The Effect of Glucose and of a Treatment by Glucocorticoids on the Inactivation in vitro of Liver Glycogen Phosphorylase

1970 ◽  
Vol 15 (1) ◽  
pp. 9-12 ◽  
Author(s):  
Willy Stalmans ◽  
Henri De Wulf ◽  
Beatrice Lederer ◽  
Henri-Gery Hers
Keyword(s):  
Glycogen Phosphorylase ◽  
Liver Glycogen ◽  
Effect Of Glucose

scholarly journals The effect of glucose on the potency of two distinct glycogen phosphorylase inhibitors

2002 ◽  
Vol 367 (2) ◽  
pp. 443-450 ◽  
Author(s):  
Birgitte ANDERSEN ◽  
Niels WESTERGAARD
Keyword(s):  
Synergistic Effect ◽  
Glycogen Phosphorylase ◽  
Rat Hepatocytes ◽  
Rabbit Muscle ◽  
Ic50 Value ◽  
Cultured Rat Hepatocytes ◽  
Effect Of Glucose ◽  
Glycogen Phosphorylase Inhibitors ◽  
Glucose Analogue

Two distinct glycogen phosphorylase inhibitors, 5-chloro-1H-indole-2-carboxylic acid [1-(4-fluorobenzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxoethyl]amide (CP-320,626) and 1,4-dideoxy-1,4-d-arabinitol (DAB), were characterized in vitro with respect to the influence of glucose on their potencies. CP-320,626 has previously been shown to bind to a newly characterized indole site, whereas DAB seems to act as a glucose analogue, but with slightly different properties from those of glucose. When analysed in pig liver glycogen phosphorylase a (GPa) activity assays, the two inhibitors showed very different properties. When GPa activity was measured in the physiological direction (glycogenolysis), DAB was the most potent inhibitor with an IC50 value of 740±9nM compared with the IC50 value for CP-320-626 of 2.39±0.37μM. There was no effect of glucose on the inhibitory properties of DAB, whereas a glucose analogue N-acetyl-β-d-glucopyranosylamine (1-GlcNAc) antagonized the effect of DAB. Likewise, there was no synergistic effect of CP-320,626 and glucose, whereas CP-320,626 and 1-GlcNAc inhibited GPa in synergy. Moreover, the synergistic effect of glucose and CP-320,626 was GPa-isoform-specific, since CP-320,626 and glucose inhibited rabbit muscle GPa in synergy when the GPa activity was measured towards glycogenolysis. When GPa activity was measured towards glycogen synthesis, CP-320,626 showed a synergistic effect with glucose, whereas the effect of DAB was slightly antagonized by glucose in this assay direction. Caffeine was included in the investigation as a control GP inhibitor, and both glucose and 1-GlcNAc potentiated the effect of caffeine independent of the assay direction. In primary cultured rat hepatocytes 1-GlcNAc and CP-320,626 inhibited basal and glucagon-induced glycogenolysis in synergy, whereas the ability of DAB to inhibit basal or glucagon-induced glycogenolysis was unaltered by 1-GlcNAc. Glucose had no effect on either CP-320,626 or DAB inhibition of glycogenolysis in cultured rat hepatocytes. In conclusion, the present study shows that the two GP inhibitors are kinetically very distinct and neither of the inhibitors demonstrates a physiologically relevant glucose dependence in vitro.

Endogenous effectors of human liver glycogen phosphorylase modulate effects of indole-site inhibitors

2005 ◽  
Vol 289 (3) ◽  
pp. E366-E372 ◽  
Author(s):  
Nacide Ercan-Fang ◽  
Miriam R. Taylor ◽  
Judith L. Treadway ◽  
Carolyn B. Levy ◽  
Paul E. Genereux ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Human Liver ◽  
Glycogen Phosphorylase ◽  
Liver Glycogen ◽  
Inhibitory Effect ◽  
Small Molecular Weight ◽  
Glucose Lowering ◽  
Glycogen Phosphorylase Inhibitors

