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New Insights into the Role of Glycogen Synthase Kinase (GSK) in Health and Diseases

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (15 March 2020) | Viewed by 69643

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Special Issue Editor

Prof. Dr. James Andrew McCubrey

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Guest Editor

Department of Microbiology and Immunology, The Brody School of Medicine, Greenville, NC, USA
Interests: signaling pathways; chemotherapeutic drugs and ionizing radiation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We would like you to submit a manuscript or review article on GSK-3 signaling and human disease.

Glycogen synthase kinase-3 (GSK-3) was isolated originally due to its role in the regulation of glycogen synthase (GS) activity. It was soon discovered that GSK-3 had critical functions in the modulation of many proteins involved in various physiological processes ranging from the regulation of cell growth, metabolism, cancer, and neurology. The activity of the GSK kinase is often aberrantly regulated in various diseases including cancers and brain disorders. Due to the diversity of GSK-3 cellular targets, global inhibition of the kinase may lead to severe side-effects. Thus, a selective modulation of a specific cellular pool of GSK-3 or specific down- or upstream partners of the kinase might provide more efficient therapies. The roles that GSK-3 plays in various diseases, as well as how this pivotal kinase interacts with multiple signaling pathways such as HEDGEHOG, NOTCH, PI3K/PTEN/Akt/mTOR, RAS/RAF/MEK/ERK, TP53, WNT/beta-catenin, and others will be discussed. Mutations that occur in these and other pathways can alter the effects that GSK-3 activity has on regulating these signaling circuits that can lead to various diseases. The roles that microRNAs play in GSK-3 regulation will also be evaluated. Targeting GSK-3 and these other pathways may improve therapy and overcome therapeutic resistance. In this special issue of Cells, manuscripts will discuss various novel aspects concerning the pleiotropic activities of GSK-3 and how they affect human health and disease progression.

Prof. Dr. James Andrew McCubrey
Guest Editor

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Keywords

AKT
beta-Catenin
neurogenerative diseases
cancer
metabolism

Published Papers (12 papers)

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Research

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11 pages, 3248 KiB

Open AccessArticle

Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3β) Improves Systemic Glucose Tolerance with Maintained Heart Function in Established Obesity

by Manisha Gupte, Prachi Umbarkar, Anand Prakash Singh, Qinkun Zhang, Sultan Tousif and Hind Lal

Cells 2020, 9(5), 1120; https://doi.org/10.3390/cells9051120 - 30 Apr 2020

Cited by 7 | Viewed by 3207

Abstract

Obesity is an independent risk factor for cardiovascular diseases (CVD), including heart failure. Thus, there is an urgent need to understand the molecular mechanism of obesity-associated cardiac dysfunction. We recently reported the critical role of cardiomyocyte (CM) Glycogen Synthase Kinase-3 beta (GSK-3β) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3β prior to obesity). In the present study, we investigated the role of CM-GSK-3β in a clinically more relevant model of established obesity (deletion of CM-GSK-3β after established obesity). CM-GSK-3β knockout (GSK-3β^{fl/flCre+/−}) and controls (GSK-3β^{fl/flCre−/−}) mice were subjected to a high-fat diet (HFD) in order to establish obesity. After 12 weeks of HFD treatment, all mice received tamoxifen injections for five consecutive days to delete GSK-3β specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3β knockout (KO) animals exhibited a globally improved glucose tolerance and maintained normal cardiac function. Mechanistically, in stark contrast to the developing obesity model, deleting CM-GSK-3β in obese animals did not adversely affect the GSK-3αS21 phosphorylation (activity) and maintained canonical β-catenin degradation pathway and cardiac function. As several GSK-3 inhibitors are in the trial to treat various chronic conditions, including metabolic diseases, these findings have important clinical implications. Specifically, our results provide critical pre-clinical data regarding the safety of GSK-3 inhibition in obese patients. Full article

(This article belongs to the Special Issue New Insights into the Role of Glycogen Synthase Kinase (GSK) in Health and Diseases)

