UNIPROT:P01275 - FACTA Search

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Query: UNIPROT:P01275 (glucagon)
26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Addition of glucagon (20 nM) to the isolated hepatocytes from 24-h starved male rats results in an inactivation of glycogen synthase. The A0.5 for glucose-6-P is increased 2-fold over the control but the S0.5 for UDP-glucose is not significantly affected. The glucagon-stimulated inactivation of glycogen synthase is also accompanied by a 60-120% increase in the phosphorylation of the synthase. Glycogen synthase labeled with 32P by incubation of the hepatocytes with [32P] PO4(3-) was recovered by immunoprecipitation and the resulting immunoprecipitate was subjected to tryptic digestion. Analysis of the 32P-labeled peptides reveals that the sites corresponding to those phosphorylated by cAMP-dependent protein kinase and glycogen synthase (casein) kinase-1 (Itarte, E., and Huang, K.-P. (1979) J. Biol. Chem. 254, 4052-4057) are rapidly phosphorylated in response to glucagon. These results demonstrate that glucagon not only triggers the activation of cAMP-dependent protein kinase through an increase in the intracellular level of cAMP but also, by an unknown mechanism, activates a Ca2+- and cAMP-independent protein kinase.
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PMID:Glucagon-stimulated phosphorylation of rat liver glycogen synthase in isolated hepatocytes. 391 19

The direct effects of insulin and glucose on glycogen accumulation were compared using monolayers of chicken embryo hepatocytes which, when cultured in chemically defined medium without hormones, retain viability for several days but become depleted of glycogen. The data strongly suggest that insulin is the major direct signal for hepatic glycogen synthesis, while glucose supports glycogen accumulation primarily in its role as a substrate. Insulin alone, when added to the cells in physiological concentrations, either shortly after isolation or throughout culture, restored glycogen to the maximal levels found in the liver of the fed chicken. Addition of increasing amounts of glucose in the absence of insulin, in contrast, yielded proportional but limited increases in glycogen deposition attaining not more than 30% of the maximal storage capacity of the cells. This hormone-independent glycogenesis was characterized by a 30-min burst of glycogen deposition immediately following a stepped increase of glucose, with no detectable change in glycogen synthase activity. Insulin-dependent glycogenesis evidenced a much slower rate of glycogen deposition and was accompanied by a near tripling of glycogen synthase activity. Insulin-induced glycogen stores were broken down following removal of the hormone, even when glucose was present in great excess, indicating that the cells require insulin to maintain as well as build up maximal levels of glycogen. In the presence of glucagon, insulin-induced glycogen stores were rapidly degraded, but glucose-induced glycogenesis was not inhibited. The actions of insulin and glucose in this system are both qualitatively and quantitatively similar to those that have been observed in the diabetic animal.
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PMID:Insulin, not glucose, controls hepatocellular glycogen deposition. A re-evaluation of the role of both agents in cultured liver cells. 392 11

The activation (dephosphorylation) of glycogen synthase and the inactivation (dephosphorylation) of phosphorylase in rat liver extracts on the administration of fructose were examined. The lag in the conversion of synthase b into a was cancelled, owing to the accumulation of fructose 1-phosphate. A decrease in the rate of dephosphorylation of phosphorylase a was also observed. The latency re-appeared in gel-filtered liver extracts. Similar latency was demonstrated in extracts from glucagon-treated rats. Addition of fructose 1-phosphate to the extract was able to abolish the latency, and the activation of glycogen synthase and the inactivation of phosphorylase occurred simultaneously. Fructose 1-phosphate increased the activity of glycogen synthase b measured in the presence of 0.2-0.4 mM-glucose 6-phosphate. According to kinetic investigations, fructose 1-phosphate increased the affinity of synthase b for its substrate, UDP-glucose. The accumulation of fructose 1-phosphate resulted in glycogen synthesis in the liver by inducing the enzymic activity of glycogen synthase b in the presence of glucose 6-phosphate in vivo and by promoting the activation of glycogen synthase.
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PMID:Effect of fructose 1-phosphate on the activation of liver glycogen synthase. 393 80

