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:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To study the mechanism of action of sulfonylurea agents on peripheral tissues without the potentially confounding influences of insulin, the direct effect of glyburide (i.e., in the absence of insulin) was evaluated in the L6 cultured myogenic cell line. Glyburide approximately doubled the incorporation of [14C]-glucose into glycogen. The rate-determining enzymes of glycogen metabolism, glycogen synthase and glycogen phosphorylase, were unaffected by the drug. Glucose transport (2-deoxyglucose uptake) was also approximately doubled. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) also doubled glucose transport and showed the same lag period (4-6 h) as glyburide before an effect occurred. Blockade of protein kinase C activity by either 1-(5-isoquinolinesulfonyl)-2 methyl piperazine (H7) or chronic exposure to TPA completely abolished the stimulation by glyburide. Cycloheximide, a protein synthesis inhibitor, also completely eliminated the effect of glyburide. The presence of ATP-sensitive K+ channels was assessed by measuring 86Rb efflux in ATP-depleted L6 muscle cells and RINm5F cells (which served as a positive control). Such channels were present and responded appropriately to glyburide and diazoxide in pancreatic beta-cells but were not present in muscle cells. Glyburide stimulation of glucose transport was completely eliminated by both Quin 2, an intracellular chelator of Ca2+, and verapamil, a Ca2+ channel blocker. However, glyburide did not raise intracellular Ca2+ levels. We conclude that glyburide stimulates glucose transport in cultured L6 muscle cells by a protein kinase C-mediated pathway that requires new protein synthesis. Although intracellular Ca2+ metabolism may also be involved, the initial step in the mechanism of action is probably different between pancreatic beta-cells and muscle cells.
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PMID:Glyburide-stimulated glucose transport in cultured muscle cells via protein kinase C-mediated pathway requiring new protein synthesis. 193 11

Oleate, linoleate, linolenate, arachidonate and eicosapentaenoate, but not myristate, palmitate and stearate, stimulated glycogen phosphorylase activity by 2-8-fold when added to cultured rat hepatocytes. Addition of BSA or Ca2- to the incubation medium decreased the stimulating effects of the unsaturated fatty acids. The combination of oleate or linolenate, with corticosterone, testosterone or estradiol produced synergistic stimulations of phosphorylase activity. The stimulation of glycogen phosphorylase activity by linolenate was inhibited by staurosporine or sphingosine. Staurosporine (80 nM) alone also decreased basal phosphorylase activities by about 60%. The results show that unsaturated fatty acids can be used as model agonists to stimulate phosphorylase activity by a mechanism that probably involves protein kinase C. On the basis of the fatty acid: BSA ratios used, this stimulation should only occur in vivo at high fatty acid concentrations when accompanied by hypoalbuminaemia.
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PMID:Unsaturated fatty acids activate glycogen phosphorylase in cultured rat hepatocytes. 203 70

The ability of Ca2(+)-mobilizing hormones to promote changes in the subcellular distribution of protein kinase C (PKC) was studied in isolated hepatocytes. In recently isolated cells the distribution of PKC between the soluble and particulate fractions was 47 and 53% respectively. Exposure of the hepatocytes to 100 nM-vasopressin produced an increased phosphoinositide turnover, as reflected by the changes in the concentrations of inositol trisphosphate and Ca2+, and in glycogen phosphorylase a activity. However, the distribution of both PKC activity and [3H]phorbol dibutyrate binding between the cytosol and the membranes remained unchanged under these conditions. To determine the threshold values of the concentrations of Ca2+ and diacylglycerol required to produce a redistribution of PKC, the hepatocytes were treated with the Ca2+ ionophore ionomycin, and with permeant diacylglycerol derivatives. Hepatocytes incubated in the presence of 100 nM-vasopressin required concentrations of Ca2+ 2.5 times those produced physiologically by the hormone to produce translocation of PKC from the cytosol to the membranes. These studies suggest that, at least in hepatocytes, activation of PKC in response to Ca2(+)-mobilizing hormones involves only the pre-existent membrane-bound enzyme without affecting the soluble enzyme.
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PMID:Lack of translocation of protein kinase C from the cytosol to the membranes in vasopressin-stimulated hepatocytes. 216 91

