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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The peripheral cycle AMP phosphodiesterase from rat liver plasma membranes binds with high affinity (2.4 nM) to a single class of receptor sites on the liver plasma membrane. These receptor sites appear to be proteins, as they are trypsin- and heat-labile. The sensitivity of these sites to denaturation by trypsin and heat is a first-order process. The presence of Ca2+ (5 mM) increases the affinity of these sites for the enzyme, but does not alter their total number. The receptor sites and the cyclic AMP phosphodiesterase occur in similar numbers, at around 2 pmol/mg of plasma-membrane protein. It is proposed that the peripheral, liver plasma-membrane cyclic AMP phosphodiesterase is attached to a specific site on the insulin receptor and that the binding of insulin to the receptor site triggers a conformational change in the enzyme such that the enzyme can be phosphorylated and activated by an endogenous cyclic AMP-dependent protein kinase.
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PMID:The insulin-stimulated cyclic AMP phosphodiesterase binds to a single class of protein sites on the liver plasma membrane. 627 57

Forskolin increased cyclic AMP accumulation in isolated adipocytes and markedly potentiated the elevation of cyclic AMP due to isoproterenol. In adipocyte membranes, forskolin stimulated adenylate cyclase activity at concentrations of 0.1 microM or greater. Forskolin did not affect the EC50 for activation of adenylate cyclase but did increase the maximal effect of isoproterenol. Neither the soluble nor particulate low-Km cyclic AMP phosphodiesterase activity was affected by forskolin. Low concentrations of forskolin (0.1-1.0 microM), which significantly elevated cyclic AMP levels, did not increase lipolysis, whereas similar increases in cyclic AMP levels due to isoproterenol elevated lipolysis. Forskolin did not inhibit the activation of triacylglycerol lipase by cyclic AMP-dependent protein kinase or the subsequent hydrolysis of triacylglycerol. Higher concentrations of forskolin (10-100 microM) did increase lipolysis. Both the increased cyclic AMP production and lipolysis due to forskolin were inhibited by the antilipolytic agents insulin and N6-(phenylisopropyl)adenosine. Hypothyroidism reduced the ability of forskolin to stimulate cyclic AMP production and lipolysis. These results indicate that forskolin increases cyclic AMP production in adipocytes through an activation of adenylate cyclase. Lipolysis is activated by forskolin but at higher concentrations of total cyclic AMP than for catecholamines.
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PMID:Forskolin as an activator of cyclic AMP accumulation and lipolysis in rat adipocytes. 628 66

Egg albumin decreased the cyclic AMP content and the protein kinase ratio of sensitized guinea-pig tracheal smooth muscle. The effect preceded the contraction of the tracheal preparation. Antigen challenge increased cyclic AMP phosphodiesterase activity without changing the Km value. In tracheal preparations of desensitized guinea-pigs, the mechanical and metabolic effects of egg albumin were markedly reduced. These results suggest that the effects on the cyclic AMP system in response to immunological challenge might represent an important mechanism modulating the contractile response of guinea-pig tracheal smooth muscle.
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PMID:The cyclic AMP system in sensitized and desensitized guinea-pig tracheal smooth muscle. 629 Feb 41

To elucidate the intracellular mechanism of the bursting activity which is characteristic of seizure discharge, the behavior of the intracellular cyclic nucleotide and the intracellular calcium during pentylenetetrazole (PTZ)-induced bursting activity in snail neurons was investigated. Cyclic AMP was increased about 3-fold by the incubation of ganglia with PTZ. The effect of PTZ on phosphodiesterase activity measured using either cyclic AMP or cyclic GMP as substrate showed a slight increase in cyclic AMP phosphodiesterase activity. The release of calcium from the lysosome fraction was increased by the incubation of ganglia with dibutyryl cyclic AMP. Protein kinase activity was stimulated by the incubation of ganglia with PTZ. Adenylate cyclase activity was stimulated by the incubation of ganglia with PTZ. These findings suggest that PTZ-induced bursting activity in snail neurons is initiated by an intracellular increase of cyclic AMP, which promotes calcium release from lysosomes and induces protein kinase activation.
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PMID:Behavior of intracellular cyclic nucleotide and calcium in pentylenetetrazole-induced bursting activity in snail neurons. 630 20

