title: The skeletal muscle-specific glycogen-targeted protein phosphatase 1 plays a major role in the regulation of glycogen metabolism by adrenaline in vivo.
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.
authors.affiliation: Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Toole
authors.forename: Patricia T W
authors.initials: PT
authors.lastname: Cohen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004837:Epinephrine / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D010449:Peptide Mapping; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054645:Protein Phosphatase 1
chemical_list: D007328:Insulin; D006003:Glycogen; D006006:Glycogen Synthase; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D004837:Epinephrine