Regulation of Ca2+-dependent glycogen phosphorylase activity by alpha 1-adrenergic and H1-histamine receptors has been examined in BC3H-1 muscle cells. Stimulation by either norepinephrine or histamine elevates the phosphorylase activity ratio within 5 s from a resting value of 0.37 +/- 0.03 to maximal values of 0.8-0.9. Phosphorylase activation by alpha-adrenergic agonists is sustained over 20-30 min of agonist exposure, whereas histamine exposure only transiently activates phosphorylase during the initial 5 min of stimulation. The initial activation of phosphorylase by either receptor is not attenuated by treated cells with Ca2+-deficient and [ethylenebis(oxyethylenenitrilo)]tetraacetic acid-supplemented buffer, whereas the response to sustained adrenergic stimulation depends largely, but not totally, upon extracellular Ca2+. The involvement of protein kinase C in agonist responses was tested by treating cells with phorbol 12-myristate 13-acetate. Phorbol 12-myristate 13-acetate inhibits receptor-mediated mobilization of intracellular Ca2+ (IC50 = 3.6 nM) yet activates phosphorylase independently of agonist. Phorbol 12-myristate 13-acetate has no effect on cellular 45Ca2+ fluxes in the absence of agonist. Thus, the two receptors coordinately regulate intracellular signaling through Ca2+- and protein kinase C-mediated pathways. alpha 1-Adrenergic receptors elicit sustained phosphorylase activation whereas H1-histaminergic receptors desensitize.
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PMID:Temporal integration of alpha 1-adrenergic responses in BC3H-1 muscle cells. Regulation of glycogen phosphorylase activity. 254 74

It has been hypothesized on the basis of studies on BC3H-1 myocytes that diacylglycerol generation with activation of protein kinase C (PKC) is involved in the stimulation of glucose transport in muscle by insulin (Standaert, M. L., Farese, R. V., Cooper, R. D., and Pollet, R. J. (1988) J. Biol. Chem. 263, 8696-8705). In the present study, we used the rat epitrochlearis muscle to evaluate the possibility that PKC activity mediates the stimulation of glucose transport by insulin in mammalian skeletal muscle. Phospholipase C from Clostridium perfringens (PLC-Cp), which generates diacylglycerol from membrane phospholipids, and 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) induced increases in glucose transport activity (assessed using 3-O-methylglucose transport) that were approximately 80 and approximately 20% as great, respectively, as that induced by a maximal insulin stimulus. PLC-Cp and PMA both caused a approximately 2-fold increase in membrane-associated PKC activity. In contrast, insulin did not affect PKC activity. These findings argue against a role of diacylglycerol-mediated PKC activation in the stimulation of skeletal muscle glucose transport by insulin. They also show that the BC3H-1 myocyte is not a good model for studying regulation of glucose transport in skeletal muscle. Neither the submaximal nor maximal effects of PLC-Cp and insulin on glucose transport were additive, suggesting that PLC-Cp interferes with insulin action. The maximal effects of PLC-Cp and hypoxia or muscle contractions were also not additive. However, the submaximal effects of hypoxia and PLC-Cp were completely additive. These findings raise the possibility that PLC-Cp stimulates glucose transport by the exercise/hypoxia-activated, not the insulin-activated, pathway in skeletal muscle. Exposure to PLC-Cp activated glycogen phosphorylase and potentiated twitch tension in response to electrical stimulation, providing evidence that PLC-Cp increases cytoplasmic Ca2+ concentration. Dantrolene, an inhibitor of Ca2+ release from the sarcoplasmic reticulum, completely blocked both the activation of phosphorylase and the stimulation of glucose transport by PLC-Cp. These findings provide evidence that an increase in cytoplasmic Ca2+ concentration is involved in the activation of glucose transport in skeletal muscle by PLC-Cp.
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PMID:Activation of glucose transport in skeletal muscle by phospholipase C and phorbol ester. Evaluation of the regulatory roles of protein kinase C and calcium. 260 81

