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At least 127 records · Page 7Linked to original sources
PubMed1981

Influence of electrically induced tachyarrhythmia on the release of cyclic AMP and PGE in canine coronary sinus blood and on the level of cyclic AMP in myocardial tissue.

In anaesthetized open-chest dogs tachyarrhythmia (TA) was electrically induced by above-threshold stimuli via the right ventricle. During TA a significant increase in the release of PGE and cyclic AMP of 20% and 40% of the control levels, respectively, was observed in the canine coronary sinus blood (CSB), whereas the level of PGF2 alpha remained nearly unchanged under these conditions. The efflux of cyclic AMP corresponded with a concomitant increase in the left ventricular tissue level of this nucleotide by 59% during TA. Pretreatment with the beta-adrenergic blocking agent propranolol (1.0 mg/kg i.v.) prevented the TA induced changes in the level of PGE as well as cyclic AMP in the CSB and in the tissue levels of cyclic AMP. Propranolol alone was without any effect on the efflux of cyclic AMP, but decreased significantly the efflux of PGE by 32%. There was an increase in the activity of phosphorylase a in the myocardial tissue from 10% to 20% of the total (a + b) activity of this enzyme during TA, which could be abolished by propranolol pretreatment. The results suggest possible interrelationships between catecholamines, cyclic AMP and PGE.

Adenosine Triphosphate↗
PubMed1989

Effects of either forskolin, the 1,9-dideoxy derivative of forskolin, or 8-bromocyclic AMP on cyclic AMP and melatonin production in the Syrian hamster pineal gland in organ culture.

The possible involvement of cyclic AMP in the regulation of melatonin production was investigated in cultured Syrian hamster pineal glands. Addition of forskolin, an adenylate cyclase activator, to the incubation medium caused marked increases in both cyclic AMP and melatonin levels in glands collected in the second half of the dark period. 8-Bromocyclic AMP, an analogue of cyclic AMP, also increased melatonin production. The 1,9-dideoxy derivative of forskolin, which is unable to activate the cyclase, was ineffective in stimulating either cyclic AMP levels or melatonin production. These results support a primary role for cyclic AMP in the nocturnal increase of melatonin production in the Syrian hamster pineal gland.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1976

Endogenous cyclic AMP in thyroid cell culture. Effect of thyroid-stimulating hormone and dibutyryl cyclic AMP.

We have studied the variations of endogenous cyclic AMP levels in thyroid cells cultured over a period of 7 days in several conditions: in the presence of thyroid-stimulating hormone or dibutyryl cyclic AMP which both promote the aggregation of isolated cells into follicles, and in their absence when cells develop as a typical monolayer. In follicle-forming cells, the cyclic AMP level was found to rise during the first day of culture, then to fall rapidly. In monolayer-forming cells, the cyclic AMP content slightly increases attaining the same level as found in other cells at the fourth day, which remains stable till the seventh day. We have investigated the response of these cells cultured in the presence of dibutyryl cyclic AMP retain the capability of increasing their cyclic AMP concentration whereas monolayer-forming cells do not preserve this quality of thyroid cells.

Animals↗
PubMed1982

Hyperoxic-induced alterations in lung cell structure and function. Effects on cellular cyclic AMP content and comparison to alterations produced by exogenous cyclic AMP.

Hyperoxic exposure in vitro of two lung-derived cell types (the epithelial-derived L2 cells and WI-38 fibroblasts) inhibits cellular replication, produces striking morphologic changes and may result in cell death; these effects have been observed consistently in other cell types. Hyperoxic exposure of L2 cells is associated with an increase in cellular cyclic AMP content (cellular cyclic AMP content 454 +/- 115 fmol/micrograms DNA in cells exposed to pO2 677 Torr for 96 h compared to 136 +/- 17 fmol/microgram DNA in air-grown cells). Hyperoxic exposure of WI-38 fibroblasts is not associated with increased cyclic AMP content. Although cultivation of L2 cells in the presence of exogenous dibutyryl cyclic AMP does inhibit replication and produce morphologic alterations, similar effects are produced by sodium butyrate alone. Hyperoxic exposure alters cyclic AMP metabolism in some cell types, but the structural and functional alterations observed in L2 cells and WI-38 fibroblasts following hyperoxic exposure are not produced by changes in cellular cyclic AMP content.

Anaerobiosis↗
PubMed2004

Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP, and rolipram.

