scholarly journals Calcium ions and glycogen act synergistically as inhibitors of hepatic glycogen-synthase phosphatase

1985 ◽  
Vol 232 (3) ◽  
pp. 697-704 ◽  
Author(s):  
L Mvumbi ◽  
M Bollen ◽  
W Stalmans
Keyword(s):  
Proteinase Inhibitors ◽  
Glycogen Synthase ◽  
Liver Extract ◽  
Inhibitory Effect ◽  
Hepatic Glycogen ◽  
Calmodulin Antagonists ◽  
Maximal Inhibition ◽  
Fed State ◽  
Micromolar Range

We investigated the inhibitory effect of Ca2+ in the micromolar range on the activation of glycogen synthase in crude gel-filtered liver extracts [van de Werve (1981) Biochem. Biophys. Res. Commun. 102, 1323-1329]. The magnitude of the inhibition was highly dependent on the glycogen concentration in the final liver extract. Ca2+ inhibited the activation of purified hepatic synthase b by the G-component of synthase phosphatase, as present in the isolated glycogen-protein complex. The cytosolic S-component was not inhibited. Maximal inhibition of the crude G-component occurred at 0.3 microM-Ca2+. The inhibition was not influenced by the addition of either calmodulin or calmodulin antagonists, or by various proteinase inhibitors. The use of purified G-component revealed that the inhibition by 0.3 microM-Ca2+ increased from 45% to 85% when the concentration of glycogen was raised from 1.5 to 20 mg/ml. Muscle glycogen synthase, extensively phosphorylated in vitro, was also used as substrate for purified G-component. Activation and dephosphorylation were similarly inhibited by 0.3 microM-Ca2+, but the magnitude of the inhibition was much greater with the hepatic substrate. No effect of 0.3 microM-Ca2+ was found on the activity of phosphorylase phosphatase in various liver preparations. We conclude that the inhibition of synthase activation by Ca2+ is one of the mechanisms by which cyclic AMP-independent glycogenolytic hormones promote the inactivation of glycogen synthase in the liver, especially in the fed state.

Neural network dysfunction in bipolar depression: clues from the efficacy of lamotrigine

2009 ◽  
Vol 37 (5) ◽  
pp. 1080-1084 ◽  
Author(s):  
Charles H. Large ◽  
Elena Di Daniel ◽  
Xingbao Li ◽  
Mark S. George
Keyword(s):  
Bipolar Disorder ◽  
Valproic Acid ◽  
Protein Kinase ◽  
Glycogen Synthase ◽  
Bipolar Depression ◽  
Inhibitory Effect ◽  
Mood Stabilizers ◽  
Mitogen Activated Protein Kinase ◽  
Facilitatory Effect

One strategy to understand bipolar disorder is to study the mechanism of action of mood-stabilizing drugs, such as valproic acid and lithium. This approach has implicated a number of intracellular signalling elements, such as GSK3β (glycogen synthase kinase 3β), ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) or protein kinase C. However, lamotrigine does not seem to modulate any of these targets, which is intriguing given that its profile in the clinic differs from that of valproic acid or lithium, with greater efficacy to prevent episodes of depression than mania. The primary target of lamotrigine is the voltage-gated sodium channel, but it is unclear why inhibition of these channels might confer antidepressant efficacy. In healthy volunteers, we found that lamotrigine had a facilitatory effect on the BOLD (blood-oxygen-level-dependent) response to TMS (transcranial magnetic stimulation) of the prefrontal cortex. This effect was in contrast with an inhibitory effect of lamotrigine when TMS was applied over the motor cortex. In a follow-up study, a similar prefrontal specific facilitatory effect was observed in a larger cohort of healthy subjects, whereas valproic acid inhibited motor and prefrontal cortical TMS-induced BOLD response. In vitro, we found that lamotrigine (3–10 μM) enhanced the power of gamma frequency network oscillations induced by kainic acid in the rat hippocampus, an effect that was not observed with valproic acid (100 μM). These data suggest that lamotrigine has a positive effect on corticolimbic network function that may differentiate it from other mood stabilizers. The results are also consistent with the notion of corticolimbic network dysfunction in bipolar disorder.