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15 pages, 2559 KiB

Open AccessArticle

A Unique GSK-3β inhibitor B10 Has a Direct Effect on Aβ, Targets Tau and Metal Dyshomeostasis, and Promotes Neuronal Neurite Outgrowth

by Xiao-Long Shi, Ning Yan, Ying-Jie Cui and Zhao-Peng Liu

Cells 2020, 9(3), 649; https://doi.org/10.3390/cells9030649 - 7 Mar 2020

Cited by 17 | Viewed by 2717

Abstract

Due to the complicated pathogenesis of Alzheimer’s disease (AD), the development of multitargeted agents to simultaneously interfere with multiple pathological processes of AD is a potential choice. Glycogen synthase kinase-3β (GSK-3β) plays a vital role in the AD pathological process. In this study, we discovered a novel 1H-pyrrolo[2,3-b]pyridine derivative B10 as a GSK-3β inhibitor that features with a quinolin-8-ol moiety to target the metal dyshomeostasis of AD. B10 potently inhibited GSK-3β with an IC₅₀ of 66 ± 2.5 nM. At the concentration of 20 μM, B10 increased β-catenin abundance (β-catenin/GAPDH: 0.83 ± 0.086 vs. 0.30 ± 0.016), phosphorylated GSK-3β at Ser9 (p-GSK-3β/GAPDH: 0.53 ± 0.045 vs. 0.35 ± 0.012), and decreased the phosphorylated tau level (p-tau/GAPDH: 0.33 ± 0.065 vs. 0.83 ± 0.061) in SH-SY5Y cells. Unlike other GSK-3β inhibitors, B10 had a direct effect on Aβ by inhibiting Aβ_1-42 aggregation and promoting the Aβ_1-42 aggregate disassociation. It selectively chelated with Cu²⁺, Zn²⁺, Fe^3+, and Al³⁺, and targeted AD metal dyshomeostasis. Moreover, B10 effectively increased the mRNA expression of the recognized neurogenesis markers, GAP43, N-myc, and MAP-2, and promoted the differentiated neuronal neurite outgrowth, possibly through the GSK-3β and β-catenin signal pathways. Therefore, B10 is a potent and unique GSK-3β inhibitor that has a direct on Aβ and serves as a multifunctional anti-AD agent for further investigations. Full article

(This article belongs to the Special Issue New Insights into the Role of Glycogen Synthase Kinase (GSK) in Health and Diseases)

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13 pages, 3792 KiB

Open AccessArticle

Inhibition of GSK3β Reduces Ectopic Lipid Accumulation and Induces Autophagy by The AMPK Pathway in Goat Muscle Satellite Cells

by Linjie Wang, Xin Liu, Siyuan Zhan, Jiazhong Guo, Shizhong Yang, Tao Zhong, Li Li, Hongping Zhang and Yan Wang

Cells 2019, 8(11), 1378; https://doi.org/10.3390/cells8111378 - 1 Nov 2019

Cited by 6 | Viewed by 3103

Abstract

Ectopic lipid accumulation in muscle is important not only for obesity and myopathy treatment, but also for meat quality improvement in farm animals. However, the molecular mechanisms involved in lipid metabolism in muscle satellite cells are still elusive. In this study, SB216763 reduced GSK3β activation by increasing the level of pGSK3β (Ser9) and decreasing the level of total GSK3β protein. GSK3β inhibition decreased lipid accumulation and downregulated the expression level of lipogenesis-related genes in the adipogenic differentiation of goat muscle satellite cells. Furthermore, SB216763 treatment increased the levels of pAMPKα (T172) and pACC (Ser79). Further, we found that GSK3β inhibition promoted levels of LC3B-II and reduced the protein levels of p62 to induce the autophagy in muscle satellite cells. Taken together, our results provide new insight into a critical function for GSK3β: modulating lipid accumulation in goat muscle satellite cells through activating the AMPK pathway. Full article

(This article belongs to the Special Issue New Insights into the Role of Glycogen Synthase Kinase (GSK) in Health and Diseases)

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11 pages, 1309 KiB

Open AccessArticle

A Low-Therapeutic Dose of Lithium Inhibits GSK3 and Enhances Myoblast Fusion in C2C12 Cells

by Nigel Kurgan, Kennedy C. Whitley, Lucas A. Maddalena, Fereshteh Moradi, Joshua Stoikos, Sophie I. Hamstra, Elizabeth A. Rubie, Megha Kumar, Brian D. Roy, James R. Woodgett, Jeffrey A. Stuart and Val A. Fajardo

