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

---

Query: EC:2.7.11.26 (GSK)
6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obstructive sleep apnea is characterized by intermittent obstruction of the upper airway, which leads to intermittent hypoxia. Myocardial glycogen is a major energy resource for heart during hypoxia. Previous studies have demonstrated that intermittent hypoxia rapidly degrades myocardial glycogen and activates glycogen synthase (GS). However, the underlying mechanisms remain undefined. Because sleep apnea/intermittent hypoxia usually happens at night, whether intermittent hypoxia leads to GS activation in the postabsorptive state is not known. In the present study, male adult rats were studied after either an overnight fast or ad libitum feeding with or without intermittent ventilatory arrest (3 90-s periods at 10-min intervals). Hearts were quickly excised and freeze-clamped. Intermittent hypoxia induced a significant decrease in myocardial glycogen content in fed rats and stimulated GS in both fasted and fed rats. However, the portion of GS in the active form increased by approximately 38% in fasted rats compared with a larger, approximately 130% increase in fed rats. The basal G-6-P content was comparable in fasted and fed animals and increased approximately threefold after hypoxia. The basal phosphorylation states of Akt and GSK-3beta and the activity of protein phosphatase 1 (PP1) were comparable between fasted and fed control rats. Hypoxia significantly increased Akt phosphorylation and PP1 activity only in fed rats. In contrast, hypoxia did not induce significant change in GSK-3beta phosphorylation in either fasted or fed rats. We conclude that hypoxia activates GS in fed rat myocardium through a combination of rapid glycogenolysis, elevated local G-6-P content, and increased PP1 activity, and fasting attenuates this action independent of local G-6-P content.
...
PMID:Activation of glycogen synthase in myocardium induced by intermittent hypoxia is much lower in fasted than in fed rats. 1700 35

In the present study, we investigated the mechanisms by which resistin (100 nM, 1 h) affects glycogen synthesis in L6 skeletal muscle cells. The activity of glycogen synthase, the major enzyme in glycogen synthesis, is determined by both its covalent phosphorylation and allostery through intracellular glucose-6-phosphate. Covalent phosphorylation of glycogen synthase was not altered by resistin and, accordingly, phosphorylation of GSK-3alpha/beta and Akt remained unchanged. The rate of glucose-6-phosphate formation, however, was decreased by resistin both in the absence and presence of insulin; in the absence of insulin, resistin decreased glucose-6-phosphate formation by reducing hexokinase type I activity without affecting glucose uptake; by contrast, in the presence of insulin, resistin decreased glucose-6-phosphate formation by reducing the Vmax of glucose uptake without changing hexokinase type I activity. In conclusion, short-term resistin incubation impairs glycogen synthesis by reducing the rate of glucose-6-phosphate formation involving, however, differential mechanisms in basal and insulin-stimulated states.
...
PMID:Resistin impairs basal and insulin-induced glycogen synthesis by different mechanisms. 1704 21

A reduced ability of insulin to activate glucose transport in skeletal muscle, termed insulin resistance, is a primary defect leading to the development of impaired glucose tolerance and type 2 diabetes. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with important roles in the regulation of glycogen synthesis, protein synthesis, gene transcription, and cell differentiation in various cell types. An emerging body of evidence has implicated GSK-3 in the multifactorial etiology of skeletal muscle insulin resistance in obese animal models and in obese human type 2 diabetic subjects. Overexpression and overactivity of GSK-3 in skeletal muscle of rodent models of obesity and obese type 2 diabetic humans are associated with an impaired ability of insulin to activate glucose disposal and glycogen synthase. New insights into the importance of GSK-3 as a regulator of insulin action on glucose transport activity in muscle have come from studies utilizing selective and sensitive inhibitors of GSK-3. These studies have demonstrated that selective inhibition of GSK-3 in insulin-resistant skeletal muscle causes improvements in insulin-stimulated glucose transport activity that are likely caused by enhanced post-insulin receptor insulin signaling and GLUT-4 glucose transporter translocation. An additional important action of these GSK-3 inhibitors in the context of obese-associated type 2 diabetes is a reduction of hepatic glucose production, likely via downregulation of genes associated with gluconeogensis. It is clear from these studies that selectively targeting GSK-3 in skeletal muscle may be an important new strategy for the treatment of obesity-associated insulin-resistant states characterized by GSK-3 overactivity in insulin-sensitive tissues.
...
PMID:Role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes. 1710 May 83