scholarly journals Synthesis and In Vitro Screening of Novel Heterocyclic β-d-Gluco- and β-d-Galactoconjugates as Butyrylcholinesterase Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2833
Author(s):  
Krešimir Baumann ◽  
Lorena Kordić ◽  
Marko Močibob ◽  
Goran Šinko ◽  
Srđanka Tomić
Keyword(s):  
Active Site ◽  
Kinetic Studies ◽  
Inhibitory Effect ◽  
In Vitro Screening ◽  
Sugar Moiety ◽  
Brain Barrier Permeability ◽  
The Central Nervous System ◽  
Key Residues ◽  
Micromolar Range

The development of selective butyrylcholinesterase (BChE) inhibitors may improve the treatment of Alzheimer’s disease by increasing lower synaptic levels of the neurotransmitter acetylcholine, which is hydrolysed by acetylcholinesterase, as well as by overexpressed BChE. An increase in the synaptic levels of acetylcholine leads to normal cholinergic neurotransmission and improved cognitive functions. A series of 14 novel heterocyclic β-d-gluco- and β-d-galactoconjugates were designed and screened for inhibitory activity against BChE. In the kinetic studies, 4 out of 14 compounds showed an inhibitory effect towards BChE, with benzimidazolium and 1-benzylbenzimidazolium substituted β-d-gluco- and β-d-galacto-derivatives in a 10–50 micromolar range. The analysis performed by molecular modelling indicated key residues of the BChE active site, which contributed to a higher affinity toward the selected compounds. Sugar moiety in the inhibitor should enable better blood–brain barrier permeability, and thus increase bioavailability in the central nervous system of these compounds.

scholarly journals RPN2 is targeted by miR-181c and mediates glioma progression and temozolomide sensitivity via the wnt/β-catenin signaling pathway

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Jikui Sun ◽  
Quanfeng Ma ◽  
Banban Li ◽  
Chen Wang ◽  
Lidong Mo ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Inhibitory Effect ◽  
Who Grade ◽  
Pathway Network ◽  
Mechanistic Investigation ◽  
Signaling Axis ◽  
Gsk 3Β

Abstract Accumulating evidence indicates that the dysregulation of the miRNAs/mRNA-mediated carcinogenic signaling pathway network is intimately involved in glioma initiation and progression. In the present study, by performing experiments and bioinformatics analysis, we found that RPN2 was markedly elevated in glioma specimens compared with normal controls, and its upregulation was significantly linked to WHO grade and poor prognosis. Knockdown of RPN2 inhibited tumor proliferation and invasion, promoted apoptosis, and enhanced temozolomide (TMZ) sensitivity in vitro and in vivo. Mechanistic investigation revealed that RPN2 deletion repressed β-catenin/Tcf-4 transcription activity partly through functional activation of glycogen synthase kinase-3β (GSK-3β). Furthermore, we showed that RPN2 is a direct functional target of miR-181c. Ectopic miR-181c expression suppressed β-catenin/Tcf-4 activity, while restoration of RPN2 partly reversed this inhibitory effect mediated by miR-181c, implying a molecular mechanism in which TMZ sensitivity is mediated by miR-181c. Taken together, our data revealed a new miR-181c/RPN2/wnt/β-catenin signaling axis that plays significant roles in glioma tumorigenesis and TMZ resistance, and it represents a potential therapeutic target, especially in GBM.

scholarly journals α-1-Anti-trypsin, an inhibitor of renin

1976 ◽  
Vol 153 (2) ◽  
pp. 505-507 ◽  
Author(s):  
S Scharpé ◽  
M Eid ◽  
W Cooreman ◽  
A Lauwers
Keyword(s):  
Human Plasma ◽  
Competitive Inhibition ◽  
Proteinase Inhibitors ◽  
Competitive Inhibitor ◽  
Inhibitory Effect ◽  
Renin Activity ◽  
Pig Kidney ◽  
Naturally Occurring ◽  
The Hill