Cells 2019, 8(11), 1340; https://doi.org/10.3390/cells8111340 - 29 Oct 2019

Cited by 26 | Viewed by 6261

Abstract

Glycogen synthase kinase 3 (GSK3) slows myogenic differentiation and myoblast fusion partly by inhibiting the Wnt/β-catenin signaling pathway. Lithium, a common medication for bipolar disorder, inhibits GSK3 via Mg⁺ competition and increased Ser21 (GSK3α) or Ser9 (GSK3β) phosphorylation, leading to enhanced myoblast fusion and myogenic differentiation. However, previous studies demonstrating the effect of lithium on GSK3 have used concentrations up to 10 mM, which greatly exceeds concentrations measured in the serum of patients being treated for bipolar disorder (0.5–1.2 mM). Here, we determined whether a low-therapeutic (0.5 mM) dose of lithium could promote myoblast fusion and myogenic differentiation in C2C12 cells. C2C12 myotubes differentiated for three days in media containing 0.5 mM lithium chloride (LiCl) had significantly higher GSK3β (ser9) and GSK3α (ser21) phosphorylation compared with control myotubes differentiated in the same media without LiCl (+2–2.5 fold, p < 0.05), a result associated with an increase in total β-catenin. To further demonstrate that 0.5 mM LiCl inhibited GSK3 activity, we also developed a novel GSK3-specific activity assay. Using this enzyme-linked spectrophotometric assay, we showed that 0.5 mM LiCl-treated myotubes had significantly reduced GSK3 activity (−86%, p < 0.001). Correspondingly, 0.5 mM LiCl treated myotubes had a higher myoblast fusion index compared with control (p < 0.001) and significantly higher levels of markers of myogenesis (myogenin, +3-fold, p < 0.001) and myogenic differentiation (myosin heavy chain, +10-fold, p < 0.001). These results indicate that a low-therapeutic dose of LiCl is sufficient to promote myoblast fusion and myogenic differentiation in muscle cells, which has implications for the treatment of several myopathic conditions. Full article

(This article belongs to the Special Issue New Insights into the Role of Glycogen Synthase Kinase (GSK) in Health and Diseases)

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16 pages, 2355 KiB

Open AccessArticle

GSK-3β at the Crossroads in Regulating Protein Synthesis and Lipid Deposition in Zebrafish

by Yaqi Gu, Lili Gao, Qiang Han, Ao Li, Hairui Yu, Dongwu Liu and Qiuxiang Pang

Cells 2019, 8(3), 205; https://doi.org/10.3390/cells8030205 - 28 Feb 2019

Cited by 17 | Viewed by 4155

Abstract

In this study, the mechanism by which GSK-3β regulates protein synthesis and lipid deposition was investigated in zebrafish (Danio rerio). The vector of pEGFP-N1-GSK-3β was constructed and injected into the muscle of zebrafish. It was found that the mRNA and protein expression of tuberous sclerosis complex 2 (TSC2) was significantly increased. However, the mRNA and protein expression of mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase 1 (S6K1), and 4E-binding protein 1 (4EBP1) was significantly decreased by the pEGFP-N1-GSK-3β vector in the muscle of zebrafish. In addition, the mRNA and protein expression of β-catenin, CCAAT/enhancer binding protein α (C/EBPα), and peroxisome proliferators-activated receptor γ (PPARγ) was significantly decreased, but the mRNA expression of fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), ATP-citrate lyase (ACL), and HMG-CoA reductase (HMGCR) was significantly increased by the pEGFP-N1-GSK-3β vector. The activity of FAS, ACC, ACL, and HMGCR as well as the content of triglyceride (TG), total cholesterol (TC), and nonesterified fatty acids (NEFA) were significantly increased by the pEGFP-N1-GSK-3β vector in the muscle of zebrafish. The content of free amino acids Arg, Lys, His, Phe, Leu, Ile, Val, and Thr was significantly decreased by the pEGFP-N1-GSK-3β vector. The results indicate that GSK-3β may participate in regulating protein synthesis via TSC2/mTOR signaling and regulating lipid deposition via β-catenin in the muscle of zebrafish (Danio rerio). Full article

(This article belongs to the Special Issue New Insights into the Role of Glycogen Synthase Kinase (GSK) in Health and Diseases)

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Review

Jump to: Research

26 pages, 585 KiB

Open AccessReview

Glycogen Synthase Kinase-3: A Focal Point for Advancing Pathogenic Inflammation in Depression

by Ryan T. McCallum and Melissa L. Perreault

Cells 2021, 10(9), 2270; https://doi.org/10.3390/cells10092270 - 1 Sep 2021

Cited by 6 | Viewed by 4326

Abstract

Increasing evidence indicates that the host immune response has a monumental role in the etiology of major depressive disorder (MDD), motivating the development of the inflammatory hypothesis of depression. Central to the involvement of chronic inflammation in MDD is a wide range of signaling deficits induced by the excessive secretion of pro-inflammatory cytokines and imbalanced T cell differentiation. Such signaling deficits include the glutamatergic, cholinergic, insulin, and neurotrophin systems, which work in concert to initiate and advance the neuropathology. Fundamental to the communication between such systems is the protein kinase glycogen synthase kinase-3 (GSK-3), a multifaceted protein critically linked to the etiology of MDD and an emerging target to treat pathogenic inflammation. Here, a consolidated overview of the widespread multi-system involvement of GSK-3 in contributing to the neuropathology of MDD will be discussed, with the feed-forward mechanistic links between all major neuronal signaling pathways highlighted. Full article

