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PubMed1993

Lithium restores glycogen synthesis from glucose in hepatocytes from diabetic rats.

In hepatocytes incubated in the presence of 20 mM glucose, strong stimulation of glycogen synthesis by LiCl was observed in cells from both normal and streptozotocin-induced diabetic rats. This stimulation was concentration- and time-dependent, and it was related to an increase in the glycogen synthase activity ratio. No effects of LiCl on glycogen phosphorylase activity were detected under these conditions. When hepatocytes were incubated with LiCl and insulin together, an additive effect on glycogen synthesis from glucose was observed. However, when hepatocytes were incubated in the presence of gluconeogenic precursors, such as lactate and pyruvate, and then with LiCl, no effect on glycogen accumulation was observed. Under these conditions, simultaneous activation of glycogen synthase and glycogen phosphorylase occurred. These results indicate that lithium ions, like insulin, are able to stimulate glycogen synthesis from glucose in diabetic rat hepatocytes, although the mechanisms of action of the two effectors on hepatic glycogen metabolism are probably different.

Adenosine Diphosphate↗

PubMed2001

Synthesis and mobilization of glycogen during metamorphosis of the medfly Ceratitis capitata.

There are no recent reports focusing on insect glycogen metabolism that take the advances made in mammalian and yeast systems into account. Moreover, little is known about glycogen synthesis and degradation during insect metamorphosis. The biosynthesis and mobilization of insect glycogen were measured during the larva to adult transition in the Medfly, Ceratitis capitata. The glycogen accumulated by larva decreased to reach almost undetectable levels at the beginning of the pupation process. Histological preparations of 40 h muscles and fat body confirmed a low glycogen content, in contrast with high glycogen images in third larva tissues. After 40 h, glycogen was synthesized de novo and accumulates up to adult ecdysis. We obtained the metamorphosis-dependent profiles of phosphorylase, glycogen synthase, and a glycogenin-like protein. This novel insect glycogen initiator protein (the first measured in an arthropod) appeared to be similar to the homologous enzymes from vertebrates and yeast. We have correlated these results with other biochemical events and anatomical landmarks to understand the use of storage carbohydrates during the sequence of metamorphosis events.

Amylases↗

PubMedDate not supplied

Regulation of glycogen synthase activation in isolated hepatocytes.

Glycogen synthase, the regulatory enzyme of glycogen synthesis undergoes multisite phosphorylation leading to its inactivation. The kinases responsible for this covalent modification (ex. cAMP-dependent protein kinase, protein kinase C and glycogen synthase kinase-3) are controlled by the second messengers generated by different hormones. The isolated hepatocytes has been used as one of the experimental models for studying this complex regulatory process. Inactivation of glycogen synthase by glucagon and vasopressin has been shown to be accompanied with incorporation of phosphate into the enzyme protein. Insulin has been shown to activate glycogen synthase by inhibition of kinases and activation of synthase phosphatase. Glycogen synthase is activated by several gluconeogenic substrates, in addition to glucose. Studies in hepatocytes with activators and inhibitors of protein kinase C show that this enzyme negatively controls glycogen synthase. The differential effects of the phosphatase inhibitors, calyculin A and okadaic acid in liver cells provide supporting evidence that protein phosphatase type-1 plays a major role in the regulation of glycogen synthase. Hepatocytes isolated from diabetic rats of both types (insulin-dependent and non-insulin-dependent) mimic the defective glycogen synthase activation seen in vivo.

Animals↗

PubMed1990

Fractionation of particulate glycogen and bound enzymes using high-performance liquid chromatography.

