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 subcellular distribution of the endogenous phosphodiesterase activator and its release from membranes by a cyclic AMP-dependent ATP:protein phosphotransferase was studied in fractions and subfractions of rat brain homogenate. These fractions were obtained by differential centrifugation and sucrose density gradient; their identity was ascertained by electron microscopy and specific enzyme markers. In the subcellular particulate fractions, the concentration of activator is highest in the microsomal fraction, followed by the mitochondrial and nuclear fractions. Gradient centrifugation of the main mitochondrial subfraction revealed that activator was concentrated in those fractions containing mainly synaptic membranes. Activator was releasted from membranes by a cyclic AMP-dependent phosphorylation of membrane protein. The release of activator occurred mainly from the mitochondrial subfractions containing synaptic membranes and synaptic vesicles. The data support the view that a release of activator from membranes may be important in normalizing the elevated concentration of cyclic AMP following persistent transsynaptic activation of adenylate cyclase.
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PMID:Release of the phosphodiesterase activator by cyclic AMP-dependent ATP:protein phosphotransferase from subcellular fractions of rat brain. 19 Oct 91

In a previous paper, a model was presented showing how the group of Ca2+/calmodulin-dependent protein kinase II molecules contained within a postsynaptic density could stably store a graded synaptic weight. This paper completes the model by showing how bidirectional control of synaptic weight could be achieved. It is proposed that the quantitative level of the activity-dependent rise in postsynaptic Ca2+ determines whether the synaptic weight will increase or decrease. It is further proposed that reduction of synaptic weight is governed by protein phosphatase 1, an enzyme indirectly controlled by Ca2+ through reactions involving phosphatase inhibitor 1, cAMP-dependent protein kinase, calcineurin, and adenylate cyclase. Modeling of this biochemical system shows that it can function as an analog computer that can store a synaptic weight and modify it in accord with the Hebb and anti-Hebb learning rules.
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PMID:A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. 255 18

1.) Application of serotonin to Aplysia sensory neurons can result in facilitated synaptic transmission, both short- and long-term. This facilitation is likely to be produced by a complex set of molecular mechanisms: serotonin activates adenylate cyclase, increasing cAMP and protein kinase (Cedar and Schwartz, 1972); serotonin also changes the subcellular distribution of the Ca2+/calmodulin-dependent protein kinase (Saitoh and Schwartz, 1983). Recently, phorbol esters also have been shown to produce facilitation. We have therefore investigated how protein kinase C (PKC) participates in serotonin-mediated synaptic facilitation. 2.) We found that the Aplysia genome encodes PKC, which is expressed in nervous tissue as at least two abundant transcripts (about 0.003% of the total message). Its inferred amino acid sequence is 85% homologous to that of enzymes from mammals and Drosophila, and over 95% homologous if compared to both. The specific activity of the Aplysia kinase is comparable to that found in rat brain, with similar reaction parameters and dependencies on phosphatidylserine (PS), Ca2+, diacylglycerol and phorbol esters. While PKC is found on neuronal membrane in the basal state, the PKC activators, Ca2+ and phorbol esters, further translocate the kinase to membrane in crude extracts of neuronal tissue. The amounts of membrane-bound PKC, as determined by 3H-phorbol-ester binding, are greatest in neuropil and nerve. 3.) Exposure of sensory neurons and their terminals in Aplysia pleural-pedal ganglia to facilitating doses of either phorbol ester or serotonin results in the translocation of PKC from cytosol to membrane, activating the enzyme. cAMP does not produce this translocation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of protein kinase C by serotonin: biochemical evidence that it participates in the mechanisms underlying facilitation in Aplysia. 327 94

The guinea pig adrenal cortex is composed of two chromatically distinct concentric zones. The steroidogenic response to ACTH by the two zones is likewise distinct: ACTH stimulates cholesterol side-chain cleavage activity in the outermost zone, but fails to do so in the inner zone. This despite the fact that adenylate cyclase activation by ACTH and cAMP formation are similar for the two zones. To further examine this model, protein kinase activity and protein phosphorylation have been examined. It was found that the cAMP-dependent, Ca2+/phospholipid-dependent, and Ca2+/calmodulin-dependent protein kinase activities were significantly higher in the outer zone than in the inner zone by 70, 60 and 800%, respectively. Although the physiological meaning of a zonal difference in protein kinase activity is not as yet clear, the marked difference in Ca2+/calmodulin-dependent protein kinase activity between the inner and outer zones correlates well with the marked difference in steroidogenesis that exists between the two zones. Of the Ca2+/calmodulin-dependent protein kinases known to exist, there is preliminary evidence to suggest the presence of kinase III in the guinea pig adrenal cortex. Protein phosphorylation induced by the three kinase systems in the two adrenocortical zones revealed notable differences in phosphoprotein patterns. In addition, it was found that exogenous calmodulin was phosphorylated and that the kinase responsible for this was more active in the inner zone.
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PMID:Calcium-dependent protein kinase activity and protein phosphorylation in zones of the adrenal cortex. 337 30

