AMP-activated protein kinase

a sensor of glycogen as well as AMP and ATP?

A. McBride, D. G Hardie

    Research output: Contribution to journalReview article

    82 Citations (Scopus)

    Abstract

    The classical role of the AMP-activated protein kinase (AMPK) is to act as a sensor of the immediate availability of cellular energy, by monitoring the concentrations of AMP and ATP. However, the beta subunits of AMPK contain a glycogen-binding domain, and in this review we develop the hypothesis that this is a regulatory domain that allows AMPK to act as a sensor of the status of cellular reserves of energy in the form of glycogen. We argue that the pool of AMPK that is bound to the glycogen particle is in an active state when glycogen particles are fully synthesized, causing phosphorylation of glycogen synthase at site 2 and providing a feedback inhibition of further extension of the outer chains of glycogen. However, when glycogen becomes depleted, the glycogen-bound pool of AMPK becomes inhibited due to binding to alpha 1 -> 6-linked branch points exposed by the action of phosphorylase and/or debranching enzyme. This allows dephosphorylation of site 2 on glycogen synthase by the glycogen-bound form of protein phosphatase-1, promoting rapid resynthesis of glycogen and replenishment of glycogen stores. This is an extension of the classical role of AMPK as a 'guardian of cellular energy', in which it ensures that cellular energy reserves are adequate for medium-term requirements. The literature concerning AMPK, glycogen structure and glycogen-binding proteins that led us to this concept is reviewed.

    Original languageEnglish
    Pages (from-to)99-113
    Number of pages15
    JournalActa Physiologica
    Volume196
    Issue number1
    DOIs
    Publication statusPublished - May 2009

    Keywords

    • AMP-activated protein kinase
    • energy balance
    • glycogen
    • glycogen synthase
    • glycogen-binding domains
    • laforin
    • RABBIT SKELETAL-MUSCLE
    • DEBRANCHING ENZYME
    • BRANCHING ENZYME
    • AS160 PHOSPHORYLATION
    • SYNTHASE KINASE-3
    • CRYSTAL-STRUCTURE
    • STRUCTURAL BASIS
    • BINDING DOMAIN
    • GAMMA-SUBUNITS
    • IN-VIVO

    Cite this

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    title = "AMP-activated protein kinase: a sensor of glycogen as well as AMP and ATP?",
    abstract = "The classical role of the AMP-activated protein kinase (AMPK) is to act as a sensor of the immediate availability of cellular energy, by monitoring the concentrations of AMP and ATP. However, the beta subunits of AMPK contain a glycogen-binding domain, and in this review we develop the hypothesis that this is a regulatory domain that allows AMPK to act as a sensor of the status of cellular reserves of energy in the form of glycogen. We argue that the pool of AMPK that is bound to the glycogen particle is in an active state when glycogen particles are fully synthesized, causing phosphorylation of glycogen synthase at site 2 and providing a feedback inhibition of further extension of the outer chains of glycogen. However, when glycogen becomes depleted, the glycogen-bound pool of AMPK becomes inhibited due to binding to alpha 1 -> 6-linked branch points exposed by the action of phosphorylase and/or debranching enzyme. This allows dephosphorylation of site 2 on glycogen synthase by the glycogen-bound form of protein phosphatase-1, promoting rapid resynthesis of glycogen and replenishment of glycogen stores. This is an extension of the classical role of AMPK as a 'guardian of cellular energy', in which it ensures that cellular energy reserves are adequate for medium-term requirements. The literature concerning AMPK, glycogen structure and glycogen-binding proteins that led us to this concept is reviewed.",
    keywords = "AMP-activated protein kinase, energy balance, glycogen, glycogen synthase, glycogen-binding domains, laforin, RABBIT SKELETAL-MUSCLE, DEBRANCHING ENZYME, BRANCHING ENZYME, AS160 PHOSPHORYLATION, SYNTHASE KINASE-3, CRYSTAL-STRUCTURE, STRUCTURAL BASIS, BINDING DOMAIN, GAMMA-SUBUNITS, IN-VIVO",
    author = "A. McBride and Hardie, {D. G}",
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    language = "English",
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    AMP-activated protein kinase : a sensor of glycogen as well as AMP and ATP? / McBride, A.; Hardie, D. G.