Calcineurin is selectively enriched within neurons of the central nervous system. The mechanism of calcineurin inhibitor-induced neurotoxicity remains poorly understood. The purpose of this study is to examine whether glycogen synthase-3 (GSK-3) is involved in calcineurin inhibitor-induced apoptosis. Calcineurin inhibitors such as cyclosporine A (CsA) and FK506 increased apoptotic cell death with morphological changes characterized by cell shrinkage, nuclear condensation of fragmentation, and internucleosomal DNA fragmentation. Alsteropaullone and 1-azakenpaullone, GSK-3 inhibitors, prevented calcineurin inhibitor-induced apoptosis. In addition, insulin growth factor-I (IGF-I) and cycloheximide completely blocked cell death. Moreover, caspase-3 activation was accompanied by calcineurin inhibitor-induced cell death. These results suggest that calcineurin inhibitors induce caspase-dependent apoptosis and activation of GSK-3 is involved in cell death in rat cortical neurons.
...
PMID:Caspase-dependent apoptosis induced by calcineurin inhibitors was prevented by glycogen synthase kinase-3 inhibitors in cultured rat cortical cells. 1716 86

An association between glycogen synthase kinase-3 (GSK3) in skeletal muscle and insulin resistance has been demonstrated in type 2 diabetic patients. In addition, inhibition of GSK3 improves insulin action. The aim of the present study was to elucidate the role of the alpha-isoform of GSK3 in insulin resistance in human skeletal muscle cells from nondiabetic subjects maintained in culture. Transfection of muscle cells with specific antisense oligonucleotides resulted in a 30-50% decrease of GSK3alpha protein expression (P < 0.05). Whereas neither the basal fractional velocity of glycogen synthase (GS FV) (an indicator of the activation state of the enzyme) nor glucose uptake (GU) were altered, reducing GSK3alpha expression resulted in increases in insulin stimulation of both GS FV and GU. GSK3alpha overexpression (60-100% increase over control) did not alter basal GS FV or GU but impaired insulin stimulation of both responses. Knockdown of GSK alpha also led to an increase in insulin receptor substrate-1 protein expression but did not alter insulin stimulation of pS473-Akt phosphorylation. However, GSK3alpha overexpression impaired insulin action on pS473-Akt. In summary, we concluded the following: 1) modulation of GSK3alpha expression has no effect on basal GU and glycogen synthase activities; 2) reduction of GSK3alpha expression results in improvements in insulin action; and 3) elevation of GSK3alpha in human skeletal muscle cells can induce insulin resistance for several responses. We conclude that GSK3alpha is an important regulator of muscle insulin action.
...
PMID:Role of glycogen synthase kinase-3 alpha in insulin action in cultured human skeletal muscle cells. 1756 61