The cAMP-dependent protein kinase-induced effects on phosphorylase and glycogen synthase activities and glucose production were studied in hepatocytes isolated from fed rats in the presence of the diastereomers of adenosine cyclic 3',5'-phosphorothioate, (Sp)-cAMPS and (Rp)-cAMPS. Incubation of hepatocytes with (Sp)-cAMPS or glucagon, both of which lead to cAMP-dependent protein kinase activation, resulted in a concentration-dependent increase in glycogen phosphorylase activity and a decrease in glycogen synthase activity. Incubation of hepatocytes with the cAMP-dependent protein kinase antagonist, (Rp)-cAMPS, in the absence of an agonist, had no significant effect on phosphorylase or glycogen synthase activities. Incubation of hepatocytes with a half-maximally inhibitory concentration of (Rp)-cAMPS shifted the agonist-induced activation curves for phosphorylase and the agonist-induced inhibition curves for glycogen synthase to 5-fold higher concentrations for both (Sp)-cAMPS and glucagon. Phosphorylase activity was very sensitive to the rapid, concentration-dependent inhibition by (Rp)-cAMPS of agonist-induced activation of cAMP-dependent protein kinase. The effects on phosphorylase activity were observable in 30 s and were concentration-dependent with half-maximal inhibition at 10 microM, similar to that observed for cAMP-dependent protein kinase. In contrast, glycogen synthase activity was less sensitive to (Rp)-cAMPS inhibition of agonist-induced activation of cAMP-dependent protein kinase. The effects on glycogen synthase activity lagged behind those on phosphorylase activity and the concentration dependence did not parallel the cAMP-dependent protein kinase effect, but was shifted to higher concentrations of (Rp)-cAMPS with half-maximal inhibition at 60 microM. Glucose (10 to 40 mM) increased the sensitivity of glycogen synthase to (Rp)-cAMPS inhibition of cAMP-dependent protein kinase over a narrow range of agonist concentration, but had no significant effect throughout most of the agonist-induced activation range. Thus, the diastereomers, (Sp)- and (Rp)-cAMPS, influence glycogen metabolism and the glycogenolytic enzymes through their modulation of cAMP-dependent protein kinase levels.
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PMID:Effects of the specific cAMP antagonist, (Rp)-adenosine cyclic 3',5'-phosphorothioate, on the cAMP-dependent protein kinase-induced activity of hepatic glycogen phosphorylase and glycogen synthase. 609 66

The mechanism of actions of glucagon, alpha- and beta-adrenergic agonists, vasopressin and angiotensin II in the liver proposed in this article are summarized in Fig. 8. The actions of glucagon and beta-adrenergic agonists in liver can be entirely ascribed to their interaction with specific plasma membrane receptors which activate adenylate cyclase leading to the intracellular accumulation of cAMP and activation of cAMP-dependent protein kinase. This enzyme phosphorylates phosphorylase b kinase, glycogen synthase, L-type pyruvate kinase, and other liver proteins resulting in alterations in their activities which can account for several of the known hepatic responses to glucagon. There is no clear evidence that Ca2+ ions are involved in the hepatic actions of this hormone. Glucocorticoids, but not thyroid hormones, are required for normal responsiveness of the liver to glucagon. The steroids do not modify cAMP accumulation or cAMP-dependent protein kinase activation, but may act by modulating the action of the kinase on its substrates. Glucocorticoids and thyroid hormones decrease beta-adrenergic responses in the liver apparently by decreasing the number of beta-receptors. Insulin inhibits the actions of physiological concentrations of glucagon by decreasing cAMP accumulation: its mechanism of action is unknown. The actions of alpha-adrenergic agonists, vasopressin and angiotensin II on the liver resemble those of glucagon, but do not involve accumulation of cAMP or activation of cAMP-dependent protein kinase. These agents appear to act by increasing cytosolic Ca2+ thus altering the activities of Ca2+-sensitive enzymes such as phosphorylase b kinase and calmodulin-dependent glycogen synthase kinase. Their receptors appear to be located exclusively on the plasma membrane and a major mechanism by which they raise cytosolic Ca2+ is by inducing the release of this cation from mitochondria. These considerations imply the existence of an intracellular messenger(s) for these agents which is generated at the plasma membrane in response to receptor activation and exerts effects on mitochondria or perhaps other intracellular structures. Glucocorticoids and thyroid hormones increase alpha-adrenergic responses in the liver apparently by increasing the number of alpha-receptors. Insulin inhibits the responses of the liver to alpha-agonists, but not to vasopressin or angiotensin II.
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PMID:Mechanisms of hormonal regulation of liver metabolism. 611 89