Although receptor-specific refractoriness has been suggested to be one of the regulatory mechanisms of epidermal adenylate cyclase systems, its physiologic significance has been a subject of controversy because of the requirement of unusually high concentrations of agonists to induce refractoriness. In order to determine whether the epidermal adenylate cyclase system is regulated through a refractoriness mechanism by suboptimal concentrations of receptor agonists, this study was undertaken using pig skin epidermal adenylate cyclase systems. Pretreatment of pig skin with 0.1-1 microM epinephrine in vitro resulted in the reduction of the maximal epinephrine response (epinephrine-induced cyclic AMP accumulations) to various degrees without alterations in either low or high Km cyclic AMP phosphodiesterase activities. Repeated pretreatments were shown to be more effective in inducing refractoriness than a single pretreatment. Apparently there was no change in the Km value for epinephrine, suggesting that the decrease in epinephrine response represents a reduction in the number but not in the affinity of functional beta-adrenergic adenylate cyclase receptor sites. This refractoriness by low concentrations of catecholamine pretreatment was specific to the beta-adrenergic system, since there was no reduction in histamine response after the epinephrine pretreatment. These results indicate that the epidermal beta-adrenergic adenylate cyclase system is regulated by much lower concentrations of catecholamine than were previously described. It was suggested that physiologic fluctuations of plasma catecholamine levels might have a profound effect on epidermal beta-adrenergic adenylate cyclase responsiveness, resulting in the alteration of the minimal catecholamine level required for the successive activation of cyclic AMP-dependent protein kinase, which is the predominant target of cyclic AMP in epidermis.
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PMID:Regulation of beta-adrenergic adenylate cyclase responsiveness of pig skin epidermis by suboptimal concentrations of epinephrine. 631 30

Changes in the cellular content of cyclic AMP and in the activities of adenylyl cyclase, cyclic AMP phosphodiesterase and cyclic AMP-dependent protein kinases during differentiation of rabbit bone marrow erythroid cells were investigated. The cells were separated by velocity sedimentation at unit gravity into six fractions corresponding to different stages of development: proerythroblasts, basophilic erythroblasts, polychromatic cells, early orthochromatic and late orthochromatic cells and reticulocytes. Adenylyl cyclase activity was found to decrease continuously as the cells developed, from approx. 180 pmoles cyclic AMP formed/mg of protein/20 min in proerythroblasts to 10 pmoles in circulating reticulocytes. The proerythroblasts were the richest cells in cyclic AMP which is present at a cellular concentration of approx. 1.4 microM. In basophilic cells the cyclic AMP content was about 80% lower than in proerythroblasts. No further changes in cyclic AMP levels were observed after the final cell division. Cyclic AMP phosphodiesterase was found to be very active in the most immature cells, the proerythroblasts. After differentiation into basophilic erythroblasts, a 4-fold decrease in cyclic AMP phosphodiesterase activity occurred. In polychromatic cells there was a further drop in phosphodiesterase activity and after the last cell division the enzyme activity was constant and very low. Both cytosolic cyclic AMP-binding capacity and cytosolic cyclic AMP-dependent protein kinase activity decreased in dividing rabbit bone marrow erythroblasts when calculated in terms of cell number but remained constant per cell volume. After the final cell division, cyclic AMP-dependent protein kinase activity did not change further, whereas cyclic AMP-binding capacity declined. There were no qualitative but only quantitative changes in the cyclic AMP-binding proteins that are present in the cytosol of developing erythroblasts. In the immature cells, the apparent Kd for the interaction of binding proteins with cyclic AMP was 4 . 10(-8) M. The data suggest that changes in cyclic AMP-binding activity during differentiation of erythroid cells are due both to changes in the amount of binding proteins and their affinity for cyclic AMP. The phosphorylation of rabbit erythroblast plasma membrane proteins by membrane-associated protein kinase(s) was found to be cyclic AMP-dependent in dividing cells during the early stages of differentiation. When the erythroid cells reach the non-dividing stage in their development, autophosphorylation of membrane ghosts was no longer stimulated by cyclic AMP.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Characteristics of the adenylyl cyclase system of differentiating rabbit bone marrow erythroblasts. 632 45