Phosphodiesterase catalyzes the hydrolysis of the intracellular second messenger 3',5'-cyclic AMP (cAMP) into the corresponding 5'-nucleotide. Phosphodiesterase 4 (PDE4), the major cAMP-specific PDE in inflammatory and immune cells, is an attractive target for the treatment of asthma and COPD. We have determined crystal structures of the catalytic domain of PDE4B complexed with AMP (2.0 A), 8-Br-AMP (2.13 A) and the potent inhibitor rolipram (2.0 A). All the ligands bind in the same hydrophobic pocket and can interact directly with the active site metal ions. The identity of these metal ions was examined using X-ray anomalous difference data. The structure of the AMP complex confirms the location of the catalytic site and allowed us to speculate about the detailed mechanism of catalysis. The high-resolution structures provided the experimental insight into the nucleotide selectivity of phosphodiesterase. 8-Br-AMP binds in the syn conformation to the enzyme and demonstrates an alternative nucleotide-binding mode. Rolipram occupies much of the AMP-binding site and forms two hydrogen bonds with Gln443 similar to the nucleotides.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1999

Effects of a range of beta2 adrenoceptor agonists on changes in intracellular cyclic AMP and on cyclic AMP driven gene expression in cultured human airway smooth muscle cells.

1. The effects of the selective beta2 adrenoceptor agonists salbutamol, terbutaline and salmeterol and the non-selective beta adrenoceptor agonist isoprenaline on [3H]-cyclic AMP formation and cyclic AMP response element (CRE) driven luciferase expression, assessed using the construct p6CRE/luc, were studied in primary cultures of human airway smooth muscle (HASM) cells. 2. Optimal transfection conditions for transient expression of pGL3 Control were 4 microg DNA/well71 in a 6 well plate and 1.8 microl Transfectam/microg DNA. Expression was maximal at 48 - 72 h. 3. Salbutamol (maximum response 19%, EC50 0.6 microM), terbutaline (maximum response 38%, EC50 2.3 microM) and salmeterol (maximum response 18%, EC50 0.0012 microM) were all partial agonists for cyclic AMP formation compared with isoprenaline (EC50 0.08 microM). However, all of the beta2 adrenoceptor agonists produced increases in CRE-driven luciferase activity, in cultured HASM transfected with the vector p6CRE/luc, which were equivalent or greater (salmeterol) than those seen with isoprenaline. 4. Both salbutamol and salmeterol were more potent at increasing luciferase expression than in elevating cyclic AMP levels in these cells. The potency ratios (EC50 (cyclic AMP)/EC50 (LUC)) for the agents studied were isoprenaline: 0. 2 fold, terbutaline: 3 fold, salbutamol: 24 fold, salmeterol: 38 fold. 5. These data suggest that important quantitative differences exist in the ability of beta2 adrenoceptor agonists to increase whole cell cyclic AMP levels in airway smooth muscle and to drive gene expression via a CRE-driven mechanism.

Adrenergic beta-2 Receptor Agonists↗
PubMed1995

The response of the tyrosine hydroxylase gene to cyclic AMP is mediated by two cyclic AMP-response elements.

Tyrosine hydroxylase (TH) gene transcription rate is stimulated by cyclic AMP in cultured rat pheochromocytoma cells. This effect is at least partially due to the interaction of transcription factors with the canonical cyclic AMP-response element (CRE) at position -45 to -38 within the TH gene promoter. In this study we test whether a region of the TH gene promoter, which is adjacent to and upstream of the canonical TH CRE, also participates in the response of the promoter to cyclic AMP. Using electrophoretic mobility shift assays, we demonstrate that nuclear proteins from rat pheochromocytoma cell lines bind to the region of the TH gene from -102 to -73. A comparison of promoter sequences indicates that sequences within this region of the TH gene are highly homologous to proenkephalin promoter sequences (between -110 and -80) designated ENKCRE-1 and ENKCRE-2. We designated the TH gene sequence homologous to ENKCRE-1 as TH E1 and the sequence homologous to ENKCRE-2 as TH E2. Competition displacement binding assays suggest that protein binding to the -102/-73 region of the TH gene is critically dependent on the TH E1 sequence. Transient transfection assays using minimal promoter constructs demonstrate that this region acts as a cyclic AMP-responsive element. Mutagenesis of the TH E1 sequence within the normal context of the TH gene proximal promoter leads to a 50% decrease in the cyclic AMP inducibility of the promoter. These results support the hypothesis that the full response of the TH gene to cyclic AMP requires both the canonical TH CRE and this newly discovered element, which we term TH CRE2.

Adrenal Gland Neoplasms↗
PubMed1980

Regulation of ornithine decarboxylase activity by corticotropin in adrenocortical tumor cell clones: roles of cyclic AMP and cyclic AMP-dependent protein kinase.

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.