To investigate the increased incidence of respiratory distress syndrome (RDS) that occurs in infants of diabetic mothers (IDM) with poor maternal glucose homeostasis, we infused glucose intravenously at a rate of 14 +/- 2 (SD) mg.kg-1.min-1 into eight twin and four singleton chronically catheterized fetal lambs from 112 days (0.77) gestation onward. Twelve catheterized and seven uncatheterized fetuses served as controls, including the eight twins of the glucose-treated fetuses. Glucose infusion resulted in a twofold elevation in fetal serum glucose levels and a 2.2-fold elevation in fetal serum insulin levels. Before 113 days (0.9) gestation, pulmonary disaturated phosphatidylcholine (DSPC) content was 1.5-fold higher in the glucose-infused fetuses than in the controls. However, after 0.9 gestation, pulmonary DSPC content increased 2.2-fold in the controls but did not increase significantly in the glucose-infused fetuses. In addition, the DSPC content of lung lavage was 5.0-fold higher in the controls and lung stability to air inflation was 2.0-fold greater and to deflation was 2.2-fold greater than in the glucose-infused fetuses. Pulmonary adenosine 3',5'-cyclic monophosphate-dependent protein kinase activity was also 1.5-fold higher, and pulmonary protein kinase C activity was 1.3-fold higher in the controls than in the glucose-infused fetuses. In contrast, glucose infusion was associated with a 1.8-fold increase in pulmonary glycogen content and with increased activities of glycogen phosphorylase kinase and glycogen phosphorylase. We conclude that the effects of chronic glucose infusion on fetal lamb lung DSPC and lung stability are compatible with a predisposition of the fetus to develop RDS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of glucose infusion on surfactant and glycogen regulation in fetal lamb lung. 282 81

The actions of cyclic AMP are subject to several levels of post-receptor modulation in cardiac tissue. Isoproterenol and prostaglandin E1 both stimulate cAMP accumulation, but only isoproterenol causes activation of particulate cAMP-dependent protein kinase, leading to activation of phosphorylase kinase and glycogen phosphorylase, and inhibition of glycogen synthase. Through the use of isolated, adult ventricular myocytes, we have determined that the hormone-specific activation of glycogen phosphorylase is due to subcellular compartmentation of cAMP. There is some evidence that cyclic nucleotide phosphodiesterases, whose activity is stimulated by alpha 1-adrenergic agonists in isolated myocytes, may have a role in compartmentation. Phosphoinositide hydrolysis is stimulated by alpha 1 and muscarinic agonists, presumably leading to activation of protein kinase C, which in turn has multiple effects on hormone-sensitive adenylate cyclase.
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PMID:Post-receptor modulation of the effects of cyclic AMP in isolated cardiac myocytes. 284 10

To study the effects of beta-2 agonist on metabolic regulation in fetal lamb lung, ritodrine hydrochloride, a preferential beta-2 agonist, was infused i.v. at a rate of 1.3 +/- 0.4 micrograms/kg/min (mean +/- S.D.) for 24 hr into six twin chronically catheterized fetal lambs starting between 0.86 and 0.91 gestation. Lung glycogen was depleted 56% in the ritodrine-infused twins and glycogen phosphorylase a activity was increased 1.8-fold whereas glycogen synthase activity remained unchanged. Cyclic AMP-dependent protein kinase activity increased 1.7-fold, calcium-calmodulin-dependent protein kinase (phosphorylase kinase) activity increased 1.4-fold and calcium-phospholipid-dependent protein kinase (protein kinase C) activity increased 1.6-fold. In addition, the maximal binding capacity of pulmonary beta receptors decreased 49% in the ritodrine-infused twins. However, lung cyclic AMP content was unchanged after 24 hr of ritodrine infusion. We conclude that beta-2 agonist activates protein kinases, depletes glycogen and reduces the binding capacity of beta receptors in the fetal lamb lung. We speculate that these adrenergic mechanisms are involved in regulating the effects of beta-2 agonist on fetal lung liquid and surfactant production.
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PMID:Effects of beta-2 agonist on metabolic regulation in the fetal lamb lung. 288 40

