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


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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Available from: Norio Ishida, Aug 07, 2015
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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; 12(8). DOI:10.1016/j.celrep.2015.07.037 · 8.36 Impact Factor
    • "In humans, some mutations in clock genes are associated with the sleep-wake cycle. Of note, treatment of bipolar disorder can include lithium which exerts some of its actions via GSK-3beta, a key regulator of the intracellular molecular clock (Iitaka et al. 2005 "
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    ABSTRACT: Psychiatric disorders such as unipolar depression have complex pathologies, which include disruptions in circadian and sleep-wake cycles. At the neurochemical level, psychiatric diseases can also be accompanied by changes in neuromodulator systems such as orexin/hypocretin and the monoamines. Indeed, for decades the monoamine hypothesis of depression has been instrumental in driving discoveries and developments of antidepressant drugs. Recent preclinical and clinical advancement strongly suggests that neuropeptides such as orexin can play an important part in the pathophysiology of depression. Due to the complexity and extensive connectedness of neurobiological systems, understanding the biological causes and mechanisms of psychiatric disorders present major research challenges. In this chapter, we review experimental and computational studies investigating the complex relationship between orexinergic, monoaminergic, circadian oscillators, and sleep-wake neural circuitry. Our main aim is to understand how these physiological systems interact and how alteration in any of these factors can contribute to the behaviours commonly observed in depressive patients. Further, we examine how modelling across different levels of neurobiological organization enables insight into these interactions. We propose that a multiscale systems approach is necessary to understand the complex neurobiological systems whose dysfunctions are the underlying causes of psychiatric disorders. Such an approach could illuminate future treatments.
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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.
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