A naturally occurring competitive inhibitor of pig kidney renin has been identified in human plasma. The inhibitor was shown to be α-1 anti-trypsin and the effect in vitro on the renin activity was examined. The slope in the Hill plot is compatible with the assumption of one-site competitive inhibition. Other proteinase inhibitors, such as α-2-macroglobulin and C1 inactivator, however, have no inhibitory effect on the renin-angiotensinogen reaction.

scholarly journals Effect of antimycotic agents on the activity of aspartyl proteinases secreted by Candida albicans

2003 ◽  
Vol 52 (3) ◽  
pp. 247-249 ◽  
Author(s):  
Martin Schaller ◽  
Nikola Krnjaic ◽  
Markus Niewerth ◽  
Gerald Hamm ◽  
Bernhard Hube ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Proteinase Inhibitors ◽  
Inhibitory Effect ◽  
Antifungal Drugs ◽  
Immunodeficiency Virus ◽  
Antimycotic Agent ◽  
Pepstatin A ◽  
Aspartyl Proteinases

The inhibitory effect of human immunodeficiency virus (HIV) proteinase inhibitors amprenavir and saquinavir and antifungal agents terbinafine, ketoconazole, amphotericin B and ciclopiroxolamine on aspartyl proteinases (Saps) secreted by Candida albicans was tested in an in vitro spectophotometric assay. As expected, both HIV proteinase inhibitors showed a significant inhibitory effect on Sap activity, which was comparable to that of the classical aspartyl proteinase inhibitor pepstatin A (P < 0.001). Antifungal drugs such as ketoconazole, terbinafine and amphotericin B had no, or only minor, inhibitory effects on proteolytic activity. In contrast, a significant reduction in Sap activity could be demonstrated during treatment with the antifungal agent ciclopiroxolamine (P < 0.001). These results point to a multiple effect of this antimycotic agent and might explain the reduced adherence of C. albicans to human epithelial cells at subinhibitory doses.

Effect of vasoactive intestinal polypeptide on glycogen metabolism in rat hepatocytes

1982 ◽  
Vol 242 (4) ◽  
pp. E262-E272 ◽  
Author(s):  
C. L. Wood ◽  
J. J. Blum
Keyword(s):  
Phosphatase Activity ◽  
Vasoactive Intestinal Polypeptide ◽  
Glycogen Synthase ◽  
Gut Hormones ◽  
Rat Hepatocytes ◽  
Glycogen Metabolism ◽  
Hepatic Glycogen ◽  
Glycogen Deposition ◽  
Intestinal Polypeptide

The effects of vasoactive intestinal polypeptide (VIP) on several enzymes of glycogen metabolism in rat hepatocytes were compared with those of glucagon and of vasopressin (ADH). VIP caused phosphorylase activation and glycogenolysis in hepatocytes from fed rats. In hepatocytes from fasted rats incubated with glucose, lactate, and pyruvate, VIP inhibited net glycogen deposition, inactivated glycogen synthase, and activated phosphorylase. VIP was about 100-fold less potent than glucagon and 1,000-fold less potent than ADH in causing activation of phosphorylase. The ability of VIP to activate phosphorylase was not altered by chelation of the calcium in the medium. The half maximal effective doses of VIP for both phosphorylase activation and stimulation of glycogenolysis were 10-30 nM. Treatment with VIP, ADH, or glucagon did not decrease phosphorylase phosphatase activity. Each of these hormones, however, lengthened the lag time before synthase phosphatase activity was expressed in vitro. Other gut hormones tested did not affect hepatocyte glycogen metabolism. These results do not support the concept of physiologic control of hepatic glycogen metabolism by VIP or by other gut hormones.

scholarly journals The inhibitory effect of phosphorylase a on the activation of glycogen synthase depends on the type of synthase phosphatase