Incubation of rat hepatocytes with angiotensin II (1 nM) produced a time-dependent accumulation of 1, 2-diacylglycerol and inactivation of glycogen synthase with maximum effects at 10 min. The level of diacylglycerol then gradually declined and the activity of glycogen synthase I returned to control values at 30 min. In contrast, angiotensin II caused an increase in cytosolic Ca2+ and an activation of glycogen phosphorylase which were rapid and transient, reaching maximum values in less than 2 min and then returning to control levels at 15 min. There were excellent correlations between the changes in glycogen synthase I and diacylglycerol levels and between the changes in phosphorylase alpha and cytosolic Ca2+ in these time-course studies. However, there was no correlation between the changes in diacylglycerol and phosphorylase alpha or between the changes in cytosolic Ca2+ and glycogen synthase I. Norepinephrine also caused a slow increase in diacylglycerol and inactivation of glycogen synthase, and a rapid increase in cytosolic free Ca2+ and activation of glycogen phosphorylase. Addition of an alpha1-adrenergic blocker (prazosin or phentolamine) caused rapid decreases in cytosolic free Ca2+ and phosphorylase alpha, but only slowly reversed the inactivation of synthase and accumulation of diacylglycerol. The dose-response curves for norepinephrine and prazosin on glycogen synthase were well correlated with those on diacylglycerol. It is proposed that in liver cells, Ca2+-mobilizing hormones regulate phosphorylase a through a Ca2+-dependent mechanism and inactivate glycogen synthase through the generation of diacylglycerol, at least in part. The data provide additional support for the view that protein kinase C may be important in the regulation of glycogen synthase in liver.
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PMID:Regulation of hepatic glycogen phosphorylase and glycogen synthase by calcium and diacylglycerol. 309 Oct 81

1. In isolated hepatocytes NaF increased the rate of 45Ca2+ exchange, the cytoplasmic free Ca2+ concentration ([Ca2+]i) (monitored by using quin2), and the activity of glycogen phosphorylase a in a Ca2+-dependent manner. 2. In cells previously incubated in the absence of extracellular Ca2+(Ca2+o), NaF caused a pronounced enhancement in the increases in the activity of glycogen phosphorylase and in [Ca2+]i observed when Ca2+ was subsequently added. The effect of NaF on glycogen phosphorylase activity was inhibited by verapamil and deferoxamine, and was potentiated by AlCl3. 3. The actions of NaF were associated with (a) increases in [3H]inositol polyphosphates, which were slower in onset and about half the magnitude of those induced by vasopressin, in hepatocytes labelled with [3H]inositol, and (b) enhanced rates of O2 utilization and decreased concentrations of ATP. The latter effects were not potentiated by AlCl3. 4. Preincubation of hepatocytes with vasopressin in the absence of added Ca2+o for times up to 30 min did not diminish the ability of a subsequent addition of extracellular Ca2+ to activate glycogen phosphorylase. 5. 12-O-Tetradecanoylphorbol 13-acetate had little effect on 45Ca2+ exchange and did not enhance the activation by Ca2+o of phosphorylase in hepatocytes incubated in the absence of Ca2+o. 6. On the basis of the observation that AlF4- activates GTP-binding regulatory proteins [Sternweiss & Gilman (1982) Proc. Natl. Acad. Sci. U.S.A. 79, 4888-4891], it is concluded that the present results provide evidence for the function of a GTP-binding regulatory protein in the mechanism by which hormones stimulate plasma-membrane Ca2+ inflow in the liver cell, and indicate that an increase in [Ca2+]i and the activation of protein kinase C are not part of this mechanism.
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PMID:The stimulation by sodium fluoride of plasma-membrane Ca2+ inflow in isolated hepatocytes. Evidence that a GTP-binding regulatory protein is involved in the hormonal stimulation of Ca2+ inflow. 311 43


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