Phosphorylase is regulated by a number of small-molecular-weight effectors that bind to three sites on the enzyme. Recently, a fourth site referred to as the indole-inhibitor site has been identified. Synthetic compounds bind to the site and inhibit activity. However, the effects of these compounds in the presence of other endogenous effectors are unknown. We have determined the effects of four indole derivative glycogen phosphorylase inhibitors (GPI) on recombinant human liver glycogen phosphorylase a activity. The GPIs tested were all potent inhibitors. However, the endogenous inhibitors (glucose, ADP, ATP, fructose 1-phosphate, glucose 6-phosphate, UDP-glucose) and the activator (AMP) markedly reduced the inhibitory effect of GPIs. Consistent with these in vitro findings, the IC50 for the inhibition of glycogenolysis in cells and the liver drug concentration associated with glucose-lowering activity in diabetic ob/ ob mice in vivo were also significantly higher than those determined in in vitro enzyme assays. The inhibitory effect of indole-site effectors is modulated by endogenous small-molecular-weight effectors of phosphorylase a activity. However, at higher concentrations (10–30 μM), the GPI effect was dominant and resulted in inhibition of phosphorylase a activity irrespective of the presence or absence of the other modulators of the enzyme.

Temporal patterns of tissue glycogen, glucose, and glycogen phosphorylase activity prior to hibernation in freeze-tolerant chorus frogs, Pseudacris triseriata

2008 ◽  
Vol 86 (10) ◽  
pp. 1095-1100 ◽  
Author(s):  
Steve C. Dinsmore ◽  
David L. Swanson
Keyword(s):  
Glycogen Phosphorylase ◽  
Threshold Level ◽  
Liver Glycogen ◽  
Critical Threshold ◽  
Hepatic Glycogen ◽  
Phosphorylase Activity ◽  
Continuous Increase ◽  
Glycogen Accumulation ◽  
Chorus Frogs ◽  
Glycogen Stores

Freezing survival may differ among winters in chorus frogs ( Pseudacris triseriata (Wied-Neuwied, 1838)), and low freezing survival is associated with low hepatic glycogen stores. The pattern of prehibernation liver glycogen accumulation in chorus frogs is unknown. Frogs might accumulate hepatic glycogen stores until a threshold level sufficient for winter survival is attained, after which frogs enter hibernation (critical threshold hypothesis). According to this model, frogs active late in the season should only be those with low hepatic glycogen stores. Alternatively, hepatic glycogen levels might continue to increase throughout the fall as long as frogs remain active (continuous increase hypothesis). We tested these hypotheses by measuring liver and leg muscle glycogen, glucose, and glycogen phosphorylase activities in chorus frogs throughout the fall prehibernation period in southeastern South Dakota. Hepatic glycogen levels were significantly related to date and increased throughout the fall period, consistent with the continuous increase hypothesis. This suggests that hepatic glycogen levels do not serve as a cue for entrance into hibernation. Liver phosphorylase activity did not vary significantly with progression of the fall season and activity was lower than in winter, suggesting that the winter increment of phosphorylase activity requires some stimulus during hibernation (e.g., low temperatures).

scholarly journals Heterologous desensitization of the cyclic AMP-independent glycogenolytic response in rat liver cells

1981 ◽  
Vol 200 (3) ◽  
pp. 509-514 ◽  
Author(s):  
B Bréant ◽  
S Keppens ◽  
H De Wulf
Keyword(s):  
Cyclic Amp ◽  
Glycogen Phosphorylase ◽  
Liver Glycogen ◽  
Receptor Interaction ◽  
Alpha Adrenergic Receptors ◽  
Rat Liver Cells ◽  
Heterologous Desensitization ◽  
Highly Correlated ◽  
Alpha Agonist

Vasopressin and alpha-adrenergic agonists are known to be potent cyclic AMP-independent Ca2+-dependent activators of liver glycogen phosphorylase. When hepatocytes are pre-incubated with increasing concentrations of vasopressin or of the alpha-agonist phenylephrine, they become progressively unresponsive to a second addition of the respective agonist. The relative abilities of six vasopressin analogues and of five alpha-agonists to activate glycogen phosphorylase and to cause subsequent desensitization are highly correlated, indicating that the same vasopressin and alpha-adrenergic receptors are involved in both responses. About 5-times-higher peptide concentrations are needed to desensitize the cells than to activate their glycogen phosphorylase, whereas the concentrations of alpha-agonists required for the desensitization are only twice those needed for the activation of phosphorylase. The desensitization is not mediated by a perturbation in the agonist-receptor interaction. It is clearly heterologous, i.e. it is not agonist-specific, and must therefore involve a mechanism common to both series of agonists. The evidence for a role of Ca2+ movements or phosphatidylinositol turnover is briefly discussed.

Sign in / Sign up

Export Citation Format

Share Document