1983 ◽  
Vol 212 (2) ◽  
pp. 407-416 ◽  
Author(s):  
L Mvumbi ◽  
F Doperé ◽  
W Stalmans
Keyword(s):  
Skeletal Muscle ◽  
Phosphatase Activity ◽  
Protein Kinases ◽  
Rat Liver ◽  
Muscle Glycogen ◽  
Glycogen Synthase ◽  
Liver Extract ◽  
Inhibitory Effect ◽  
Specific Inhibition ◽  
Muscle Extract

The activity of glycogen synthase phosphatase in rat liver stems from the co-operation of two proteins, a cytosolic S-component and a glycogen-bound G-component. It is shown that both components possess synthase phosphatase activity. The G-component was partially purified from the enzyme-glycogen complex. Dissociative treatments, which increase the activity of phosphorylase phosphatase manyfold, substantially decrease the synthase phosphatase activity of the purified G-component. The specific inhibition of glycogen synthase phosphatase by phosphorylase a, originally observed in crude liver extracts, was investigated with purified liver synthase b and purified phosphorylase a. Synthase phosphatase is strongly inhibited, whether present in a dilute liver extract, in an isolated enzyme-glycogen complex, or as G-component purified therefrom. In contrast, the cytosolic S-component is insensitive to phosphorylase a. The activation of glycogen synthase in crude extracts of skeletal muscle is not affected by phosphorylase a from muscle or liver. Consequently we have studied the dephosphorylation of purified muscle glycogen synthase, previously phosphorylated with any of three protein kinases. Phosphorylase a strongly inhibits the dephosphorylation by the hepatic G-component, but not by the hepatic S-component or by a muscle extract. These observations show that the inhibitory effect of phosphorylase a on the activation of glycogen synthase depends on the type of synthase phosphatase.

scholarly journals Mechanism of hepatic glycogen synthase inactivation induced by Ca2+-mobilizing hormones. Studies using phospholipase C and phorbol myristate acetate

1986 ◽  
Vol 237 (1) ◽  
pp. 235-242 ◽  
Author(s):  
P F Blackmore ◽  
W G Strickland ◽  
S B Bocckino ◽  
J H Exton
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phospholipase C ◽  
Glycogen Synthase ◽  
Partial Purification ◽  
Hepatic Glycogen ◽  
Kinase C ◽  
Low Concentrations ◽  
Dependent Inactivation

Incubation of hepatocytes with the protein kinase C activator and tumour promoter 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) produced a time- and concentration-dependent inactivation of glycogen synthase, but no change in phosphorylase. The same rate and extent of inactivation occurred in hepatocytes depleted of Ca2+ by treatment with the Ca2+ chelator EGTA. When hepatocytes were treated with the Ca2+-mobilizing hormone vasopressin (10 nM), the rate of glycogen synthase inactivation was similar to that observed with PMA (1 microM). Depletion of intracellular Ca2+ stores with EGTA abolished the ability of vasopressin to mobilize Ca2+ and activate phosphorylase without abolishing its ability to inactivate glycogen synthase and increase 1,2-diacylglycerol (DAG), the endogenous activator of protein kinase C. Protein kinase C, either in membranes or after partial purification, was shown to be activated in vitro by PMA in the presence of very low concentrations of Ca2+. Exogenous phospholipase C from Clostridium perfringens, at low concentrations, inactivated glycogen synthase and increased DAG without affecting cell Ca2+ or phosphorylase. It is proposed that the inactivation of glycogen synthase elicited by the Ca2+-mobilizing hormones is due, at least in part, to generation of DAG and activation of protein kinase C.

scholarly journals Glucose-induced glycogenesis in the liver involves the glucose-6-phosphate-dependent dephosphorylation of glycogen synthase

