In vivo regulation of glycogen synthase kinase 3β activity in neurons and brains

Krishnankutty, Ambika; Kimura, Taeko; Saito, Taro; Aoyagi, Kyota; Asada, Akiko; Takahashi, Shin‐Ichiro; Ando, Kanae; Ohara‐Imaizumi, Mica; Ishiguro, Koichi; Hisanaga, Shin‐ichi

doi:10.1038/s41598-017-09239-5

Cited by 96 publications

(64 citation statements)

References 55 publications

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“…Many competitive inhibitors of GSK3β have been developed to target the catalytic (ATP-binding) site of the kinase in its active form/conformation, and are thus obliged to compete with ATP for binding 33 , 34 . Although GSK3β is often considered to be constitutively active, there is strong evidence that Ser9 phosphorylation induces kinase inactivation and inhibits substrate binding 22 , 35 , 36 , perhaps by favoring the DFG- out (inactive) conformation. Considering that GSK3β has the key DFG regulatory motif in its activation loop, in common with other Ser/Thr kinases, we hypothesized that Ser9 phosphorylation is likely to favor a flip to the inactive conformation, thereby inhibiting substrate binding.…”

Section: Discussionmentioning

confidence: 99%

Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs

Balasubramaniam

Mainali

Kuarm

et al. 2020

Sci Rep

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Glycogen synthase kinase-3β (GSK3β) controls many physiological pathways, and is implicated in many diseases including Alzheimer’s and several cancers. GSK3β-mediated phosphorylation of target residues in microtubule-associated protein tau (MAPTAU) contributes to MAPTAU hyperphosphorylation and subsequent formation of neurofibrillary tangles. Inhibitors of GSK3β protect against Alzheimer’s disease and are therapeutic for several cancers. A thiadiazolidinone drug, TDZD-8, is a non-ATP-competitive inhibitor targeting GSK3β with demonstrated efficacy against multiple diseases. However, no experimental data or models define the binding mode of TDZD-8 with GSK3β, which chiefly reflects our lack of an established inactive conformation for this protein. Here, we used metadynamic simulation to predict the three-dimensional structure of the inactive conformation of GSK3β. Our model predicts that phosphorylation of GSK3β Serine9 would hasten the DFG-flip to an inactive state. Molecular docking and simulation predict the TDZD-8 binding conformation of GSK3β to be inactive, and are consistent with biochemical evidence for the TDZD-8–interacting residues of GSK3β. We also identified the pharmacophore and assessed binding efficacy of second-generation TDZD analogs (TDZD-10 and Tideglusib) that bind GSK3β as non-ATP-competitive inhibitors. Based on these results, the predicted inactive conformation of GSK3β can facilitate the identification of novel GSK3β inhibitors of high potency and specificity.

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Section: Discussionmentioning

confidence: 99%

Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs

Balasubramaniam

Mainali

Kuarm

et al. 2020

Sci Rep

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“…However, we did not detect a significant difference for either isoform in the lithium‐fed group compared with the control group. Notably, phosphorylation is not an accurate indicator of GSK3 activity (Krishnankutty et al., 2017), which is important in the context of lithium treatment because its Ser21 and Ser9 phosphorylation of GSK3α and GSK3β represents only the indirect mode of GSK3 inhibition (Freland & Beaulieu, 2012). Indeed, in vitro work has shown that GSK3βS9A mutants, which cannot be phosphorylated at Ser9, can still be inhibited with lithium treatment (Stambolic, Ruel, & Woodgett, 1996) probably acting through Mg 2+ competition.…”

Section: Discussionmentioning

confidence: 99%

Low‐dose lithium feeding increases the SERCA2a‐to‐phospholamban ratio, improving SERCA function in murine left ventricles