During a study aimed at the specificity of binding of phosphorylase and glycogen synthase to glycogen particles we investigated the separation of these particles with the technique of high-performance liquid chromatography using several media. The technique allowed relatively rapid fractionations with little, if any, loss of enzyme activity. The basis of some separations was molecular weight of the particle. Of the molecular exclusion media used, Superose 6 had an exclusion limit large enough to accommodate most glycogens but excluded mouse liver and bovine liver glycogen particles. Toyopearl HW-75 F was a medium that could accommodate liver glycogen and gave us reasonably well-defined separation of the particles that carried phosphorylase and glycogen synthase. Separations on ion-exchange columns, that were obviously based on the overall charge of proteins associated with the glycogen particles, were not very effective in terms of allowing the separation of different types of particle. Of all the media used the hydrophobic interaction column was best in terms of separating what appeared to be distinct populations of particles that had definite preferences in terms of binding phosphorylase and glycogen synthase. As expected, these separations were based on the hydrophobic interaction of the proteins associated with the glycogen particles, since particles that had been deproteinized by a cold water extraction procedure did not bind to the column.

Animals↗

PubMedDate not supplied

The relationships between glycogen stores and muscle ultimate pH in commercially slaughtered pigs.

Small samples of liver and m. adductor (AD) were collected within 45 minutes of death from the carcasses of a total of 604 pigs killed at three bacon factories. Glycogen concentrations were measured and part of the muscle sample allowed to complete post-mortem glycolysis in order to estimate ultimate pH (pHu) values. Liver glycogen levels were also used to predict overall food withdrawal times. Muscle glycogen concentrations ranged from 2.2 to 15.3 mg/g, liver glycogen from 0.01 to 50.7 mg/g and pHu in the AD from 5.51 t 6.76. The overall average predicted fasting time was 16.5 +/- 0.54 (SEM) hours and 22% of pigs had pHu values in the AD greater than 6.2 indicative of potentially dark, firm, dry meat. Muscle glycogen concentration was positively correlated with liver glycogen (r = 0.27, P less than 0.01) and negatively correlated with predicted fasting time (r = -0.30, P less than 0.001). The pHu in the AD was negatively correlated with liver glycogen (r = -0.34, P less than 0.001) and positively correlated with predicted fasting time (r = 0.37, P less than 0.001). Therefore, pigs which had reduced concentrations of glycogen in their livers, indicative of longer food withdrawal times before slaughter, tended to have less glycogen in their muscles and a higher pHu in the meat.

Abattoirs↗

PubMed1994

Regional distribution of glycogen, glucose and phosphorylated sugars in rat brain after intoxicating doses of ethanol.

Ethanol and anaesthetics increase glycogen levels in the brain. However, no data have been reported about the effect of ethanol on glycogen and glucose metabolism in specific brain regions. We have studied the concentrations of glycogen, glucose, glucose 6-P, glucose 1,6-P2 and fructose 2,6-P2 and the activities of glycogen synthase, glycogen phosphorylase and glycogen phosphorylase kinase in seven brain regions of starved rats following treatment with a single dose or several doses of ethanol. Our results show that: (1) the effect of ethanol on glucose metabolism depends on whether it is given in one single dose or in a series of doses; (2) glycogen concentration increases after a single dose of ethanol but not after long exposure; (3) glucose, glucose 6-P in some areas, and the bisphosphorylated sugar, fructose 2,6-P2 significantly increase after prolonged exposure to ethanol; and (4) the enzymatic activities of glycogen metabolism are not modified after a long exposure to ethanol. In summary, these data show that ethanol may modify the use of glycogen, glucose and derivatives in brain. Moreover, the changes produced depend on the pattern of ethanol intake and the brain area considered.

Alcoholic Intoxication↗

PubMed1987

Effects of oxytetracycline treatment on enzymes of hepatic glycogen metabolism in genetically diabetic (db/db) mice.

