible for inhibitory modulation of adenylate cyclase activity.
378 citations
TL;DR: Modification of platelet cyclic AMP metabolism through inhibition of phosphodiesterase activity was found to be the probable mechanism of their antiaggregating effect.
348 citations
Journal Article•
TL;DR: Inhibition of adenylate cyclase was specific for psychoactive cannabinoids, since cannabinol and cannabidiol produced minimal or no response, and was also stereoselective, since dextronantradol did not produce the response.
Abstract: Adenylate cyclase in plasma membranes was inhibited by micromolar concentrations of delta 8-tetrahydrocannabinol and delta 9-tetrahydrocannabinol and by levonantradol and desacetyllevonantradol. This inhibition was noncompetitive for stimulation of the enzyme at the prostanoid receptor by prostaglandin E1 or prostacyclin, or at the peptide receptor by secretin or vasoactive intestinal peptide. Forskolin-activated adenylate cyclase was also inhibited by cannabimimetic agents. Inhibition by cannabinoid compounds was neither synergistic nor additive with muscarinic or alpha-adrenergic agents when each was present at maximally inhibitory concentrations. Cannabinoid inhibition was not blocked by atropine, yohimbine, or naloxone, suggesting that muscarinic, alpha 2-adrenergic and certain opiate receptors may not be required for the response. The inhibition of adenylate cyclase was specific for psychoactive cannabinoids, since cannabinol and cannabidiol produced minimal or no response. Inhibition was also stereoselective, since dextronantradol did not produce the response. A biphasic log dose-response curve was observed for each of the cannabinoid drugs, such that reversal of the inhibition occurred at 3-10 microM. Possible mechanisms for the effects of cannabinoid drugs on adenylate cyclase activity are discussed.
347 citations
TL;DR: The inhibitory and stimulatory guanine nucleotide-binding regulatory components (Gi and Gs) of adenylate cyclase both have an alpha X beta subunit structure, and the beta (35,000 Da) and 41,000-Da subunits are functionally indistinguishable.
TL;DR: The adenylate cyclase system is composed of an activating hormone or neurotransmitter, its receptor (R), the guanosine triphosphate (GTP) binding protein (Gs), and the catalytic unit (C), which involves a transient change in conformation, from a loose binding of the neurotransmitter H to an extremely tight interaction, termed locking.
Abstract: The adenylate cyclase system is composed of an activating hormone or neurotransmitter (H), its receptor (R), the guanosine triphosphate (GTP) binding protein (Gs), and the catalytic unit (C). The activation of the receptor R involves a transient change in conformation, from a loose binding of the neurotransmitter H to an extremely tight interaction, termed locking. The system is regulated in the activation steps and also by three deactivation processes. A guanosine triphosphatase activity is built into the Gs protein so that the active GsGTP has only a limited lifetime during which it is able to activate C. In addition, the continued occupation of R by H causes desensitization of R. Finally, there are inhibitory receptors, such as alpha-adrenergic and opiate receptors, which inhibit the adenylate cyclase by way of a specific GTP binding protein (Gi). Yet to be determined are the conformational transformations of pure R on binding of an agonist or a partial agonist; the genes that code for the many different receptors that activate the adenylate cyclase, and the possibility that the G components interact with systems in the cell other than the adenylate cyclase.
TL;DR: The inhibitory and stimulatory guanine nucleotide-binding regulatory components (Gi and Gs) of adenylate cyclase both have an alpha X beta subunit structure, and the beta subunits are functionally indistinguishable.
TL;DR: Data underscore the role of pertussis toxin in the disease and provide the first direct evidence that adenylate cyclase and hemolysin are important in the pathogenesis of the infection.
Abstract: A wild-type strain of Bordetella pertussis and a series of transposon Tn5-induced mutants deficient in the production of various factors believed to play a role in pertussis (whooping cough) were tested for virulence in infant mice. The 50% lethal dose of the wild-type strain in these animals was 2 X 10(3) bacteria. A mutant deficient in the production of the filamentous hemagglutinin was almost as virulent as the wild type. Avirulent phase mutants (i.e., deficient in the production of all toxins), a pertussis-toxin mutant, and a double mutant deficient in both hemolysin and adenylate cyclase were severely impaired in the ability to cause pertussis. These data underscore the role of pertussis toxin in the disease and provide the first direct evidence that adenylate cyclase and hemolysin are important in the pathogenesis of the infection.
TL;DR: A potential role for protein kinase C in regulating beta-adrenergic receptor function is suggested in regulatingalpha-phorbol diesters or catecholamines and in promoting adenylate cyclase desensitization in duck erythrocytes with tumor promotion.
TL;DR: The findings indicate that decreased receptor-Ns coupling is correlated with receptor phosphorylation and that phorbol esters can influence the responsiveness of hormone-sensitive adenylate cyclase in certain cell types.
