The skeletal muscle-specific glycogen-targeted protein phosphatase 1 plays a major role in the regulation of glycogen metabolism by adrenaline in vivo

Barry J. Toole, Patricia T. W. Cohen

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    20 Citations (Scopus)

    Abstract

    Adrenaline and insulin are the major hormones regulating glycogen metabolism in skeletal muscle. We have investigated the effects of these hormones on the rate-limiting enzymes of glycogen degradation and synthesis (phosphorylase and glycogen synthase respectively) in GM-/- mice homozygous for a null allele of the major skeletal muscle glycogen targeting subunit (GM) of protein phosphatase 1 (PP1). Hyperphosphorylation of Ser14 in phosphorylase, and Ser7, Ser640 and Ser640/644 of GS, in the skeletal muscle of GM-/- mice compared with GM+/+ mice indicates that the PP1-GM complex is the major phosphatase that dephosphorylates these sites in vivo. Adrenaline caused a 2.4-fold increase in the phosphorylase (-/+AMP) activity ratio in the skeletal muscle of control mice compared to a 1.4 fold increase in GM-/- mice. Adrenaline also elicited a 67% decrease in the GS (-/+G6P) activity ratio in control mice but only a small decrease in the skeletal muscle of GM-/- mice indicating that GM is required for the full response of phosphorylase and GS to adrenaline. PP1-GM activity and the amount of PP1 bound to GM decreased 40% and 45% respectively, in response to adrenaline in control mice. The data support a model in which adrenaline stimulates phosphorylation of phosphorylase Ser14 and GS Ser7 in GM+/+ mice by both kinase activation and PP1-GM inhibition and the phosphorylation of GS Ser640 and Ser640/644 by PP1-GM inhibition alone. Insulin decreased the phosphorylation of GS Ser640 and Ser640/644 and stimulated the GS (-/+G6P) activity ratio by approximately 2-fold in the skeletal muscle of either GM-/- and or control mice, but the low basal and insulin stimulated GS activity ratios in GM-/- mice indicate that PP1-GM is essential for maintaining normal basal and maximum insulin stimulated GS activity ratios in vivo.
    Original languageEnglish
    Pages (from-to)1044-1055
    Number of pages12
    JournalCellular Signalling
    Volume19
    Issue number5
    DOIs
    Publication statusPublished - 2007

    Keywords

    • Amino Acid Sequence
    • Animals
    • Epinephrine
    • Glycogen
    • Glycogen Synthase
    • Insulin
    • Mice
    • Mice, Inbred C57BL
    • Mice, Knockout
    • Molecular Sequence Data
    • Muscle, Skeletal
    • Myocardium
    • Peptide Mapping
    • Phosphoprotein Phosphatases
    • Phosphorylation
    • Protein Phosphatase 1

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