The effects of daily oxytetracycline treatment on the activities of hepatic glycogen synthase, glycogen phosphorylase, plasma glucose, and insulin, and on liver glycogen, free fatty acid, and triglyceride levels were examined in 8- to 15-week-old genetically diabetic and lean mice. Oxytetracycline administration resulted in substantial reductions in the plasma glucose and immunoreactive-insulin levels in both diabetic and lean mice. The drug had no significant effect on the liver glycogen content in either phenotype, regardless of age, but it increased hepatic lipids and depressed body weights in lean animals. The most prominent effect of the drug was in markedly altering the activities of both glycogen synthase and phosphorylase in the liver of older diabetic mice. Oxytetracycline treatment produced a three-fold increase in the percentage of glycogen synthase I activity and reduced by one-third the percentage of glycogen phosphorylase a activity in 15-week-old diabetic mice. In age-matched lean mice treated with oxytetracycline, the percentage of glycogen synthase I activity increased significantly, but the percentage of phosphorylase a activity was unchanged. These data suggest that the drug may alter an aspect of hepatic glycogen metabolism which might lead to an inhibition of glycogenolysis and subsequent diminution of blood sugar levels in the diabetic. The present results show that, while oxytetracycline may be effective in reducing the severity of some of the diabetic symptoms associated with carbohydrate metabolism in this animal model of maturity-onset diabetes, the drug may have adverse effects on aspects of protein and lipid metabolism in these animals.

Animals↗

PubMed2001

Primary cultures as a model for studying ependymal functions: glycogen metabolism in ependymal cells.

Ependymal cells form a single-layered, ciliated epithelium at the interface between the cerebrospinal fluid and the brain parenchyma. Although their morphology has been studied in detail, ependymal functions remain largely speculative. We have established and characterized a previously described cell culture model to investigate ependymal glycogen metabolism. During growth in minimal medium lacking many non-essential amino acids including L-glutamate, but containing glucose at physiological concentration, the cells contained negligible amounts of glycogen (7+/-3 nmol glucosyl residues/mg protein) despite the presence of insulin. However, during a period of 24 h, the cells accumulated glycogen to very high levels after transferal to a medium containing insulin, glucose at a 5-fold higher concentration, and all proteinogenic amino acids except L-asparagine and L-serine (990+/-112 nmol glucosyl residues/mg protein). Omission of insulin resulted in a 50% reduction in glycogen accumulation. Upon glucose deprivation, glycogen was degraded with a half-life of 21 min. The ependymal primary cultures contained 80+/-5 mU glycogen phosphorylase (Pho)/mg protein and stained positively with antibodies raised against this enzyme. Astroglial cultures built up less glycogen and had less Pho activity under identical conditions. Ependymal glycogen was mobilized by noradrenaline and serotonin. Our results indicate that ependymal cells maintain glycogen as a functional energy store, subject to rapid turnover dependent on the availability of energy substrates and the presence of appropriate signal molecules. Thus ependymocytes appear to be active players in the multitude of processes resulting in normal brain function, and ependymal primary cultures are suggested as a suitable model for studying the role of ependymal cells in these processes.

Animals↗

PubMed1977

Glycogen metabolism in vesicles of hydatidiform mole in vitro.

Glycogen content, glycogen synthetase, and glycogen phosphorylase were studied in placental tissue of normal pregnancy and in vesicles of hydatidiform mole. The glycogen content of placental tissue of normal pregnancy decreased significantly with increased gestational age: 6 to 10 weeks, 716.6 +/- 55.7 mg/100 gm wet weight (mean +/- standard error of the mean); 15 to 20 weeks, 216.1 +/- 11.2 mg/100 gm; and 37 to 41 weeks, 176.1 +/- 18.1 mg/100 gm. The decrease in placental glycogen content was accompanied by a corresponding decrease in the placental glycogen synthetase enzyme levels, whereas no remarkable change was found in the glycogen phosphorylase enzyme levels. The glycogen content of hydatidiform mole tissue from 10 patients (13 to 20 weeks of gestation) was 507.0 +/- 58.0 mg/100 gm and was significantly (P less than 0.005) higher than that of normal placental tissue with a corresponding period of gestation. A possible cause of this phenomenon may be the marked decrease in the glycogen phosphorylase enzyme level in hydatidiform mole tissue, which was about one-third that of the normal placental tissue.

Female↗

PubMed2002

Glycogen depletion and resynthesis during 14 days of chronic low-frequency stimulation of rabbit muscle.