Fast-frozen pectoralis muscle samples were taken from normal chickens (lines 200 and 412) and chickens having hereditary muscular dystrophy (line 304). The glycogen phosphorylase activity ratio (activity without AMP/activity with AMP) was significantly greater in dystrophic muscles (0.306 +/- 0.046) than it was in normal muscles (0.090 +/- 0.023). Glucagon treatment did not cause any changes in phosphorylase activity ratios. Isoproterenol treatment of both normal and dystrophic muscles raised the phosphorylase activity ratio of normal muscles to 0.446 +/- 0.054, which was not significantly different from that of the dystrophic muscles. The dystrophic muscles had significantly less glycogen than normal muscles (23.3 +/- 2.8 compared with 36.8 +/- 2.8 mumoles glucosyl units/g of muscle). There was no relationship of muscular dystrophy to total phosphorylase activity (measured in the presence of 1 mM AMP) and to glycogen synthase activities measured without and with glucose 6-phosphate. Normal muscles had 28% less cAMP and 49% less cGMP than dystrophic muscles, but these differences were eliminated by treatment of the chickens with glucagon.
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PMID:Glycogen cycle enzymes and cyclic nucleotides in avian muscular dystrophy. 624 56

Perfusion of livers from fed rats with medium containing glucagon (2 x 10(-10) or 1 x 10(-8) M) resulted in both time- and concentration-dependent inactivation of glycogen synthase phosphatase. Expected changes occurred in cAMP, cAMP-dependent protein kinase, glycogen synthase, and glycogen phosphorylase. The effect of glucagon on synthase phosphatase was partially reversed by simultaneous addition of insulin (4 x 10(-8) M), an effect paralleled by a decrease in cAMP. Addition of arginine vasopressin (10 milliunits/ml) resulted in a similar inactivation of synthase phosphatase and activation of phosphorylase, but independent of any changes in cAMP or its kinase. Phosphorylase phosphatase activity was unaffected by any of these hormones. Synthase phosphatase activity, measured as the ability of a crude homogenate to catalyze the conversion of purified rat liver synthase D to the I form, was no longer inhibited by glucagon or vasopressin when phosphorylase antiserum was added to the phosphatase assay mixture in sufficient quantity to inhibit 90-95% of the phosphorylase a activity. These data support the following conclusions: 1) hepatic glycogen synthase phosphatase activity is acutely modulated by hormones, 2) hepatic glycogen synthase phosphatase and phosphorylase phosphatase are regulated differently, 3) the hormone-mediated changes in synthase phosphatase cannot be explained by an alteration of the synthase D molecule affecting its behavior as a substrate, and 4) glycogen synthase phosphatase activity is at least partially controlled by the level of phosphorylase a.
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PMID:Hormonal regulation of hepatic glycogen synthase phosphatase. 625 45