Adenylyl Cyclases↗
PubMed2000

Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding.

The AMP-activated protein kinase (AMPK) cascade plays an important role in the regulation of energy homeostasis within the cell. AMPK is a heterotrimer composed of a catalytic subunit (alpha) and two regulatory subunits (beta and gamma). We have isolated and characterized two isoforms of the gamma subunit, termed gamma2 and gamma3. Both gamma2 (569 amino acids) and gamma3 (492 amino acids) have a long N-terminal domain which is not present in the previously characterized isoform, gamma1. As with gamma1, mRNA encoding gamma2 is widely expressed in human tissues, whereas significant expression of gamma3 mRNA was only detected in skeletal muscle. Using isoform-specific antibodies, we determined the AMPK activity associated with the different gamma isoforms in a number of rat tissues. In most tissues examined more than 80% of total AMPK activity was associated with the gamma1 isoform, with the remaining activity being accounted for mainly by the gamma2 isoform. Exceptions to this were testis and, more notably, brain where all three isoforms contributed approximately equally to activity. There was no evidence for any selective association between the alpha1 and alpha2isoforms and the various gamma isoforms. However, the AMP-dependence of the kinase complex is markedly affected by the identity of the gamma isoform present, with gamma2-containing complexes having the greatest AMP-dependence, gamma3 the lowest, and gamma1 having an intermediate effect. Labelling studies, using the reactive AMP analogue 8-azido-[(32)P]AMP, indicate that the gamma subunit may participate directly in the binding of AMP within the complex.

AMP-Activated Protein Kinases↗
PubMed1977

Comparative activation by AMP and cyclic-AMP of rat erythrocyte and reticulocyte glycolysis.

Incubation of raty erythrocytes and reticulocytes in Tris-Ringer's medium with 5 mM cyclic-AMP or AMP increased lactate formation and glucose utilization. The glycolysis-stimulating effect of cyclic-AMP is very similar to that of AMP and, in both cases, it seems to be higher in reticulocytes than in erythrocytes. 0.5 mM norepinephrine produced a much higher lactate formation in reticulocytes than in erythrocytes, suggesting a greater adenylate cyclase activity in younger cells. 300 micrometer cyclic-AMP and AMP reverse inhibition produced by ATP (up to 1.5 micrometer) on phosphofructokinase from rat reticulocyte haemolysates. Both nucleotides are positive allosteric effectors of the enzyme as shown by displacement of F6P-saturation curve to hyperbolic kinetics. Similar results were previously obtained with rat erythrocytes. This deinhibitory effect is suggested to be responsible of the above glycolysis-stimulating effect.

Adenosine Monophosphate↗
PubMed1985

Beta-adrenergic receptor subtypes and subcellular compartmentation of cyclic AMP and cyclic AMP-dependent protein kinase in rabbit cardiomyocytes.

In purified ventricular myocytes from adult rabbit, beta-adrenergic stimulation causes cyclic AMP accumulation and cyclic AMP-protein kinase activation in both particulate and soluble fractions of the cell, whereas prostaglandin E1 elevates cyclic AMP and cyclic AMP-protein kinase activity in the soluble fraction exclusively. Only activation of particulate cyclic AMP-protein kinase activity results in phosphorylase b----a conversion. Using radioligand binding technics, we have determined whether beta 1- and beta 2-receptor subtypes mediate beta-adrenergic effects in particulate and soluble subcellular compartments, respectively. The non-selective antagonist [125I]iodocyanopindolol binds to intact ventricular myocytes with KD of 25 pM and a Bmax of 2.6 X 10(5) receptors/myocyte. Competition for [125I]iodocyanopindolol binding to intact myocytes by the beta-receptor subtype-specific antagonists practolol (beta 1) and zinterol (beta 2) results in monophasic curves with antagonist KD values of 1 microM and 1.5 microM, respectively. We conclude that adult rabbit cardiac myocytes do not possess detectable beta 2 receptors. Further, the ability of isoproterenol to cause elevation of cyclic AMP in two functionally distinct regions within the myocyte must pertain to the actions of a single subtype of beta-receptor, the beta 1-receptor.

Alprostadil↗
PubMed1978

Kinetic studies of adenylyl cyclase of fat cell membranes. II. Comparison of activities measured in the presence of Mn++-AMP-P(NH)P and Mg++-AMP-P(NH)P. Effects of insulin, fluoride, isoproterenol, and GMP-P(NH)P.