Electro-stimulation alters muscle metabolism and the extent of this change depends on application intensity and duration. The effect of 14 days of chronic electro-stimulation on glycogen turnover and on the regulation of glycogen synthase in fast-twitch muscle was studied. The results showed that macro- and proglycogen degrade simultaneously during the first hour of stimulation. After 3 h, the muscle showed net synthesis, with an increase in the proglycogen fraction. The glycogen content peaked after 4 days of stimulation, macroglycogen being the predominant fraction at that time. Glycogen synthase was determined during electro-stimulation. The activity of this enzyme was measured at low UDPG concentration with either high or low Glu-6-P content. Western blots were performed against glycogen synthase over a range of stimulation periods. Activation of this enzyme was maximum before the net synthesis of glycogen, partial during net synthesis, and low during late synthesis. These observations suggest that the more active, dephosphorylated and very low phosphorylated forms of glycogen synthase may participate in the first steps of glycogen resynthesis before net synthesis is observed, while partially phosphorylated forms are most active during glycogen elongation.

Animals↗

PubMed2003

A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias.

The AMP-activated protein kinase (AMPK) is an alphabetagamma heterotrimer that is activated by low cellular energy status and affects a switch away from energy-requiring processes and toward catabolism. While it is primarily regulated by AMP and ATP, high muscle glycogen has also been shown to repress its activation. Mutations in the gamma2 and gamma3 subunit isoforms lead to arrhythmias associated with abnormal glycogen storage in human heart and elevated glycogen in pig muscle, respectively. A putative glycogen binding domain (GBD) has now been identified in the beta subunits. Coexpression of truncated beta subunits lacking the GBD with alpha and gamma subunits yielded complexes that were active and normally regulated. However, coexpression of alpha and gamma with full-length beta caused accumulation of AMPK in large cytoplasmic inclusions that could be counterstained with anti-glycogen or anti-glycogen synthase antibodies. These inclusions were not affected by mutations that increased or abolished the kinase activity and were not observed by using truncated beta subunits lacking the GBD. Our results suggest that the GBD binds glycogen and can lead to abnormal glycogen-containing inclusions when the kinase is overexpressed. These may be related to the abnormal glycogen storage bodies seen in heart disease patients with gamma2 mutations.

AMP-Activated Protein Kinases↗

PubMed2001

The level of the glycogen targetting regulatory subunit R5 of protein phosphatase 1 is decreased in the livers of insulin-dependent diabetic rats and starved rats.

Hepatic glycogen synthesis is impaired in insulin-dependent diabetic rats owing to defective activation of glycogen synthase by glycogen-bound protein phosphatase 1 (PP1). The identification of three glycogen-targetting subunits in liver, G(L), R5/PTG and R6, which form complexes with the catalytic subunit of PP1 (PP1c), raises the question of whether some or all of these PP1c complexes are subject to regulation by insulin. In liver lysates of control rats, R5 and R6 complexes with PP1c were found to contribute significantly (16 and 21% respectively) to the phosphorylase phosphatase activity associated with the glycogen-targetting subunits, G(L)-PP1c accounting for the remainder (63%). In liver lysates of insulin-dependent diabetic and of starved rats, the phosphorylase phosphatase activities of the R5 and G(L) complexes with PP1c were shown by specific immunoadsorption assays to be substantially decreased, and the levels of R5 and G(L) were shown by immunoblotting to be much lower than those in control extracts. The phosphorylase phosphatase activity of R6-PP1c and the concentration of R6 protein were unaffected by these treatments. Insulin administration to diabetic rats restored the levels of R5 and G(L) and their associated activities. The regulation of R5 protein levels by insulin was shown to correspond to changes in the level of the mRNA, as has been found for G(L). The in vitro glycogen synthase phosphatase/phosphorylase phosphatase activity ratio of R5-PP1c was lower than that of G(L)-PP1c, suggesting that R5-PP1c may function as a hepatic phosphorylase phosphatase, whereas G(L)-PP1c may be the major hepatic glycogen synthase phosphatase. In hepatic lysates, more than half the R6 was present in the glycogen-free supernatant, suggesting that R6 may have lower affinity for glycogen than R5 and G(L)

Amino Acid Sequence↗

PubMed1975

Glycogen synthesis in the perfused liver of streptozotocin-diabetic rats.