(This article belongs to the Special Issue New Insights into the Role of Glycogen Synthase Kinase (GSK) in Health and Diseases)

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17 pages, 2495 KiB

Open AccessReview

The Role of GSK-3 in Cancer Immunotherapy: GSK-3 Inhibitors as a New Frontier in Cancer Treatment

by Giuseppa Augello, Maria R. Emma, Antonella Cusimano, Antonina Azzolina, Giuseppe Montalto, James A. McCubrey and Melchiorre Cervello

Cells 2020, 9(6), 1427; https://doi.org/10.3390/cells9061427 - 9 Jun 2020

Cited by 47 | Viewed by 5853

Abstract

The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified because of its key role in the regulation of glycogen synthesis. However, it is now well-established that GSK-3 performs critical functions in many cellular processes, such as apoptosis, tumor growth, cell invasion, and metastasis. Aberrant GSK-3 activity has been associated with many human diseases, including cancer, highlighting its potential therapeutic relevance as a target for anticancer therapy. Recently, newly emerging data have demonstrated the pivotal role of GSK-3 in the anticancer immune response. In the last few years, many GSK-3 inhibitors have been developed, and some are currently being tested in clinical trials. This review will discuss preclinical and initial clinical results with GSK-3β inhibitors, highlighting the potential importance of this target in cancer immunotherapy. As described in this review, GSK-3 inhibitors have been shown to have antitumor activity in a wide range of human cancer cells, and they may also contribute to promoting a more efficacious immune response against tumor target cells, thus showing a double therapeutic advantage. Full article

(This article belongs to the Special Issue New Insights into the Role of Glycogen Synthase Kinase (GSK) in Health and Diseases)

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31 pages, 1100 KiB

Open AccessReview

Glycogen Synthase Kinase 3β in Cancer Biology and Treatment

by Takahiro Domoto, Masahiro Uehara, Dilireba Bolidong and Toshinari Minamoto

Cells 2020, 9(6), 1388; https://doi.org/10.3390/cells9061388 - 3 Jun 2020

Cited by 50 | Viewed by 4770

Abstract

Glycogen synthase kinase (GSK)3β is a multifunctional serine/threonine protein kinase with more than 100 substrates and interacting molecules. GSK3β is normally active in cells and negative regulation of GSK3β activity via phosphorylation of its serine 9 residue is required for most normal cells to maintain homeostasis. Aberrant expression and activity of GSK3β contributes to the pathogenesis and progression of common recalcitrant diseases such as glucose intolerance, neurodegenerative disorders and cancer. Despite recognized roles against several proto-oncoproteins and mediators of the epithelial–mesenchymal transition, deregulated GSK3β also participates in tumor cell survival, evasion of apoptosis, proliferation and invasion, as well as sustaining cancer stemness and inducing therapy resistance. A therapeutic effect from GSK3β inhibition has been demonstrated in 25 different cancer types. Moreover, there is increasing evidence that GSK3β inhibition protects normal cells and tissues from the harmful effects associated with conventional cancer therapies. Here, we review the evidence supporting aberrant GSK3β as a hallmark property of cancer and highlight the beneficial effects of GSK3β inhibition on normal cells and tissues during cancer therapy. The biological rationale for targeting GSK3β in the treatment of cancer is also discussed at length. Full article

(This article belongs to the Special Issue New Insights into the Role of Glycogen Synthase Kinase (GSK) in Health and Diseases)

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28 pages, 3483 KiB

Open AccessFeature PaperReview

Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

by Przemysław Duda, Shaw M. Akula, Stephen L. Abrams, Linda S. Steelman, Alberto M. Martelli, Lucio Cocco, Stefano Ratti, Saverio Candido, Massimo Libra, Giuseppe Montalto, Melchiorre Cervello, Agnieszka Gizak, Dariusz Rakus and James A. McCubrey

Cells 2020, 9(5), 1110; https://doi.org/10.3390/cells9051110 - 30 Apr 2020

Cited by 145 | Viewed by 13606

Abstract

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/β-catenin signaling and β-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-κB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth. Full article

