Glycogen synthase kinase-3 - An overview of an over-achieving protein kinase

Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.
Current drug targets (Impact Factor: 3.6). 12/2006; 7(11):1377-88. DOI: 10.2174/1389450110607011377
Source: PubMed

ABSTRACT Glycogen synthase kinase-3 (GSK-3) has attracted much scrutiny due to its plethora of cellular functions, novel mechanisms of regulation and its potential as a therapeutic target for several common diseases. In mammals, GSK-3 is encoded by two genes, termed GSK-3alpha and GSK-3beta, that yield related but distinct protein-serine kinases. GSK-3 is unusual in that its protein kinase activity tends to be high in resting cells and cellular stimuli, such as hormones and growth factors, result in its catalytic inactivation. Further, many of the substrate proteins of GSK-3 are functionally inhibited by phosphorylation. Thus, signals that inhibit GSK-3 often cause activation of its diverse array of target proteins. Regulation of GSK-3 is important for normal development, regulation of metabolism, neuronal growth and differentiation and modulation of cell death. Dysregulation of GSK-3 activity has been implicated in human pathologies such as neurodegenerative diseases and type-2 diabetes. In this introductory chapter we provide a primer on the modes of GSK-3 regulation and a description of the various signaling pathways and cellular processes in which GSK-3 is an active participant.