1. Net glycogen accumulation was measured in sequentially removed samples during perfusion of the liver of starved streptozotocin-diabetic rats, and shown to be significantly impaired, compared with rates in normal (starved) rats. 2. In perfusions of normal livers with glucose plus C3 substrates, there was an increase in the proportion of glycogen synthetase 'a', compared with that in the absence of substrates. This response to substrates, followed in sequential synthesis and enzymic sensitivity in the perfused liver of diabetic rats were reversed by pretreatment in vivo with glucose plus fructose, or insulin. Glucose alone did not produce this effect. 4. Glucose, fructose, insulin or cortisol added to e perfusion medium (in the absence of pretreatment in vivo) did not stimulate glycogen synthesis in diabetic rats. 5. In intact diabetic rats, there was a decline in rates of net hepatic glycogen accumulation, and the response of glycogen synthetase to substrates. The most rapid rates of synthesis were obtained after fructose administration. 6. These results demonstrate that there is a marked inherent impairment in hepatic glycogen synthesis in starved diabetic rats, which can be rapidly reversed in vivo but no in perfusion. Thus hepatic glycogen synthesis does not appear to be sensitive to either the short-term direct action of insulin (added alone to perfusions) of to long-term insulin deprivation in vivo. The regulatory roles of substrates, insulin and glycogen synthetase in hepatic glycogen accumulation are discussed.

Animals↗

PubMed1979

Glycogen synthesis by hepatocytes from diabetic rats.

Hepatocytes prepared from streptozotocin- and alloxan-diabetic rats starved for 24 h contain 0.5--2% wet wt. of glycogen. Glycogen synthesis in the hepatocytes from such rats, after prior depletion of the glycogen by glucagon injection, was studied. As distinct from cells from normal animals, there was no glycogen synthesis from glucose as sole substrate, even at concentrations of 60 mM. When supplied with glucose, a gluconeogenic precursor (lactate, dihydroxyacetone or fructose), and with glutamine there was concurrent synthesis of glucose and of glycogen. Without glutamine there was little or no glycogen synthesis. The rate of glycogen formation was in the same range as for cells from control rats. Glutamine addition markedly activated glycogen synthase in cells of starved diabetic rats, but there was no effect on phosphorylase. We obtained very little synthesis of glycogen with hepatocytes from fed diabetic rats, whereas with normal animals, synthesis by such cells equals or exceeds that obtained from starved rats. The conversion of synthase b (inactive) into the active form was studied in rat liver homogenates. The activation of the synthase in cells from starved diabetic rats is somewhat less than that from normal animals, but that from fed diabetic rats is markedly decreased compared with that in livers of fed control animals or that of starved diabetic animals.

Alloxan↗

PubMed2006

Gene expression profiling of mice with genetically modified muscle glycogen content.

Glycogen, a branched polymer of glucose, forms an energy re-serve in numerous organisms. In mammals, the two largest glyco-gen stores are in skeletal muscle and liver, which express tissue-specific glycogen synthase isoforms. MGSKO mice, in which mGys1 (mouse glycogen synthase) is disrupted, are devoid of muscle glycogen [Pederson, Chen, Schroeder, Shou, DePaoli-Roach and Roach (2004) Mol. Cell. Biol. 24, 7179-7187]. The GSL30 mouse line hyper-accumulates glycogen in muscle [Manchester, Skurat, Roach, Hauschka and Lawrence (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 10707-10711]. We performed a microarray analysis of mRNA from the anterior tibialis, medial gastrocnemius and liver of MGSKO mice, and from the gastroc-nemius of GSL30 mice. In MGSKO mice, transcripts of 79 genes varied in their expression in the same direction in both the anterior tibialis and gastrocnemius. These included several genes encoding proteins proximally involved in glycogen metabolism. The Ppp1r1a [protein phosphatase 1 regulatory (inhibitor) sub-unit 1A] gene underwent the greatest amount of downregulation. In muscle, the downregulation of Pfkfb1 and Pfkfb3, encoding isoforms of 6-phosphofructo-2-kinase/fructose-2,6-bisphospha-tase, is consistent with decreased glycolysis. Pathways for branched-chain amino acid, and ketone body utilization appear to be downregulated, as is the capacity to form the gluconeogenic precursors alanine, lactate and glutamine. Expression changes among several members of the Wnt signalling pathway were identified, suggesting an as yet unexplained role in glycogen meta-bolism. In liver, the upregulation of Pfkfb1 and Pfkfb3 expression is consistent with increased glycolysis, perhaps as an adaptation to altered muscle metabolism. By comparing changes in muscle expression between MGSKO and GSL30 mice, we found a subset of 44 genes, the expression of which varied as a function of muscle glycogen content. These genes are candidates for regulation by glycogen levels. Particularly interesting is the observation that 11 of these genes encode cardiac or slow-twitch isoforms of muscle contractile proteins, and are upregulated in muscle that has a greater oxidative capacity in MGSKO mice.

