The Glycogen-Binding Domain on the AMPK β Subunit Allows the Kinase to Act as a Glycogen Sensor
Open accessAbstract
AMPK beta subunits contain a conserved domain that causes association with glycogen. Although glycogen availability is known to affect AMPK regulation in vivo, the molecular mechanism for this has not been clear. We now show that AMPK is inhibited by glycogen, particularly preparations with high branching content. We synthesized a series of branched oligosaccharides and show that those with a single alpha1-->6 branch are allosteric inhibitors that also inhibit phosphorylation by upstream kinases. Removal of the outer chains of glycogen using phosphorylase, thus exposing the outer branches, renders inhibition of AMPK more potent. Inhibition by all carbohydrates tested was dependent on the glycogen-binding domain being abolished by mutation of residues required for carbohydrate binding. Our results suggest the hypothesis that AMPK, as well as monitoring immediate energy availability by sensing AMP/ATP, may also be able to sense the status of cellular energy reserves in the form of glycogen.
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Deliberately withholding CHO after a high quality training session may benefit by minimizing glycogen restoration and extending the period during which adaptive responses are elevated.
“there may even be benefits from deliberately withholding CHO after a high quality training session to minimise glycogen restoration and extend the period during which adaptive responses are elevated (65).”
From Postexercise muscle glycogen resynthesis in humans. (2017) · cites this paper as [65]
The Introduction and Discussion (pages unavailable) link muscle glycogen levels to AMPK regulation and propose that glycogen depletion may make AMPK available to act on downstream targets. They do not assess withholding carbohydrate after training or show that it extends elevated adaptive responses, so the proposed benefit goes beyond the paper's findings. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAMPK can be activated by low glycogen.
“AMPK can be activated by low glycogen [66]”
From Using Molecular Biology to Maximize Concurrent Training (2014) · cites this paper as [66]
When glycogen is depleted, AMPK is more active.
“These data suggest that when glycogen is depleted AMPK is more active.”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [20]
AMPK has the capacity to be modulated by the glycogen storage status of a cell; the β-subunit of AMPK binds to specific branch points on glycogen, inhibiting the enzyme and preventing it from being phosphorylated by upstream kinases.
“In addition to being a direct AMP:ATP ratio sensor, AMPK also has the capacity to be modulated by the glycogen storage status of a cell [20].The β-subunit of AMPK binds to specific branch points on glycogen inhibiting the enzyme and preventing it from being phosphorylated by upstream kinases [20].”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [20]
Mutations in the CBM prevent glycogen binding and reduce total AMPK activity in cell-free assays and in vivo.
“Recently, mutations in the CBM have been shown to prevent glycogen binding and reduce total AMPK activity in cell-free assays [130] and in vivo [131].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [130]
Glycogen can inhibit AMPK, suggesting that AMPK may regulate cellular energy status through glycogen sensing.
“Glycogen can also inhibit AMPK, suggesting that AMPK may regulate cellular energy status through glycogen sensing [130].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [130]
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- Authors
- McBride, A., Ghilagaber, S., Nikolaev, A., & Hardie, D. G.
- Affiliations
- University of Dundee (GB)
- Corresponding author
- Hardie, D. Grahame
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 9
- Issue
- 1
- Pages
- 23-34
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC2642990
- OpenAlex
- W2123429601
- Cited by
- 432
- References
- 40
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 14 · 2023: 19 · 2022: 18 · 2021: 23 · 2020: 22 · 2019: 19 · 2018: 31 · 2017: 21 · 2016: 28 · 2015: 31 · 2014: 27 · 2013: 28 · 2012: 36
- FWCI
- 16.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Merck KGaA
- Wellcome Trust
- European Commission (LSHMCT-2004-005272)
- 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 › Biochemical and Molecular Research
- Keywords
- AMPK, allosteric inhibition, branched oligosaccharides, phosphorylase, energy reserves, kinase regulation, carbohydrate binding
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Allosteric Regulation, Amino Acid Sequence, Animals, Binding Sites, Cattle, Energy Metabolism, Glycogen, Glycogen Synthase, Molecular Sequence Data, Mutation, Oligosaccharides, Phosphorylation, Mutagenesis, Site-Directed, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Rats, Calcium-Calmodulin-Dependent Protein Kinase Kinase, AMP-Activated Protein Kinases
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