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    • "On the other hand, insulin promotes the dephosphorylation and activation of glycogen synthase (GS) by inactivating glycogen synthase kinase-3 (GSK-3) through phosphorylation [26]. GSK-3 is inactivated through phosphorylation by insulin stimulation through the PI3K/AKT-dependent pathway [27]. Thus, the PI3K/ AKT signaling pathway plays an important role in the modulation of insulin sensitivity and glucose metabolism. "
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    ABSTRACT: Accumulating evidence indicates that chronic treatment with atypical antipsychotics (AAPs) leads to metabolic syndrome (MetS) and cognitive dysfunction. It has been found that patients receiving antipsychotic treatment with MetS have significantly worse cognitive function when compared to those without the MetS, suggesting an intrinsic relationship between MetS and cognitive dysfunction. Thus, investigating the reasons for the side effects induced by AAPs is an important step in the effort to understand the patholophysiology of this condition. The 5-HT2c receptor (5-HT2cR) antagonist properties of AAPs are likely to contribute to AAP-induced MetS. There is crosstalk between phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and 5-HT2cR. PTEN negatively regulates the activity of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, which plays an important role in obesity-induced insulin resistance in peripheral tissue. In the central nervous system, PI3K/AKT signaling modulates synaptic plasticity, a mechanism underlying learning and memory processes. This suggests that PI3K/AKT signaling contributes to both metabolic and cognitive activities. Since PTEN negatively regulates PI3K/AKT signaling and has crosstalk with 5-HT2cR, we hypothesized that the 5-HT2cR antagonism of AAPs may disrupt its crosstalk with PTEN and then trigger the PI3K/AKT signaling, and AAP-induced MetS and cognitive impairments may occur via this analogous signaling pathway.
    Medical Hypotheses 01/2013; 80(4). DOI:10.1016/j.mehy.2013.01.012 · 1.07 Impact Factor
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    • "It has been shown that GSK3 is an essential element of Wnt/beta-catenin pathway, which is involved in the control of gene expression, cell adhesion and cell polarity, and plays major roles in neurodevelopment and in the regulation of neuronal plasticity and cell survival (Grimes and Jope, 2001). GSK3 is constitutively active and regulates the activity of a number of targets including transcriptional factors, enzymes and cytoskeletal proteins (Kockeritz et al., 2006). Converging studies in animal models show an involvement of GSK3 in the regulation of behavior by 5- HT and dopamine (DA), and in the mechanism of action of lithium and serotonergic antidepressants (Gould and Manji, 2005; Beaulieu et al., 2009).The inhibition of GSK3 occurs in the context of the signaling cascades in response to serotonin (5-HT), 5-HT 1 receptor agonists, lithium, and several antidepressants (Beaulieu et al., 2009). "
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    ABSTRACT: The present study examined the antihyperalgesic effect of a specific inhibitor of Glycogen Synthase Kinase 3 (GSK3), AR-A014418, on the partial ligation of the sciatic nerve (PSNL), a neuropathic pain model in mice and investigated some mechanisms of action. AR-A014418 (0.01–1 mg/kg) administered by intraperitoneal route (i.p.) inhibited mechanical hyperalgesia. This action started 30 min after i.p. administration and remained significant up to 2 h. When administered daily for 5 days, AR-A014418 (0.3 mg/kg, i.p.) significantly reduced the mechanical hyperalgesia caused by PSNL. Intraperitoneal (i.p.) treatment with AR-A014418 (0.3 mg/kg) also significantly inhibited cold hyperalgesia induced by PSNL. Pre-administration of PCPA (100 mg/kg, i.p., inhibitor of serotonin synthesis) and AMPT (100 mg/kg, i.p., inhibitor of tyrosine hydroxylase), but not l-arginine (600 mg/kg, i.p., a nitric oxide precursor), significantly reduced the mechanical hyperalgesia elicited by AR-A014418. Furthermore, the administration of AR-A014418 significantly prevented the increase of TNF-α (inhibition of 76 ± 8%) and IL-1β (inhibition of 62 ± 10%), but did not alter lumbar spinal cord IL1-ra and IL-10 levels. Finally, intraperitoneal administration of AR-A014418 did not affect locomotor activity in the open-field test. Taken together, these results provide experimental evidence indicating that AR-A014418 produces marked antihyperalgesic effects in neuropathic pain in mice, possibly due to mechanisms that reduce proinflammatory cytokines, as well as increases in serotonergic and catecholaminergic pathways. The present study suggests that GSK3 may be a novel pharmacological target for the treatment of neuropathic pain and AR-A014418 might be a potential molecule of interest for chronic pain relief.
    Neuroscience 09/2012; 226:411–420. DOI:10.1016/j.neuroscience.2012.09.020 · 3.33 Impact Factor
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    • "Glycogen synthase kinase 3-b (GSK3-b) is an essential element of the Wnt/beta-catenin pathway, which is involved in the control of gene expression, cell behavior, cell adhesion, and cell polarity, and has major roles in neurodevelopment and regulation of neuronal polarity, neuronal plasticity, and cell survival (Grimes and Jope, 2001b). GSK3-b is constitutively active and regulates the activity of many targets, including transcriptional factors, enzymes and cytoskeletal proteins (Kockeritz et al, 2006). GSK3-b is considered a primary regulator in a range of cellular processes, including differentiation, growth, motility, and apoptosis: increasing GSK3 activity increases apoptosis in neuronal cells, whereas inhibiting GSK has neuroprotective effects (Forde and Dale, 2007). "
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    ABSTRACT: Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase 3-β (GSK3-β). The less active GSK3-β promoter gene variants have been associated with less detrimental clinical features of BD. GSK3-β gene variants and lithium can influence brain gray matter structure in psychiatric conditions. Diffusion tensor imaging (DTI) measures of white matter (WM) integrity showed widespred disruption of WM structure in BD. In a sample of 70 patients affected by a major depressive episode in course of BD, we investigated the effect of ongoing long-term lithium treatment and GSK3-β promoter rs334558 polymorphism on WM microstructure, using DTI and tract-based spatial statistics with threshold-free cluster enhancement. We report that the less active GSK3-β rs334558*C gene-promoter variants, and the long-term administration of the GSK3-β inhibitor lithium, were associated with increases of DTI measures of axial diffusivity (AD) in several WM fiber tracts, including corpus callosum, forceps major, anterior and posterior cingulum bundle (bilaterally including its hippocampal part), left superior and inferior longitudinal fasciculus, left inferior fronto-occipital fasciculus, left posterior thalamic radiation, bilateral superior and posterior corona radiata, and bilateral corticospinal tract. AD reflects the integrity of axons and myelin sheaths. We suggest that GSK3-β inhibition and lithium could counteract the detrimental influences of BD on WM structure, with specific benefits resulting from effects on specific WM tracts contributing to the functional integrity of the brain and involving interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections.Neuropsychopharmacology advance online publication, 19 September 2012; doi:10.1038/npp.2012.172.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2012; 38(2). DOI:10.1038/npp.2012.172 · 7.83 Impact Factor
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