Animals↗

PubMed1988

The modulator protein dissociates the catalytic subunit of hepatic protein phosphatase G from glycogen.

1. The phosphorylase phosphatase and glycogen-synthase phosphatase activities associated with the glycogen particles from rat liver were progressively inhibited by incubation with modulator protein. However, the phosphorylase phosphatase activity of the catalytic subunit was entirely recovered after destruction of the modulator and the regulatory subunit(s) by trypsin. 2. Inhibition of protein phosphatase G by modulator was associated with a translocation of the phosphorylase phosphatase activity (measured after incubation with trypsin) from glycogen to the soluble fraction. The degree of inhibition of phosphatase G corresponded closely to the extent to which the phosphorylase phosphatase activity was released from the glycogen particles. Incubation of glycogen-free protein phosphatase G with modulator did not change the affinity of the enzyme for added glycogen, but decreased the amount of phosphatase that could be bound to glycogen. 3. The phosphorylase phosphatase activity that was released from the glycogen particles by modulator migrated on gel filtration as a complex (Mr 106,000) of the catalytic subunit with modulator. Phosphorylase phosphatase activity could be transferred from glycogen-bound protein phosphatase G to modulator that was covalently bound to Sepharose. After elution from the column, the enzyme was identified as the free catalytic subunit (Mr 37,000).

Animals↗

PubMed1997

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

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-alpha-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.

Animals↗

PubMed2000

Glycogen synthase kinase-3beta facilitates staurosporine- and heat shock-induced apoptosis. Protection by lithium.

The potential role of glycogen synthase kinase-3beta in modulating apoptosis was examined in human SH-SY5Y neuroblastoma cells. Staurosporine treatment caused time- and concentration-dependent increases in the activities of caspase-3 and caspase-9 but not caspase-1, increased proteolysis of poly(ADP-ribose) polymerase, and induced morphological changes consistent with apoptosis. Overexpression of glycogen synthase kinase-3beta to levels 3.5 times that in control cells did not alter basal indices of apoptosis but potentiated staurosporine-induced activation of caspase-3, caspase-9, proteolysis of poly(ADP-ribose) polymerase, and morphological changes indicative of apoptosis. Inhibition of glycogen synthase kinase-3beta by lithium attenuated the enhanced staurosporine-induced activation of caspase-3 in cells overexpressing glycogen synthase kinase-3beta. In cells subjected to heat shock, caspase-3 activity was more than three times greater in glycogen synthase kinase-3beta-transfected than control cells, and this potentiated response was inhibited by lithium treatment. Thus, glycogen synthase kinase-3beta facilitated apoptosis induced by two experimental paradigms. These findings indicate that glycogen synthase kinase-3beta may contribute to pro-apoptotic-signaling activity, that inhibition of glycogen synthase kinase-3beta can contribute to anti-apoptotic-signaling mechanisms, and that the neuroprotective actions of lithium may be due in part to its inhibitory modulation of glycogen synthase kinase-3beta.

Apoptosis↗