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

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 G(M)(-/-) mice homozygous for a null allele of the major skeletal muscle glycogen targeting subunit (G(M)) of protein phosphatase I (PP1). Hyperphosphorylation of Ser14 in phosphorylase, and Ser7, Ser640 and Ser640/644 of GS, in the skeletal muscle of G(M)(-/-) mice compared with G(M)(+/+) mice indicates that the PP1-G(M) 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 G(M)(-/-) 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 G(M)(-/-) mice indicating that Gm is required for the full response of phosphorylase and GS to adrenaline. PP1-G(M) 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 G(M)(+/+) mice by both kinase activation and PP1-G(M) inhibition and the phosphorylation of GS Ser640 and Ser640/644 by PP1-G(M) inhibition alone. Insulin decreased the phosphorylation of GS Ser-640 and Ser640/644 and stimulated the (IS (-/+G6P) activity ratio by similar to 2-fold in the skeletal muscle of either G(M)(-/-) and or control mice, but the low basal and insulin stimulated GS activity ratios in G(M)(-/-) mice indicate that PP1-G(M) is essential for maintaining normal basal and maximum insulin stimulated GS activity ratios in vivo. (c) 2006 Elsevier Inc. All rights reserved.