Abstract: Incubation of turkey erythrocytes with the phorbol ester phorbol 12-myristate 13-acetate (PMA) results in a dose- and time-dependent desensitization of isoproterenol-stimulated adenylate cyclase activity. Compared to controls, membranes from PMA-treated cells have an isoproterenol-stimulated adenylate cyclase activity that is decreased 20%-40%, with little effect on forskolin or fluoride activation of adenylate cyclase. No change in beta-adrenergic receptor number is observed after PMA treatment, indicating that the major effect of PMA is to uncouple receptor interactions with Ns, the stimulatory guanine nucleotide regulatory protein of adenylate cyclase. Purification of beta-adrenergic receptors from 32Pi-labeled turkey erythrocytes, incubated in the presence or absence of PMA, indicates that the phorbol ester is capable of inducing a 3-fold increase in phosphorylation of the beta-adrenergic receptor. The PMA effect is similar to the phosphorylation of the beta-adrenergic receptor during isoproterenol- and dibutyryl cAMP-induced desensitization of adenylate cyclase in turkey erythrocytes. The findings indicate that decreased receptor-Ns coupling is correlated with receptor phosphorylation and that phorbol esters can influence the responsiveness of hormone-sensitive adenylate cyclase in certain cell types.
Journal Article•
TL;DR: The GABAB receptor is negatively coupled to adenylate cyclase in various brain areas, and, in the cerebellum, data suggest a granule cell localization of this activity.
Abstract: Baclofen and gamma-aminobutyric acid (GABA) are shown to inhibit basal adenylate cyclase activity in brain of rat. The response is mediated through the GABAB receptor, and the rank order of potency for agonists is (-)-baclofen (EC50 = 4 microM) greater than GABA (EC50 = 17 microM) greater than muscimol greater than (+)-baclofen. GABAA agonists are not effective inhibitors of cyclase activity. The response is bicuculline-insensitive, and diazepam does not modify the GABA or (-)-baclofen inhibition of adenylate cyclase. Studies with neurologically mutant mice correlated a loss in GABAB receptor-mediated inhibition of cyclase with a loss in cerebellar granule cells. Thus, the GABAB receptor is negatively coupled to adenylate cyclase in various brain areas, and, in the cerebellum, data suggest a granule cell localization of this activity.
TL;DR: Muscarinic receptors coupled to adenylate cyclase and the PhI response can be differentiated by virtue of their sensitivity to agonist and the efficiency with which some agonists induce receptor change and elicit receptor-mediated biochemical responses.
TL;DR: This work has utilized purified reactants and cofactors to examine the form of the stimulatory guanine nucleotide-binding regulatory component of adenylate cyclase that serves as a substrate for ADP-ribosylation by cholera toxin and investigated some of the consequences of that covalent modification.
TL;DR: In this paper, the effects of Bordetella pertussis toxin (PT) catalyzes the ADP-ribosylation of a 41,000-Da peptide believed to be a subunit of the guanyl nucleotide-binding protein (Gi) involved in cyclase inhibition and abolishes inhibitory effects of opiate agonists.
Journal Article•
TL;DR: The similarity of this bacterial adenylate cyclase to calmodulin-dependent eucaryotic adenYLate cyclases suggests that EF may have originated as a eucARYotic enzyme, which may eventually be established through comparison of the antigenic and genetic properties of the enzymes.
Abstract: Studies on the mechanism of action of anthrax toxin have led to the discovery that the edema factor component is a calmodulin-dependent adenylate cyclase. This enzyme can be obtained in milligram amounts at high purity from culture supernatants of avirulent B. anthracis strains. The cyclase binds to and probably enters eucaryotic cells to cause large, unregulated increases in cyclic AMP concentrations, an effect that may decrease an animal's ability to limit B. anthracis infection. The similarity of this bacterial adenylate cyclase to calmodulin-dependent eucaryotic adenylate cyclases suggests that EF may have originated as a eucaryotic enzyme. Such a relationship may eventually be established through comparison of the antigenic and genetic properties of the enzymes or by demonstrating that the genes have related DNA sequences. Even if such a relationship is not found, the edema factor cyclase will be a useful model for study of the properties of calmodulin-dependent enzymes.
01 Jan 1984
TL;DR: In studying the effects of PT on opiate receptors, it was found that [3H]enkephalinamide binding was reduced by approximately 90% in membranes prepared from cells incubated with PT compared to control membranes, consistent with the hypothesis that PT-catalyzed ADP-ribosylation impairs the interaction of Gi with the inhibitory receptor-ligand complex.