The kinetics of fat cell adenylyl cyclase were studied, with AMP-P(NH)P and Mn++ or Mg++ as the divalent cation. In general, the reaction times were not linear. In the presence of fluoride or GMP-P(NH)P, the time curves were concave upwards; in other cases (i.e., basal activity, insulin, or isoproterenol), transient rates tended to decrease with time during the assay. Kinetic data were analyzed according to a previously described procedures (Torres et al., 1978b) which isolates two kinetic components: initial and final. With AMP-P(NH)P, kinetic activities were about ten times lower than those for ATP. With Mn++, activities were at least two-times higher than for Mg++. Spontaneous inactivation of adenylyl cyclase was higher in assays containing Mg++ than in those supplemented with Mn++. In the latter case, insulin was able to increase the inactivation rate. Fluoride and isoproterenol both activated adenylyl cyclase in both the initial and final kinetic components; under most of the conditions explored, their effects on the final component appeared to be more dramatic. Assays with GMP-P(NH)P showed inhibited activity in the initial component and increased activity in the final one. When the results obtained with AMP-P(NH)P are compared with those of ATP (Torres et al., 1978b. J. Membrane Biol. 43:000), the following differences were found: (i) in the presence of insulin and Mn++, cyclase inactivation was higher with AMP-P(NH)P than with ATP; (ii) fluoride stimulation of the final component was more marked with ATP than with AMP-P(NH)P; (iii) cyclase stimulation by isoproterenol was slightly higher with the nucleotide analog; and (iv) GMP-P(NH)P stimulation of the final component resulted in higher activity with ATP than with AMP-P(NH)P.

Adenylyl Cyclases↗
PubMedDate not supplied

[Conformation of nucleotides, oligonucleotides and their analogues in aqueous solution. II. Syn-anti-equilibrium in solutions of adenosine, 5'-AMP, 3'-AMP, 5'-CMP and 3'-CMP].

A method for determining the equilibrium constant of sin-anti-states in the aqueous solution of purine and pyrimidine nucleotides and nucleosides has been proposed. This method is based on the measurement of the spin-lattice relaxation rate of H(1') atom of purine nucleotides before and after exchange of H(8) deuterium in the case of purine nucleotides or H(1') and H(5) atoms of pyrimidine nucleotides. The results obtained were interpreted by the two-state dynamic model. The method applied for investigation of the conformation situation in solutions of Ado, 5'-AMP, 3'-AMP, 5'-CMP and 3'-CMP. 5'-AMP and 5'-CMP were shown to exist predominantly in the anti-state (90%). In the case of 3'-nucleotides the enhancement of the relativity weight of sin-populations to 0.2 and 0.85 for 3'-CMP and 3'-AMP, respectively, was found. In the solution Ado both anti- and sin-state were equiprobable. Experimentally measured relaxation rates of H(8) of adenine or H (6) of cytosine nucleotides were used for determination of the time average orientation of nucleic bases towards the ribose ring in the anti-state. For all compounds investigated with the exception of 3'-AMP the "normal" anti-conformation was confirmed. The 3'-AMP was found to be characterized by high anti-conformation. The probable causes of the conformational situation organization and correlation between the N/S and sin/anti rations are discussed.

Adenosine Monophosphate↗
PubMed1991

19F NMR evidence for interactions between the c-AMP binding sites on the c-AMP receptor protein from E. coli.

The 19F NMR spectra of 3-fluorotyrosine containing c-AMP receptor protein (CRP) from E. coli have been recorded in the presence of increasing amounts of c-AMP. One of the signals (from Tyr B) shifts upfield by 0.6 ppm in the presence of excess c-AMP and shows both slow and fast exchange behaviour during the titration. This is evidence for interactions between the two c-AMP binding sites on the CRP dimer leading to different dissociation rate constants (less than or equal to 75 s-1; greater than or equal to 350 s-1) for complexes containing one and two c-AMP molecules.

Binding Sites↗
PubMed2001

Alteration of second messengers during acute cerebral ischemia - adenylate cyclase, cyclic AMP-dependent protein kinase, and cyclic AMP response element binding protein.

