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Protein Phosphorylation and the Control of Glycogen Metabolism in Skeletal Muscle [and Discussion]
P. Cohen and T. Goldstone
Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
Vol. 302, No. 1108, Biological Roles of Protein Phosphorylation (Jul. 5, 1983), pp. 13-25
Published by: Royal Society
Stable URL: http://www.jstor.org/stable/2396038
Page Count: 13
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Glycogen metabolism in mammalian skeletal muscle is controlled by a regulatory network in which six protein kinases, four protein phosphatases and several thermostable regulatory proteins determine the activation state of glycogen phosphorylase and glycogen synthase, the rate-limiting enzymes of this process. Thirteen phosphorylation sites are involved, twelve of which have been isolated and sequenced and shown to be phosphorylated in vivo. The effects of adrenalin and insulin on the state of phosphorylation of each site have been determined. The neural control of glycogen metabolism is mediated by calcium ions and involves phosphorylase kinase, and a specific calmodulin-dependent glycogen synthase kinase. The β-adrenergic control of the system is mediated by cyclic AMP, and involves the phosphorylation of phosphorylase kinase, glycogen synthase and inhibitor 1 by cyclic-AMP-dependent protein kinase. Inhibitor 1 is a specific inhibitor of protein phosphatase 1, the major phosphatase involved in the control of glycogen metabolism. The stimulation of glycogen synthesis by insulin results from the dephosphorylation of glycogen synthase at sites (3a + 3b + 3c), which are introduced by the enzyme glycogen synthase kinase 3. The structure, regulation and substrate specificities of the protein phosphatases involved in glycogen metabolism are reviewed. Protein phosphatase 1 can exist in an inactive form termed the Mg-ATP-dependent protein phosphatase, which consists of a complex between the catalytic subunit and a thermostable protein termed inhibitor 2. Activation of this complex is catalysed by glycogen synthase kinase 3. It involves the phosphorylation of inhibitor 2 and its dissociation from the catalytic subunit. Protein phosphatase 2A can be resolved into three forms by ion exchange chromatography. These species contain the same catalytic subunit and other subunits that may have a regulatory function. Protein phosphatase 2B is a Ca2+-dependent enzyme composed of two subunits, A and B. Its activity is increased tenfold by calmodulin, which interacts with the A-subunit. The B-subunit is a Ca2+-binding protein that is homologous with calmodulin. Its N-terminus contains the unusual myristyl blocking group, only found previously in the catalytic subunit of cyclic-AMP-dependent protein kinase. Protein phosphatase 2C is a Mg2+-dependent enzyme that accounts for a very small proportion of the glycogen synthase phosphatase activity in skeletal muscle. It is likely to be involved in the regulation of other metabolic processes in vivo such as cholesterol synthesis. Recent evidence suggests that many of the proteins involved in the control of glycogen metabolism have much wider roles, and that they participate in the neural and hormonal regulation of a variety of intracellular processes.
Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences © 1983 Royal Society