    In: Acta Physiologica, Vol. 196, No. 1, 05.2009, p. 99-113.

    Research output: Contribution to journalReview article

    TY - JOUR

    T1 - AMP-activated protein kinase

    T2 - a sensor of glycogen as well as AMP and ATP?

    AU - McBride, A.

    AU - Hardie, D. G

    PY - 2009/5

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    N2 - The classical role of the AMP-activated protein kinase (AMPK) is to act as a sensor of the immediate availability of cellular energy, by monitoring the concentrations of AMP and ATP. However, the beta subunits of AMPK contain a glycogen-binding domain, and in this review we develop the hypothesis that this is a regulatory domain that allows AMPK to act as a sensor of the status of cellular reserves of energy in the form of glycogen. We argue that the pool of AMPK that is bound to the glycogen particle is in an active state when glycogen particles are fully synthesized, causing phosphorylation of glycogen synthase at site 2 and providing a feedback inhibition of further extension of the outer chains of glycogen. However, when glycogen becomes depleted, the glycogen-bound pool of AMPK becomes inhibited due to binding to alpha 1 -> 6-linked branch points exposed by the action of phosphorylase and/or debranching enzyme. This allows dephosphorylation of site 2 on glycogen synthase by the glycogen-bound form of protein phosphatase-1, promoting rapid resynthesis of glycogen and replenishment of glycogen stores. This is an extension of the classical role of AMPK as a 'guardian of cellular energy', in which it ensures that cellular energy reserves are adequate for medium-term requirements. The literature concerning AMPK, glycogen structure and glycogen-binding proteins that led us to this concept is reviewed.

    AB - The classical role of the AMP-activated protein kinase (AMPK) is to act as a sensor of the immediate availability of cellular energy, by monitoring the concentrations of AMP and ATP. However, the beta subunits of AMPK contain a glycogen-binding domain, and in this review we develop the hypothesis that this is a regulatory domain that allows AMPK to act as a sensor of the status of cellular reserves of energy in the form of glycogen. We argue that the pool of AMPK that is bound to the glycogen particle is in an active state when glycogen particles are fully synthesized, causing phosphorylation of glycogen synthase at site 2 and providing a feedback inhibition of further extension of the outer chains of glycogen. However, when glycogen becomes depleted, the glycogen-bound pool of AMPK becomes inhibited due to binding to alpha 1 -> 6-linked branch points exposed by the action of phosphorylase and/or debranching enzyme. This allows dephosphorylation of site 2 on glycogen synthase by the glycogen-bound form of protein phosphatase-1, promoting rapid resynthesis of glycogen and replenishment of glycogen stores. This is an extension of the classical role of AMPK as a 'guardian of cellular energy', in which it ensures that cellular energy reserves are adequate for medium-term requirements. The literature concerning AMPK, glycogen structure and glycogen-binding proteins that led us to this concept is reviewed.

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    KW - energy balance

    KW - glycogen

    KW - glycogen synthase

    KW - glycogen-binding domains

    KW - laforin

    KW - RABBIT SKELETAL-MUSCLE

    KW - DEBRANCHING ENZYME

    KW - BRANCHING ENZYME

    KW - AS160 PHOSPHORYLATION

    KW - SYNTHASE KINASE-3

    KW - CRYSTAL-STRUCTURE

    KW - STRUCTURAL BASIS

    KW - BINDING DOMAIN

    KW - GAMMA-SUBUNITS

    KW - IN-VIVO

    U2 - 10.1111/j.1748-1716.2009.01975.x

    DO - 10.1111/j.1748-1716.2009.01975.x

    M3 - Review article

    VL - 196

    SP - 99

    EP - 113

    JO - Acta Physiologica

    JF - Acta Physiologica

    SN - 1748-1708

    IS - 1

    ER -