Article

A Role for Glycogen Synthase Kinase-3 in the Mammalian Circadian Clock

Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki, Japan
Journal of Biological Chemistry (Impact Factor: 4.57). 09/2005; 280(33):29397-402. DOI: 10.1074/jbc.M503526200
Source: PubMed

ABSTRACT The Drosophila shaggy gene product is a mammalian glycogen synthase kinase-3β (GSK-3β) homologue that contributes to the circadian clock of the
Drosophila through TIMELESS phosphorylation, and it regulates nuclear translocation of the PERIOD/TIMELESS heterodimer. We found that
mammalian GSK-3β is expressed in the suprachiasmatic nucleus and liver of mice and that GSK-3β phosphorylation exhibits robust
circadian oscillation. Rhythmic GSK-3β phosphorylation is also observed in serum-shocked NIH3T3 cells. Exposing serum-shocked
NIH3T3 cells to lithium chloride, a specific inhibitor of GSK-3β, increases GSK-3β phosphorylation and delays the phase of
rhythmic clock gene expression. On the other hand, GSK-3β overexpression advances the phase of clock gene expression. We also
found that GSK-3β interacts with PERIOD2 (PER2) in vitro and in vivo. Recombinant GSK-3β can phosphorylate PER2 in vitro. GSK-3β promotes the nuclear translocation of PER2 in COS1 cells. The present data suggest that GSK-3β plays important roles
in mammalian circadian clock.

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    • "H89 had modest effects on the distribution of V5-PER2, whereas U0126 promoted cytoplasmic retention only upon grk2 knockdown (Figures 6F and 6G). In keeping with a well-documented role of GSK3b in PER2 localization (Iitaka et al., 2005), LiCl triggered robust cytoplasmic retention in both grk2 siRNA-and NC siRNA-transfected cultures (Figures 6F and 6G). CK1d/ε inhibition evoked similar effects on GRK2-dependent V5-PER1 and V5-PER2 subcellular localization in vitro. "
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    ABSTRACT: The pacemaker properties of the suprachiasmatic nucleus (SCN) circadian clock are shaped by mechanisms that influence the expression and behavior of clock proteins. Here, we reveal that G-protein-coupled receptor kinase 2 (GRK2) modulates the period, amplitude, and entrainment characteristics of the SCN. Grk2-deficient mice show phase-dependent alterations in light-induced entrainment, slower recovery from jetlag, and longer behavioral rhythms. Grk2 ablation perturbs intrinsic rhythmic properties of the SCN, increasing amplitude and decreasing period. At the cellular level, GRK2 suppresses the transcription of the mPeriod1 gene and the trafficking of PERIOD1 and PERIOD2 proteins to the nucleus. Moreover, GRK2 can physically interact with PERIOD1/2 and promote PERIOD2 phosphorylation at Ser545, effects that may underlie its ability to regulate PERIOD1/2 trafficking. Together, our findings identify GRK2 as an important modulator of circadian clock speed, amplitude, and entrainment by controlling PERIOD at the transcriptional and post-translational levels. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 08/2015; DOI:10.1016/j.celrep.2015.07.037 · 8.36 Impact Factor
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    • "(iii) The serine-phosphorylation status of GSK3 is probably most often undergoing oscillations. These may be rapid, such as in depolarizing–repolarizing neurons, or slower, such as changes associated with varying levels of circulating hormones that regulate GSK3 (discussed in Section 3.2) or associated with the circadian rhythm in the suprachiasmatic nucleus and liver of mice, as well as in cultured cells (Iitaka et al., 2005). These fluctuations may influence the basal level of GSK3 phosphorylation and responsiveness to interventions depending on the time scales of the fluctuations and experimental manipulations. "
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    ABSTRACT: Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders.
    Pharmacology [?] Therapeutics 11/2014; 148. DOI:10.1016/j.pharmthera.2014.11.016 · 7.75 Impact Factor
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    • "The inhibition of GSK-3β by lithium has been discovered nearly two decades ago (Stambolic et al. 1996). From a bipolar disorder perspective, the most important function of GSK-3β may be its role in synaptic plasticity, apoptosis, and the circadian cycle (Bradley et al. 2012; Iitaka et al. 2005). Therefore, the effect on GSK-3β could be responsible for lithium's therapeutic action in bipolar illness, including neuroprotection and circadian regulation (Gould and Manji 2005). "
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    ABSTRACT: Background Most bipolar patients experience a reduction in urinary concentrating ability within a few weeks of starting lithium treatment. This phenomenon may be connected with the effect of lithium on the glycogen synthase kinase-3beta (GSK-3β) present in the renal tubules. The GSK-3β gene is located on chromosome 3q13 and possesses a functional -50 C/T polymorphism. In the present study, we estimated this polymorphism in a group of long-term lithium-treated patients and assessed its association with various parameters of kidney function, including novel markers of kidney injury such as serum neutrophil gelatinase-associated lipocalin (NGAL) and urinary beta2-microglobulin (β2-MG). Methods The study comprised 78 patients with bipolar mood disorder (25 males, 53 females), aged 36 to 82 (60 ± 11) years. The mean duration of bipolar illness was 6 to 50 (24 ± 10) years, and the patients have been receiving lithium for 5 to 38 (16 ± 9) years. All the patients had the following features, regarded as the phenotypes of kidney functions measured: urine examination for specific gravity evaluation, serum creatinine concentration, and estimated glomerular filtration rate (eGFR) evaluation, as well as the serum concentrations of NGAL and urinary β2-MG. Genotyping of GSK-3β gene -50 C/T polymorphism was done by polymerase chain reaction analysis. Results and discussion Thirty-four patients (6 males, 28 females) had the T/T genotype, 37 patients (16 males, 21 females) had the T/C genotype, and 7 patients (3 males, 4 females) had the C/C genotype. Patients homozygous for C allele had significantly higher urine specific gravities (1.019 ± 0.008) compared to the remaining genotypes (1.013 ± 0.007) (p = 0.035), with no influence of the duration of lithium treatment. Other parameters of kidney function (serum creatinine, eGFR, serum NGAL, and urinary β2-MG levels) were not different between genotypes and, again, were not affected by the duration of lithium treatment. There was no correlation between urine specific gravity and other kidney function parameters. The results of our study indicate that the GSK-3β genotype may be connected with lithium-induced impairment of renal concentrating ability in long-term lithium-treated bipolar patients. Limitations of the study include small size of the sample, small number of C/C genotype patients, and a lack of multiple testing analysis of genotypic differences in various measures of kidney function.
    06/2013; 1(1). DOI:10.1186/2194-7511-1-8
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