Abstract: Adenylate cyclase in NG108-15 (neuroblastoma X glioma hybrid) cells is responsive to both stimulatory and inhibitory ligands. Bordetella pertussis toxin (PT) catalyzes the ADP-ribosylation of a 41,000-Da peptide believed to be a subunit of the putative guanyl nucleotide-binding protein (Gi) involved in cyclase inhibition and abolishes inhibitory effects of opiate agonists. In studying the effects of PT on opiate receptors, we found that [3H]enkephalinamide binding was reduced by approximately 90% in membranes prepared from cells incubated with PT compared to control membranes. Agonist affinity, assessed by enkephalinamide competition for [3H]diprenorphine-binding sites, was markedly reduced in cells incubated with PT. Furthermore, inhibition by guanylylimidodiphosphate of ligand binding to opiate receptors was reduced following treatment with PT. The number of opiate receptors assessed by [3H]diprenorphine binding was unaltered by PT. These data are consistent with the hypothesis that PT-catalyzed ADP-ribosylation impairs the interaction of Gi with the inhibitory receptor-ligand complex, effectively uncoupling the inhibitory receptor from Gi and the cyclase catalytic unit.
TL;DR: Caffeine is identified 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.
TL;DR: The synthetic atrial natriuretic factor (ANF) inhibited adenylate cyclase activity in aorta washed particles, mesenteric artery, and renal artery homogenates in a concentration dependent manner with an apparent Ki between 0.1 to 1nM .
TL;DR: It is concluded that the effect of glucose in increasing the concentration of fructose 2,6-bisphosphate in S. cerevisiae is mediated by the successive activation of adenylate cyclase and of cyclic-AMP-dependent protein kinase and by the phosphorylation of 6-phosphofructo-2-kinase by the latter enzyme.
Abstract: When glucose was added to a suspension of Saccharomyces cerevisiae in stationary phase, it caused a transient increase in the concentration of cyclic AMP and a more persistent increase in the concentration of hexose 6-phosphate and of fructose 2,6-bisphosphate. These effects of glucose on cyclic AMP and fructose 2,6-bisphosphate but not that on hexose 6-phosphate were greatly decreased in the presence of 0.15 mM acridine orange or when a temperature-sensitive mutant deficient in adenylate cyclase was used at the restrictive temperature. Incubation of the cells in the presence of dinitrophenol and in the absence of glucose increased the concentration of both cyclic AMP and fructose 2,6-bisphosphate, but with a minimal change in that of hexose 6-phosphate. Glucose induced also in less than 3 min a severalfold increase in the activity of 6-phosphofructo-2-kinase and this effect was counteracted by the presence of acridine orange. When a cell-free extract of yeast in the stationary phase was incubated with ATP-Mg and cyclic AMP, there was a 10-fold activation of 6-phosphofructo-2-kinase. Finally, the latter enzyme was purified 150-fold and its activity could then be increased about 10-fold upon incubation with ATP-Mg and the catalytic subunit of cyclic-AMP-dependent protein kinase. This activation resulted from a 4.3-fold increase in V and a 2-fold decrease in Km. Both forms of the enzyme were inhibited by sn-glycerol 3-phosphate. From these results it is concluded that the effect of glucose in increasing the concentration of fructose 2,6-bisphosphate in S. cerevisiae is mediated by the successive activation of adenylate cyclase and of cyclic-AMP-dependent protein kinase and by the phosphorylation of 6-phosphofructo-2-kinase by the latter enzyme. In deep contrast with what is known of the liver enzyme, yeast 6-phosphofructo-2-kinase is activated by phosphorylation instead of being inactivated.
TL;DR: Results indicate that desensitization of turkey erythrocyte adenylate cyclase is highly correlated with phosphorylation of the beta-adrenergic receptor and that these events are mediated, at least partially, by cAMP.
TL;DR: The reconstituted vesicles suggest that receptors that typically stimulate adenylate cyclase activity may also activate the inhibitory system, perhaps as one mechanism of desensitization.
TL;DR: It is demonstrated that cannabinoid and nantradol compounds decrease cyclic AMP accumulation in neuronally derived cells, and that this results from an inhibition of basal and hormone-stimulated adenylate cyclase activity.
Journal Article•
TL;DR: Forskolin represents a potentially useful class of antiglaucoma agents differing in molecular mechanism of action from previously used drugs.
Abstract: Forskolin is a diterpene derivative of the plant Coleus forskohlii that stimulates adenylate cyclase activity without interacting with cell surface receptors. Forskolin lowers the intraocular pressure of rabbits, monkeys, and humans. In rabbits, net aqueous humor inflow decreases, outflow facility remains unchanged, and ciliary blood flow increases. Tolerance to the intraocular pressure lowering effect did not occur in rabbits after topical doses given every 6 hr for 15 days. In vitro forskolin activates adenylate cyclase of crude particulate homogenates prepared from cultured human ciliary epithelia or from dissected ciliary epithelial processes of rabbit or human eyes. This activation is not blocked by timolol. The stimulation of adenylate cyclase by isoproterenol in vitro is potentiated in the presence of forskolin. Forskolin represents a potentially useful class of antiglaucoma agents differing in molecular mechanism of action from previously used drugs.