Isolated liver cells from 24 h starved rats were incubated in Krebs-Ringer buffer containing 4% albumin. In the presence of 10, 20 and 30 mM glucose, addition of insulin stimulated net glycogen production by 52, 39 and 20%, respectively. 2 . 10(-9) M insulin was required for half-maximal stimulation. Increases of glycogen production and of glycogen synthase a activity were observed after 15-30 min of incubation with insulin. The stimulatory effect of insulin was additive to that of lithium. In agreement with the literature, insulin antagonized the inhibitory action of suboptimal doses of glucagon on glycogen deposition whereby a decrease of glucagon-elevated cyclic AMP levels was observed. In addition, we found that insulin also decreased the basal cyclic AMP levels in the absence of added glucagon by 22%. It is concluded that physiological concentrations of insulin stimulate net glycogen deposition in hepatocytes from fasted rats; the decrease of basal cyclic AMP levels upon insulin addition may play a role in the mechanism of the hormone action.
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PMID:Short-term stimulation of net glycogen production by insulin in rat hepatocytes. 626 93

The hormonal regulation of glycogen synthase has been studied with isolated perfused hearts that were depleted of 85% of their endogenous glycogen. Glycogen depletion alone promoted a 3-fold activation of glycogen synthase and magnified by 3-fold the response to insulin. Glycogen depletion also facilitated the detection of epinephrine-promoted glycogen synthase inactivation. Hormonal effects on glycogen synthase have been correlated with changes in phosphorylase, phosphorylase kinase, and tissue cAMP levels. Insulin activation of glycogen synthase was observed within 90 s of hormone addition and was maximal by 4 min. A half-maximum effect was obtained at an insulin concentration of 100 microunits/ml. Insulin-dependent activation is reversed by beta-adrenergic agonists, alpha-adrenergic agonists, and glucagon. Each promote the same degree of inactivation and the maximum extent of inactivation produced by each is independent of whether or not the tissue has been stimulated with insulin. beta-Adrenergic agonists and glucagon act via cAMP, alpha-agonists most likely act via intracellular Ca2+ translocation, and insulin action would appear to be independent of either cAMP or Ca2+. The action of epinephrine on cardiac glycogen synthase is mediated by interaction with both alpha- and beta-receptors. As indicated by dose-response curves, receptor occupancy of each occurs to an almost equal extent at suboptimal epinephrine concentrations. Regulation of cardiac glycogen synthase by epinephrine thus is mediated by two second messenger systems which converge to produce the end physiological response.
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PMID:Cyclic AMP-dependent and cyclic AMP-independent antagonism of insulin activation of cardiac glycogen synthase. 627 86

To determine if cGMP might function as a second messenger for insulin, an in situ liver perfusion system was established in which hepatic effects of insulin could be correlated with changes in cyclic nucleotides. Several combinations of insulin (10 mU/ml) and glucose (50 mg/ml) were infused (0.1 ml/min) for 30 min into fasted normal and diabetic rats with removal of a similar volume of blood. Samples of livers were removed at the beginning and end and at various times during the perfusion. In normal animals perfused with buffer alone, hepatic glycogen content fell. When glucose (with or without added insulin) was added to the perfusate, glycogen levels rose. With buffer alone, there was no change in the independent (I) form of glycogen synthase at 10 min but a modest increase at 30 min. With insulin and/or glucose, there as a large increase in the I-form of the enzyme at 10 min and a further rise at 30 min. Neither cGMP nor cAMP changed even though tissue samples were obtained at multiple times throughout the perfusion. Cyclic nucleotides were also measured in liver slices exposed to insulin (1 mU/ml) after 30 min of pre-incubation for stabilization. Although significant increases in cGMP were noted in the tissue exposed to insulin, similar significant rises also occurred in appropriately paired control slices. When glucagon was used in both the in situ perfusion and the paired liver slice systems, the expected rapid and large increases in cAMP levels occurred attesting to the validity of both approaches in evaluating hepatic cyclic nucleotide responses. These results plus the paucity of convincing data in the literature strongly suggest that cGMP can no longer be considered a candidate for the putative second messenger of insulin.
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PMID:Hepatic effects of glucose and insulin independent of cyclic nucleotide changes. 627 20

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