(This article belongs to the Special Issue New Insights into the Role of Glycogen Synthase Kinase (GSK) in Health and Diseases)

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20 pages, 26375 KiB

Open AccessReview

Roles of GSK-3 and β-Catenin in Antiviral Innate Immune Sensing of Nucleic Acids

by Alexandre Marineau, Kashif Aziz Khan and Marc J. Servant

Cells 2020, 9(4), 897; https://doi.org/10.3390/cells9040897 - 7 Apr 2020

Cited by 19 | Viewed by 6795

Abstract

The rapid activation of the type I interferon (IFN) antiviral innate immune response relies on ubiquitously expressed RNA and DNA sensors. Once engaged, these nucleotide-sensing receptors use distinct signaling modules for the rapid and robust activation of mitogen-activated protein kinases (MAPKs), the IκB kinase (IKK) complex, and the IKK-related kinases IKKε and TANK-binding kinase 1 (TBK1), leading to the subsequent activation of the activator protein 1 (AP1), nuclear factor-kappa B (NF-κB), and IFN regulatory factor 3 (IRF3) transcription factors, respectively. They, in turn, induce immunomodulatory genes, allowing for a rapid antiviral cellular response. Unlike the MAPKs, the IKK complex and the IKK-related kinases, ubiquitously expressed glycogen synthase kinase 3 (GSK-3) α and β isoforms are active in unstimulated resting cells and are involved in the constitutive turnover of β-catenin, a transcriptional coactivator involved in cell proliferation, differentiation, and lineage commitment. Interestingly, studies have demonstrated the regulatory roles of both GSK-3 and β-catenin in type I IFN antiviral innate immune response, particularly affecting the activation of IRF3. In this review, we summarize current knowledge on the mechanisms by which GSK-3 and β-catenin control the antiviral innate immune response to RNA and DNA virus infections. Full article

(This article belongs to the Special Issue New Insights into the Role of Glycogen Synthase Kinase (GSK) in Health and Diseases)

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34 pages, 577 KiB

Open AccessReview

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

by Leonie Hoffmeister, Mareike Diekmann, Korbinian Brand and René Huber

Cells 2020, 9(4), 820; https://doi.org/10.3390/cells9040820 - 28 Mar 2020

Cited by 81 | Viewed by 6414

Abstract

GSK3 has been implicated for years in the regulation of inflammation and addressed in a plethora of scientific reports using a variety of experimental (disease) models and approaches. However, the specific role of GSK3 in the inflammatory process is still not fully understood and controversially discussed. Following a detailed overview of structure, function, and various regulatory levels, this review focusses on the immunoregulatory functions of GSK3, including the current knowledge obtained from animal models. Its impact on pro-inflammatory cytokine/chemokine profiles, bacterial/viral infections, and the modulation of associated pro-inflammatory transcriptional and signaling pathways is discussed. Moreover, GSK3 contributes to the resolution of inflammation on multiple levels, e.g., via the regulation of pro-resolving mediators, the clearance of apoptotic immune cells, and tissue repair processes. The influence of GSK3 on the development of different forms of stimulation tolerance is also addressed. Collectively, the role of GSK3 as a kinase balancing the initiation/perpetuation and the amelioration/resolution of inflammation is highlighted. Full article

(This article belongs to the Special Issue New Insights into the Role of Glycogen Synthase Kinase (GSK) in Health and Diseases)

26 pages, 1526 KiB

Open AccessFeature PaperReview

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

by Przemysław Duda, Daria Hajka, Olga Wójcicka, Dariusz Rakus and Agnieszka Gizak

Cells 2020, 9(3), 727; https://doi.org/10.3390/cells9030727 - 16 Mar 2020

Cited by 40 | Viewed by 7687

Abstract

Glycogen synthase kinase 3β (GSK3β), originally described as a negative regulator of glycogen synthesis, is a molecular hub linking numerous signaling pathways in a cell. Specific GSK3β inhibitors have anti-depressant effects and reduce depressive-like behavior in animal models of depression. Therefore, GSK3β is suggested to be engaged in the pathogenesis of major depressive disorder, and to be a target and/or modifier of anti-depressants’ action. In this review, we discuss abnormalities in the activity of GSK3β and its upstream regulators in different brain regions during depressive episodes. Additionally, putative role(s) of GSK3β in the pathogenesis of depression and the influence of anti-depressants on GSK3β activity are discussed. Full article

(This article belongs to the Special Issue New Insights into the Role of Glycogen Synthase Kinase (GSK) in Health and Diseases)

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