In Y1 adrenocortical tumor cells, corticotropin (ACTH), cyclic AMP, and 8-bromoadenosine 3',5'-monophosphate (8BrcAMP) stimulated ornithine decarboxylase activity (L-ornithine carboxy-lyase, EC 4.1.1.17) and steroidogenesis. The concentrations required for half-maximal activation of ornithine decarboxylase were 60 pM for ACTH and 1 mM for 8BrcAMP; the concentrations required for half-maximal activation of steroidogenesis were 50 pM for ACTH and 0.2 mM for 8BrcAMP. Ornithine decarboxylase activity increased 1.5 hr after the addition of these agents, reached a maximum between 4 and 6 hr, and then declined. Mutant clones with impaired ACTH-responsive adenylate cyclase systems [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1]did not respond to ACTH with increased ornithine decarboxylase activity, but they responded normally to added cyclic AMP. These results indicate that adenylate cyclase and cyclic AMP are necessary for the stimulation of ornithine decarboxylase activity by ACTH. In a series of Y1(Kin) mutants with altered cyclic AMP-dependent protein kinase activities (ATP:protein phosphotransferase, EC 2.7.1.37), the effects of ACTH on ornithine decarboxylase also were attenuated. These findings suggest that cyclic AMP-dependent protein kinase also plays a necessary role in the stimulation of ornithine decarboxylase activity by ACTH. The effects of ACTH on ornithine decarboxylase in the Kin mutants, however, were quantitatively different from the effects on steroidogenesis and did not closely reflect the degree of defect in cyclic AMP-dependent protein kinase activity. These differences suggest that the pathways of ACTH action leading to stimulation of steroidogenesis and ornithine decarboxylase activity diverge subsequent to activation of the protein kinase.
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PMID:Regulation of ornithine decarboxylase activity by corticotropin in adrenocortical tumor cell clones: roles of cyclic AMP and cyclic AMP-dependent protein kinase. 624 65

N alpha-Toysl-L-lysine chloromethyl ketone (Tos-LysCH2Cl) was found to inhibit irreversibly the onset of the hormone-induced refractory state in intact thymocytes. When thymocytes (approximately 2 X 10(7) cells per ml) are treated with Tos-LysCH2Cl(10(-4) M, for 90 min at pH 7 and 37 degrees C) the cells retain their viability, including a full capacity to recognize and respond to hormonal stimuli, yet they selectively lose their ability to become desensitized to persistent triggering by a hormone, as reflected in the state of activation of intracellular cyclic AMP-dependent protein kinase (ATP:protein phosphotransferase, EC 2.7.1.37). Whereas upon hormonal stimulation of untreated cells the immediate rise in the state of activation of this enzyme (up to an activity ratio of > 0.85) is followed by an exponential decline to basal values within approximately 60 min, in TosLysCH2Cl-treated cells the hormone-triggered elevation in the state of activation of the enzyme is maintained for > 60 min. Evidence is presented to suggest that in thymocytes TosLysCH2Cl inhibits the regulatory process that normally uncouples the adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] system without interfering with previous or subsequent molecular events connected with the transfer of hormonal signals across the cell membrane. This technique allows, therefore, the preparation of viable thymocytes with a limited and distinct regulatory defect introduced by chemical (covalent) means. As such, it is most useful for studies aimed at the elucidation of the mechanism of cell desensitization and for further characterization and localization of key components responsible for cellular refractoriness.
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PMID:Inhibiting the onset of hormone-induced desentiziation of viable thymocytes by N alpha-tosyl-L-lysine chloromethyl ketone. 625 72