Hamstra

Kurgan

Baranowski

et al. 2020

Experimental Physiology

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The sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) pump is responsible for regulating calcium (Ca 2+ ) within myocytes, with SERCA2a being the dominant isoform in cardiomyocytes.Its inhibitor, phospholamban (PLN), acts by decreasing the affinity of SERCA for Ca 2+ . Changes in the SERCA2a:PLN ratio can cause Ca 2+ dysregulation often seen in patients with dilated cardiomyopathy and heart failure. The enzyme glycogen synthase kinase-3 (GSK3) is known to downregulate SERCA function by decreasing the SERCA2a:PLN ratio. In this study, we sought to determine whether feeding mice low-dose lithium, a natural GSK3 inhibitor, would improve left ventricular SERCA function by altering the SERCA2a:PLN ratio. To this end, male wildtype C57BL/6J mice were fed low-dose lithium via drinking water (10 mg kg −1 day −1 LiCl for 6 weeks) and left ventricles were harvested. GSK3 activity was significantly reduced in LiClfed versus control-fed mice. The apparent affinity of SERCA for Ca 2+ was also increased (pCa 50 ; control, 6.09 ± 0.03 versus LiCl, 6.26 ± 0.04, P < 0.0001) along with a 2.0-fold increase in SERCA2a:PLN ratio in LiCl-fed versus control-fed mice. These findings suggest that low-dose lithium supplementation can improve SERCA function by increasing the SERCA2a:PLN ratio.Future studies in murine preclinical models will determine whether GSK3 inhibition via low-dose lithium could be a potential therapeutic strategy for dilated cardiomyopathy and heart failure. K E Y W O R D Scalcium, cardiac muscle, GSK3, lithium supplementation, phospholamban, SERCA 1 wileyonlinelibrary.com/journal/eph Experimental Physiology. 2020;105:666-675.

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“…In the brain, the insulin signaling pathway plays a significant role in neuronal health as well as synapse formation and maintenance. Significant impairments in this pathway have been documented in both postmortem analysis and animal models of AD [51]. Furthermore, insulin resistance may also contribute to cognitive deficits in AD, seeing that healthy brain insulin signaling has been found to be crucial for learning and memory [43,52].…”

Section: Alzheimer's Disease and Type 2 Diabetes Miletusmentioning

confidence: 99%

Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

Koren-Iton

Salomon-Zimri

Smolar

et al. 2020

IJMS

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Apolipoprotein E (APOE) ε4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer’s disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we employed a model of APOE-targeted replacement mice and high-fat diet (HFD)-induced insulin resistance to investigate diabetic mechanisms associated with apoE4 pathology and the extent to which they are driven by peripheral and central processes. Results obtained revealed an intriguing pattern, in which under basal conditions, apoE4 mice display impaired glucose and insulin tolerance and decreased insulin secretion, as well as cognitive and sensorimotor characteristics relative to apoE3 mice, while the HFD impairs apoE3 mice without significantly affecting apoE4 mice. Measurements of weight and fasting blood glucose levels increased in a time-dependent manner following the HFD, though no effect of genotype was observed. Interestingly, sciatic electrophysiological and skin intra-epidermal nerve fiber density (IENFD) peripheral measurements were not affected by the APOE genotype or HFD, suggesting that the observed sensorimotor and cognitive phenotypes are related to central nervous system processes. Indeed, measurements of hippocampal insulin receptor and glycogen synthase kinase-3β (GSK-3β) activation revealed a pattern similar to that obtained in the behavioral measurements while Akt activation presented a dominant effect of diet. HFD manipulation induced genotype-independent hyperlipidation of apoE, and reduced levels of brain apoE in apoE3 mice, rendering them similar to apoE4 mice, whose brain apoE levels were not affected by the diet. No such effect was observed in the peripheral plasma levels of apoE, suggesting that the pathological effects of apoE4 under the control diet and apoE3 under HFD conditions are related to the decreased levels of brain apoE. Taken together, our data suggests that diabetic mechanisms play an important role in mediating the pathological effects of apoE4 and that consequently, diabetic-related therapy may be useful in treating apoE4 pathology in AD.

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In vivo regulation of glycogen synthase kinase 3β activity in neurons and brains

Cited by 96 publications

References 55 publications

Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs

Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs

Low‐dose lithium feeding increases the SERCA2a‐to‐phospholamban ratio, improving SERCA function in murine left ventricles

Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

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