HIV-infected patients with lipodystrophy (HIV lipodystrophy) are insulin resistant and have elevated plasma free fatty acid (FFA) concentrations. We aimed to explore the mechanisms underlying FFA-induced insulin resistance in patients with HIV lipodystrophy. Using a randomized, placebo-controlled, cross-over design, we studied the effects of an overnight acipimox-induced suppression of FFAs on glucose and FFA metabolism by using stable isotope-labeled tracer techniques during basal conditions and a two-stage euglycemic-hyperinsulinemic clamp (20 and 50 mU insulin/m(2) per min, respectively) in nine patients with nondiabetic HIV lipodystrophy. All patients received antiretroviral therapy. Biopsies from the vastus lateralis muscle were obtained during each stage of the clamp. Acipimox treatment reduced basal FFA rate of appearance by 68.9% (95% CI 52.6-79.5) and decreased plasma FFA concentration by 51.6% (42.0-58.9) (both, P < 0.0001). Endogenous glucose production was not influenced by acipimox. During the clamp, the increase in glucose uptake was significantly greater after acipimox treatment compared with placebo (acipimox: 26.85 micromol x kg(-1) x min(-1) [18.09-39.86] vs. placebo: 20.30 micromol x kg(-1) x min(-1) [13.67-30.13]; P < 0.01). Insulin increased phosphorylation of Akt Thr(308) and glycogen synthase kinase-3beta Ser(9), decreased phosphorylation of glycogen synthase (GS) site 3a + b, and increased GS activity (percent I-form) in skeletal muscle (P < 0.01). Acipimox decreased phosphorylation of GS (site 3a + b) (P < 0.02) and increased GS activity (P < 0.01) in muscle. The present study provides direct evidence that suppression of lipolysis in patients with HIV lipodystrophy improves insulin-stimulated peripheral glucose uptake. The increased glucose uptake may in part be explained by increased dephosphorylation of GS (site 3a + b), resulting in increased GS activity.
...
PMID:Inhibition of lipolysis stimulates peripheral glucose uptake but has no effect on endogenous glucose production in HIV lipodystrophy. 1760 93

Glycogen content and contraction strongly regulate glycogen synthase (GS) activity, and the aim of the present study was to explore their effects and interaction on GS phosphorylation and kinetic properties. Glycogen content in rat epitrochlearis muscles was manipulated in vivo. After manipulation, incubated muscles with normal glycogen [NG; 210.9 +/- 7.1 mmol/kg dry weight (dw)], low glycogen (LG; 108.1 +/- 4.5 mmol/ kg dw), and high glycogen (HG; 482.7 +/- 42.1 mmol/kg dw) were contracted or rested before the studies of GS kinetic properties and GS phosphorylation (using phospho-specific antibodies). LG decreased and HG increased GS K(m) for UDP-glucose (LG: 0.27 +/- 0.02 < NG: 0.71 +/- 0.06 < HG: 1.11 +/- 0.12 mM; P < 0.001). In addition, GS fractional activity inversely correlated with glycogen content (R = -0.70; P < 0.001; n = 44). Contraction decreased K(m) for UDP-glucose (LG: 0.14 +/- 0.01 = NG: 0.16 +/- 0.01 < HG: 0.33 +/- 0.03 mM; P < 0.001) and increased GS fractional activity, and these effects were observed independently of glycogen content. In rested muscles, GS Ser(641) and Ser(7) phosphorylation was decreased in LG and increased in HG compared with NG. GSK-3beta Ser(9) and AMPKalpha Thr(172) phosphorylation was not modulated by glycogen content in rested muscles. Contraction decreased phosphorylation of GS Ser(641) at all glycogen contents. However, contraction increased GS Ser(7) phosphorylation even though GS was strongly activated. In conclusion, glycogen content regulates GS affinity for UDP-glucose and low affinity for UDP-glucose in muscles with high glycogen content may reduce glycogen accumulation. Contraction increases GS affinity for UDP-glucose independently of glycogen content and creates a unique phosphorylation pattern.
...
PMID:Glycogen content and contraction regulate glycogen synthase phosphorylation and affinity for UDP-glucose in rat skeletal muscles. 1787 27

