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Cited by 196Metabolism, Diabetes, and CancerGlycogen Storage Diseases and MyoclonusProtein Kinase Regulation and GTPase Signaling

Allosteric Regulation of Glycogen Synthase Controls Glycogen Synthesis in Muscle

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Bouskila, Michale, Hunter, Roger W., Ibrahim, Adel F.M., Delattre, Lucie, Peggie, Mark, van Diepen, Janna A., Voshol, Peter J., Jensen, Jørgen +1 more·2010·Cell Metabolism
DOI 10.1016/j.cmet.2010.10.006
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Abstract

Glycogen synthase (GS), a key enzyme in glycogen synthesis, is activated by the allosteric stimulator glucose-6-phosphate (G6P) and by dephosphorylation through inactivation of GS kinase-3 with insulin. The relative importance of these two regulatory mechanisms in controlling GS is not established, mainly due to the complex interplay between multiple phosphorylation sites and allosteric effectors. Here we identify a residue that plays an important role in the allosteric activation of GS by G6P. We generated knockin mice in which wild-type muscle GS was replaced by a mutant that could not be activated by G6P but could still be activated normally by dephosphorylation. We demonstrate that knockin mice expressing the G6P-insensitive mutant display an ∼80% reduced muscle glycogen synthesis by insulin and markedly reduced glycogen levels. Our study provides genetic evidence that allosteric activation of GS is the primary mechanism by which insulin promotes muscle glycogen accumulation in vivo.

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  • Mutation of the G6P allosteric binding site on GS R582 to alanine (GS R582 KI) in mice reduces glycogen synthesis in response to insulin.

    “Mutation of the G6P allosteric binding site on GS R582 to alanine (GS R582 KI) in mice reduces glycogen synthesis in response to insulin, suggesting that the G6P allosteric control of GS is also important in controlling glycogen synthesis [127].”

    From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [127]

  • AMPK activation by AICAR promotes glucose uptake and increases G6P, which can be used for glycogen synthesis or metabolized through glycolysis to produce ATP.

    “Interestingly, AMPK activation by AICAR promotes glucose uptake and increases G6P, which can be used for glycogen synthesis or metabolized through glycolysis to produce ATP [127].”

    From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [127]

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Authors
Bouskila, M., Hunter, R. W., Ibrahim, A. F. M., Delattre, L., Peggie, M., van Diepen, J. A., Voshol, P. J., Jensen, J., & Sakamoto, K.
Affiliations
  • University of Dundee (GB)
  • Leiden University Medical Center (NL)
  • National Institute of Occupational Health (NO)
Corresponding author
Sakamoto, Kei
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2010-11
Volume
12
Issue
5
Pages
456-466
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2010.10.006
OpenAlex
W2003817405
Cited by
196
References
30
Citations by year
2026: 6 · 2025: 9 · 2024: 8 · 2023: 9 · 2022: 16 · 2021: 10 · 2020: 11 · 2019: 14 · 2018: 20 · 2017: 14 · 2016: 14 · 2015: 9 · 2014: 10 · 2013: 15 · 2012: 24
FWCI
5.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
Funders
  • AstraZeneca
  • GlaxoSmithKline
  • Boehringer Ingelheim
  • Medical Research Council
  • Novo Nordisk UK Research Foundation
  • Pfizer
  • Diabetes UK (07/0003529)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
glycogen synthase, allosteric regulation, glucose-6-phosphate, muscle glycogen synthesis, insulin signaling, glycogen synthase kinase-3, dephosphorylation, knock-in mice, glycogen accumulation
MeSH terms
Allosteric Regulation, Animals, Cell Line, Glucose, Glycogen, Glycogen Synthase, Humans, Insulin, Muscles, Mutation, Glucose-6-Phosphate, Mice, Gene Knock-In Techniques

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