1997 ◽  
Vol 322 (3) ◽  
pp. 745-750 ◽  
Author(s):  
Joan CADEFAU ◽  
Mathieu BOLLEN ◽  
Willy STALMANS
Keyword(s):  
Phosphatase Activity ◽  
Protein Phosphatase ◽  
Glycogen Synthase ◽  
Isolated Hepatocytes ◽  
Inhibitory Effect ◽  
Concentration Addition ◽  
Strong Inhibitory Effect ◽  
Glucose Derivatives

Non-metabolized glucose derivatives may cause inactivation of phosphorylase but, unlike glucose, they are unable to elicit activation of glycogen synthase in isolated hepatocytes. We report here that, after the previous inactivation of phosphorylase by one of these glucose derivatives (2-deoxy-2-fluoro-α-glucosyl fluoride), glycogen synthase was progressively activated by addition of increasing concentrations of glucose. Under these conditions, the degree of activation of glycogen synthase was linearly correlated with the intracellular glucose-6-phosphate (Glc-6-P) concentration. Addition of glucosamine, an inhibitor of glucokinase, decreased both parameters in parallel. Further experiments using an inhibitor of either protein kinases (5-iodotubercidin) or protein phosphatases (microcystin) in isolated hepatocytes indicated that Glc-6-P does not affect glycogen-synthase kinase activity but enhances the glycogen-synthase phosphatase reaction. Experiments in vitro showed that the synthase phosphatase activity of glycogen-bound type-1 protein phosphatase was increased by physiological concentrations of Glc-6-P (0.1–0.5 mM), but not by 2.5 mM fructose-6-P, fructose-1-P or glucose-1-P. At physiological ionic strength, the glycogen-associated synthase phosphatase activity was nearly entirely Glc-6-P-dependent, but Glc-6-P did not relieve the strong inhibitory effect of phosphorylase a. The large stimulatory effects of 2.5 mM Glc-6-P, with glycogen synthase b and phosphorylase a as substrates, appeared to be mostly substrate-directed, while the modest effects observed with casein and histone IIA pointed to an additional stimulation of glycogen-bound protein phosphatase-1 by Glc-6-P. We conclude that glucose elicits hepatic synthase phosphatase activity both by removal of the inhibitor, phosphorylase a, and by generation of the stimulator, Glc-6-P.

scholarly journals Insulin-Like Growth Factor 2 and the Insulin Receptor, But Not Insulin, Regulate Fetal Hepatic Glycogen Synthesis

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 741-747 ◽  
Author(s):  
Li Liang ◽  
Wei Hui Guo ◽  
Diego R. Esquiliano ◽  
Masato Asai ◽  
Susana Rodriguez ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Fetal Liver ◽  
Glycogen Synthesis ◽  
Mouse Strains ◽  
Hepatic Glycogen ◽  
Insulin Receptor Isoforms ◽  
Phosphoinositide 3 Kinase

Whether insulin or IGFs regulate glycogen synthesis in the fetal liver remains to be determined. In this study, we used several knockout mouse strains, including those lacking Pdx-1 (pancreatic duodenal homeobox-1), Insr (insulin receptor), and Igf2 (IGF-II) to determine the role of these genes in the regulation of fetal hepatic glycogen synthesis. Our data show that insulin deficiency does not alter hepatic glycogen stores, whereas Insr and Igf2 deficiency do. We found that both insulin receptor isoforms (IR-A and IR-B) are present in the fetal liver, and their expression is gestationally regulated. IR-B is highly expressed in the fetal liver; nonetheless, the percentage of hepatic IR-A isoform, which binds Igf2, was significantly higher in the fetus than the adult. In vitro experiments demonstrate that Igf2 increases phosphorylation of hepatic Insr, insulin receptor substrate-2, and Akt proteins and also the activity of glycogen synthase. Igf2 ultimately increased glycogen synthesis in fetal hepatocytes. This increase could be blocked by the phosphoinositide 3-kinase inhibitor LY294008. Taken together, we propose Igf2 as a major regulator of fetal hepatic glycogen metabolism, the insulin receptor as its target receptor, and phosphoinositide 3-kinase as the signaling pathway leading to glycogen formation in the fetal liver.

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