A variety of neurotransmitters and other chemical substances are released into the extracellular space in the brain in response to acute ischemic stress, and the biological actions of these substances are exclusively mediated by receptor-linked second messenger systems. One of the well-known second messenger systems is adenylate cyclase, which catalyzes the generation of cyclic AMP, triggering the activation of cyclic AMP-dependent protein kinase (PKA). PKA controls a number of cellular functions by phosphorylating many substrates, including an important DNA-binding transcription factor, cyclic AMP response element binding protein (CREB). CREB has recently been shown to play an important role in many physiological and pathological conditions, including synaptic plasticity and neuroprotection against various insults, and to constitute a convergence point for many signaling cascades. The autoradiographic method developed in our laboratory enables us to simultaneously quantify alterations of the second messenger system and local cerebral blood flow (lCBF). Adenylate cyclase is diffusely activated in the initial phase of acute ischemia (< or = 30 min), and its activity gradually decreases in the late phase of ischemia (2-6 h). The areas of reduced adenylate cyclase activity strictly coincide with infarct areas, which later become visible. The binding activity of PKA to cyclic AMP, which reflects the functional integrity of the enzyme, is rapidly suppressed during the initial phase of ischemia in the ischemic core, especially in vulnerable regions, such as the CA1 of the hippocampus, and it continues to decline. By contrast, PKA binding activity remains enhanced in the peri-ischemia area. These changes occur in a clearly lCBF-dependent manner. CREB phosphorylation at a serine residue, Ser(133), which suggests the activation of CREB-mediated transcription of genes containing a CRE motif in the nuclei, remains enhanced in the peri-ischemia area, which is spared of infarct damage. On the other hand, CREB phosphorylation at Ser133 rapidly diminishes in the ischemic core before the histological damage becomes manifest. The Ca2+ influx during membrane depolarization contributes to CREB phosphorylation in the initial phase of post-ischemic recirculation, while PKA activation and other signaling elements seem to be responsible in the later phase. These findings suggest that derangement of cyclic AMP-related intracellular signal transduction closely parallels ischemic neuronal damage and that persistent enhancement of this signaling pathway is important for neuronal survival in acute cerebral ischemia.

Acute Disease↗
PubMed1988

Mutations in the cyclic AMP binding site of the cyclic AMP receptor protein of Escherichia coli.

Mutants in the cyclic AMP binding site of the cyclic AMP receptor protein (CRP) of Escherichia coli have been constructed by oligonucleotide-directed mutagenesis. They have been phenotypically characterized and their ability to enhance the expression of catabolite-repressible operons has been tested. In addition, the binding of cyclic nucleotides to the mutants has been investigated. It is shown that the six mutants made fall into one of three classes: (i) those that bind cyclic AMP better than the wild type protein (Ser-62----Ala) and result in greater transcription enhancement; (ii) those that bind cyclic AMP similarly to wild type (Ser-83----Ala, Ser-83----Lys, Thr-127----Ala, Ser-129----Ala); and (iii) those that do not bind cyclic AMP at all (Arg-82----Leu). Implications of these findings with respect to present models of the cyclic nucleotide binding pocket of CRP are discussed.

Amino Acids↗
PubMed1996

Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase.

We have developed a sensitive assay for the AMP-activated protein kinase kinase, the upstream component in the AMP-activated protein kinase cascade. Phosphorylation and activation of the downstream kinase by the upstream kinase absolutely requires AMP and is antagonized by high (millimolar) concentrations of ATP. We have purified the upstream kinase >1000-fold from rat liver; a variety of evidence indicates that the catalytic subunit may be a polypeptide of 58 kDa. The physical properties of the downstream and upstream kinases, e.g. catalytic subunit masses (63 versus 58 kDa) and native molecular masses (190 versus 195 kDa), are very similar. However, unlike the downstream kinase, the upstream kinase is not inactivated by protein phosphatases. The upstream kinase phosphorylates the downstream kinase at a single major site on the alpha subunit, i.e. threonine 172, which lies in the "activation segment" between the DFG and APE motifs. This site aligns with activating phosphorylation sites on many other protein kinases, including Thr177 on calmodulin-dependent protein kinase I. As well as suggesting a mechanism of activation of AMP-activated protein kinase, this finding is consistent with our recent report that the AMP-activated protein kinase kinase can slowly phosphorylate and activate calmodulin-dependent protein kinase I, at least in vitro (Hawley, S. A., Selbert, M. A., Goldstein, E. G., Edelman, A. M., Carling, D., and Hardie, D. G. (1995) J. Biol. Chem. 270, 27186-27191).

AMP-Activated Protein Kinase Kinases↗
PubMed1978

The dependence of Escherichia coli asparaginase II formation on cyclic AMP and cyclic AMP receptor protein.

The amount of asparaginase II in an Escherichia coli wild-type strain (cya+, crp+) markedly increased upon a shift from aerobic to anaerobic growth. However, no such increase occurred in a mutant (cya) lacking cyclic AMP synthesis unless supplemented with exogenous cyclic AMP. Since a mutant (crp) deficient in cyclic AMP receptor protein also did not support the anaerobic formation of this enzyme, it is concluded that the formation of E. coli asparaginase II depends on both cyclic AMP and cyclic AMP receptor protein.

Aerobiosis↗