5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) is a commonly used pharmacological agent to study physiological effects which are similar to those of exercise. However, signal transduction pathways by which AICAR elicits downstream effects in liver are poorly understood. We report here that AICAR not only activated AMPK but also phosphorylated/deactivated glycogen synthase kinase-3 alpha/beta (GSK-3alpha/beta) and dephophorylated/activated glycogen synthase (GS) in a time-dependent manner in human hepatoma HepG2 cells. The signal connection between AICAR and GSK-3 is indirect and involves activation of Raf-1/MEK/p42/44(MAPK)/p90(RSK) signaling cascade as pharmacologic inhibition of MEK significantly reduced phosphorylation/deactivation of GSK-3 and consequent dephosphorylation/activation of GS. Moreover, silencing the expression of p90(RSK), a substrate of p42/44(MAPK), attenuated AICAR-dependent GSK-3 phosphorylation, implicating this kinase as a key mediator of AICAR signaling to GSK-3. Furthermore, consistent with the involvement of Raf-1 kinase cascade, AICAR-induced low-density lipoprotein (LDL) receptor expression in a p42/44(MAPK)-dependent manner. Finally, AICAR requires AMPK-alpha2-dependent and -independent pathways to activate Raf-1 kinase cascade as suppression of AMPKalpha2 activity, and not of AMPKalpha1, partially blocked AICAR-dependent p42/44(MAPK) activation and GSK-3 phosphorylation/deactivation. Collectively, these results highlight Raf-1 signaling cascade as the critical mediator of AICAR action on glucose and lipid metabolism in HepG2 cells.
...
PMID:AICAR positively regulate glycogen synthase activity and LDL receptor expression through Raf-1/MEK/p42/44MAPK/p90RSK/GSK-3 signaling cascade. 1794 90

Rictor is an essential component of mTOR (mammalian target of rapamycin) complex 2 (mTORC2), a kinase complex that phosphorylates Akt at Ser473 upon activation of phosphatidylinositol 3-kinase (PI-3 kinase). Since little is known about the role of either rictor or mTORC2 in PI-3 kinase-mediated physiological processes in adult animals, we generated muscle-specific rictor knockout mice. Muscle from male rictor knockout mice exhibited decreased insulin-stimulated glucose uptake, and the mice showed glucose intolerance. In muscle lacking rictor, the phosphorylation of Akt at Ser473 was reduced dramatically in response to insulin. Furthermore, insulin-stimulated phosphorylation of the Akt substrate AS160 at Thr642 was reduced in rictor knockout muscle, indicating a defect in insulin signaling to stimulate glucose transport. However, the phosphorylation of Akt at Thr308 was normal and sufficient to mediate the phosphorylation of glycogen synthase kinase 3 (GSK-3). Basal glycogen synthase activity in muscle lacking rictor was increased to that of insulin-stimulated controls. Consistent with this, we observed a decrease in basal levels of phosphorylated glycogen synthase at a GSK-3/protein phosphatase 1 (PP1)-regulated site in rictor knockout muscle. This change in glycogen synthase phosphorylation was associated with an increase in the catalytic activity of glycogen-associated PP1 but not increased GSK-3 inactivation. Thus, rictor in muscle tissue contributes to glucose homeostasis by positively regulating insulin-stimulated glucose uptake and negatively regulating basal glycogen synthase activity.
...
PMID:Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances Basal glycogen synthase activity. 1796 79

The stimulatory effects of SH (sulfatide and heparin) and two phospholipids (PI and PS) on autophosphorylation of GSK-3beta and the GSK-3beta-mediated phosphorylation of myelin basic protein (MBP) and two synthetic MBP peptides (M86 and M156) were comparatively examined in vitro. It was found that (i) both PI and SH highly stimulated the GSK-3beta-mediated phosphorylation of MBP, but not glycogen synthase, and two MBP peptides through their direct binding to these substrates and (ii) both PI and heparin, as compared with sulfatide, highly stimulated autophosphorylation of GSK-3beta. The K(m) value of MBP for GSK-3beta was highly reduced and the V(max) value was significantly increased in the presence of these acidic modulators, which augmented further phosphorylation of MBP by the kinase. Under our experimental condition, similar stimulatory effects of PI and heparin were observed with the GSK-3beta-mediated phosphorylation of tau protein (TP) in vitro. These results presented here suggest that these two phospholipids and SH may function as effective stimulators for autophosphorylation of GSK-3beta and for the GSK-3beta-mediated high phosphorylation of SH-binding proteins, including MBP and TP, in the highly accumulated levels of these acidic and sulfated modulators in the brain.
...
PMID:Biochemical characterization of phospholipids, sulfatide and heparin as potent stimulators for autophosphorylation of GSK-3beta and the GSK-3beta-mediated phosphorylation of myelin basic protein in vitro. 1803 85


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---