The effect of lactation on the regulation of lipolysis by beta- and alpha 2-adrenergic agents and by adenosine has been investigated. When changes in adipocyte mean cell volume (which decreases with lactation) are allowed for, lactation increased the maximum response both to beta-adrenergic agents and to the adenosine analogue N6-phenylisopropyladenosine, but had no apparent effect on the responsiveness of the alpha 2-adrenergic system in both subcutaneous and omental adipocytes. For subcutaneous adipocytes, there was no significant change in the number of beta-adrenergic or alpha 2-adrenergic receptors, but the amount of Gs and the maximum (forskolin-stimulated) adenylate cyclase activity were increased by lactation. In contrast, in omental adipocytes, the number of beta- (but not alpha 2-) adrenergic receptors and the amount of Gs were increased, whereas forskolin-stimulated adenylate cyclase activity was unchanged by lactation. In both types of adipocyte, cyclic AMP phosphodiesterase and total protein kinase A activities were unchanged. Lactation had no effect on the number of adenosine receptors but increased the amounts of the Gi isoforms expressed in both types of adipocyte. These various adaptations differ markedly in a number of respects from those described previously in the rat. Lactation, then, while having a similar overall effect on the response to beta-adrenergic agonists of adipocytes, achieves this by depot-specific mechanisms. In contrast, changes in response to adenosine appear to involve the same mechanism in the two depots investigated.
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PMID:Effects of lactation on the signal transduction systems regulating lipolysis in sheep subcutaneous and omental adipose tissue. 775 76

In Schizosaccharomyces pombe, meiosis is initiated by conditions of nutrient deprivation. Mutations in genes encoding elements of the cyclic AMP-dependent protein kinase (cAPK) pathway interfere with meiosis. Loss-of-function alleles of genes that stimulate the activity of cAPK allow cells to bypass the normal requirement of starvation for conjugation and meiosis. Alternatively, loss-of-function alleles of genes that inhibit cAPK lead to the inability to undergo sexual differentiation. The cgs1+ gene encodes the regulatory subunit of cAPK, and the cgs2+ gene encodes a cyclic AMP phosphodiesterase. Thus, both genes encode proteins which negatively regulate the activity of cAPK. Loss of either cgs1 or cgs2 prevents haploid cells from conjugating and diploid cells from undergoing meiosis. In addition to these defects, cells are unable to enter stationary phase. We describe a novel gene, sak1+, which when present on a plasmid overcomes the aberrant phenotypes associated with unregulated cAPK activity. Genetic analysis of sak1+ (suppressor of A-kinase) reveals that it functions downstream of cyclic AMP-dependent protein kinase to allow cells to exist the mitotic cycle and enter either stationary phase or the pathway leading to sexual differentiation. The sak1+ gene is essential for cell viability, and a null allele causes multiple defects in cell morphology and nuclear division. Thus, sak1+ is an important regulatory element in the life cycle of S. pombe. Sequence analysis shows that the predicted product of the sak1+ gene is an 87-kDa protein which shares homology to the RFX family of DNA-binding proteins identified in humans and mice. One member of this family, RFX1, is a transcription factor for a variety of viral and cellular genes.
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PMID:The sak1+ gene of Schizosaccharomyces pombe encodes an RFX family DNA-binding protein that positively regulates cyclic AMP-dependent protein kinase-mediated exit from the mitotic cell cycle. 786 41