When cellular stimulants such as neurotransmitters, hormones, autacoids, cytokines and growth factors stimulate their respective specific receptors in the plasma membranes of cells, a variety of responses are elicited. GTP-binding proteins are also involved in the reactions between receptors and cellular effectors. Stimulation of receptors are subsequently coupled to the activation of ion channels, turnover of inositol phospholipid metabolism, adenylate cyclase and guanylate cyclase, inhibition of adenylate cyclase and potentiation of all proliferation. Active substances such as the so-called second messengers are produced in the cells. In this article, two findings are described: 1) Ca2+, which increases by stimulation of receptors with neurotransmitters and hormones, stimulated Ca2+/calmodulin-dependent protein kinase II in cell systems such as NG108-15 neuroblastoma x glioma hybrid cells and primarily cultured neuronal cells of rat hippocampus. 2) Coupling preferences and possible transduction mechanisms from experiments on NG108-15 cells and NL308 neuroblastoma x fibroblast hybrid cells which have been stably transfected with DNA for m1, m2, m3 and m4 muscarinic acetylcholine receptors were examined. These results may provide a useful research model for examining and evaluating the effects and mechanisms of the drugs on a living system and may help develop useful methodology for the discovery of innovative drugs.
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PMID:[Cellular reactions after stimulation of receptors: research model for evaluation of effects and action mechanisms of drugs for discovery of innovative drugs]. 769 94

The phosphorylation of one receptor that occurs as a result of the stimulation of a different receptor on a cell is a common mechanism for heterologous regulation or "cross-talk," which has been implicated in desensitization. In this work, we focus on the mechanisms of phosphorylation of the rat pancreatic acinar cell cholecystokinin (CCK) receptor that occur upon stimulation of this cell by various agonists. Phosphorylation was allowed to occur in dispersed intact acinar cells in response to the experimental manipulation, and the phosphoreceptor was subsequently purified and quantified as an indication of response. Agonists such as vasoactive intestinal polypeptide and secretin, which act via activation of adenylate cyclase, had no effect on CCK receptor phosphorylation, whereas carbamylcholine and bombesin stimulated increased phosphorylation of the CCK receptor. Because these agents would be expected to activate protein kinase C (PKC) as well as a number of calcium-sensitive kinases and phosphatases, these activities were further dissociated by using more direct activators and inhibitors acting intracellularly. Manipulation of calcium independent of PKC by using a calcium ionophore, inhibition of calcium/calmodulin-dependent kinase II, and inhibition of calcium-dependent protein phosphatase type 2B had no effect on the state of CCK receptor phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of heterologous agonist-stimulated phosphorylation of cholecystokinin receptor. 817 63

Roles of Ca/calmodulin-dependent protein kinase II (Ca/CaM kinase II) and myosin light chain kinase (MLCK) in insulin release from rat pancreatic islets were investigated. Western blotting using polyclonal antibody to Ca/CaM kinase II suggested the presence of this kinase in the pancreatic islets. Extracts of pancreatic islets phosphorylated exogenous myosin light chain, which was inhibited by ML-9, an inhibitor of MLCK. KN-62 and KN-93, inhibitors of Ca/CaM kinase II, and ML-9 at microM concentrations inhibited insulin release stimulated by glucose or high K+. KN-62 and KN-93, but not ML-9, inhibited insulin release increased by glucose and forskolin, an activator of adenylate cyclase. These inhibitors had no effect on insulin release evoked by 12-O-tetradecanoyl phorbol-13-acetate, an activator of Ca(2+)-sensitive, diacylglycerol-dependent protein kinase. These results suggest that Ca/CaM kinase II and MLCK may participate in the control of insulin release.
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PMID:Presence and possible involvement of Ca/calmodulin-dependent protein kinases in insulin release from the rat pancreatic beta cell. 838 89

Treatment of cultured carrot (Daucus carota L.) cells with activators of adenylate cyclase, forskolin, and cholera toxin induced the biosynthesis of an antifungal isocoumarin, 6-methoxymellein, in the cells. Addition of dibutyryl cyclic AMP to carrot cell culture also stimulated the accumulation of the compound. The cyclic AMP-evoked 6-methoxymellein production was significantly depressed in the presence of certain inhibitors of calcium cascade such as Ca2+ channel blockers and inhibitors of calmodulin-dependent processes. In dibutyryl cyclic AMP- and forskolin-treated carrot cells, increase in cytosolic Ca2+ concentration was observed as monitored by the fluorescent calcium indicator fluo-3. Cyclic AMP-dependent Ca2+ influx into carrot cells was also confirmed with Ca(2+)-loaded vesicles prepared from the plasma membrane-rich fraction of the cells. Transient increase in Ca(2+)- and Ca2+/calmodulin-dependent protein kinase activity but not cyclic AMP-dependent protein phosphorylation was detected in the cells of high cyclic AMP concentration. Results obtained in the present work suggest that the increase in cyclic AMP content in carrot cells induces Ca2+ influx across plasma membrane without activating cyclic AMP-dependent protein kinase which, then, stimulates calcium cascade in the cells.
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PMID:Stimulation of calcium influx and calcium cascade by cyclic AMP in cultured carrot cells. 838 97


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