1. The possible role of cyclic AMP phosphodiesterase (PDE) in the inhibitory actions of ibudilast on tracheal smooth muscle contractility and eosinophil thromboxane generation was investigated. 2. Ibudilast was a non-selective inhibitor of partially purified cyclic nucleotide PDE isoenzymes from pig aorta and bovine tracheal smooth muscle, exhibiting only moderate potency against bovine tracheal PDE IV (IC50 = 12 +/- 4 microM, n = 3). Similar or slightly lower potencies were displayed against PDEs I, II, III and V. In contrast, rolipram exhibited selectivity for PDE IV (3 +/- 0.5 microM, n = 3). 3. Ibudilast (IC50 = 0.87 +/- 0.37 microM, n = 3), like rolipram (IC50 = 0.20 +/- 0.04 microM, n = 3), was a more potent inhibitor of membrane-bound PDE IV from guinea-pig eosinophils than of partially purified PDE IV from bovine tracheal smooth muscle. The potency of ibudilast increased when the eosinophil enzyme was solubilised with deoxycholate and NaCl (IC50 = 0.11 +/- 0.05 microM, n = 3) or exposed to vanadate/glutathione complex (V/GSH) (IC50 = 0.11 +/- 0.02 microM, n = 3). The potency of rolipram was also increased by solubilization (IC50 = 0.012 +/- 0.003, n = 3) or V/GSH (IC50 = 0.012 +/- 0.003, n = 3). 4. In intact eosinophils, ibudilast (0.032 microM-20 microM) potentiated isoprenaline-induced cyclic AMP accumulation in a concentration-dependent manner, being approximately 20 fold less potent than rolipram. Little or no effect on basal cyclic AMP levels was observed with either compound. The cyclicAMP-dependent protein kinase activity ratio was significantly increased following incubation of eosinophils with either ibudilast (20 MicroM) or rolipram (20 MicroM) in the absence or presence of isoprenaline.5. Leukotriene B4 (300 nM)-induced thromboxane generation from guinea-pig eosinophils was inhibited by ibudilast (IC50 = 11.3 +/- 3.7 MicroM, n = 5) and rolipram (IC50 = 0.280 +/- 0.067 MicroM, n = 5) in a concentration-dependent manner.6. Ibudilast (10 nM-1 MicroM), whilst generally less potent than rolipram (1 nM- 1 MicroM), produced concentration-dependent relaxation of spasmogen (methacholine, histamine, LTD4)-induced tone in the guinea pig isolated tracheal strip. Ibudilast was less potent in reversing the methacholine (IC50 = 1.95 +/- 0.40 JM,n =6)-induced contraction than those of histamine (IC50 = 0.18 +/- 0.70 MicroM, n =6) or leukotriene D4(LTD4, IC50 = 0.12 +/- 0.05 MicroM, n = 6). Rolipram also exhibited a similar pattern of activity, although the difference in potency against methacholine (IC50 = 0.1 +/- 0.01 MicroM, n = 6) compared with the other two spasmogens, histamine (IC50 = 0.034 +/- 0.017 MicroM, n = 7) and LTD4 (IC50 = 0.026 +/- 0.008 MicroM, n = 7), was not as great.7. These results demonstrate that ibudilast, like rolipram, has several biological actions on the eosinophil and airways smooth muscle which may be attributed to inhibition of cyclic AMP PDE. These actions may account, at least in part, for the recently reported anti-asthma effects of ibudilast.
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PMID:Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone. 803 94

The mechanisms responsible for the diminished lipolytic response of adipocytes to catecholamines after litter removal from lactating rats and their modulation by growth hormone have been investigated. Lactation, litter removal and growth-hormone treatment did not alter the ability of noradrenaline to activate protein kinase A (A-kinase), showing that the defect in signal transduction in rats after litter removal is after A-kinase. Litter removal had no effect on hormone-sensitive lipase activity itself, but the proportion of the lipase associated with the fat droplet was decreased; growth-hormone treatment increased hormone-sensitive lipase activity and the proportion associated with the fat droplet. In addition, a number of other adaptations in the beta-adrenergic signal-transduction system occur during the lactation cycle and in response to growth hormone treatment, including changes in receptor number, adenylate cyclase activity and cyclic AMP phosphodiesterase activity, but a defect in the ability of hormone-sensitive lipase to associate with the lipid droplet appears to be the major reason for the diminished response to catecholamines on litter removal.
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PMID:Mechanisms involved in the adaptations of the adipocyte adrenergic signal-transduction system and their modulation by growth hormone during the lactation cycle in the rat. 838 54


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