scholarly journals Insulin-stimulated Phosphorylation of the Protein Phosphatase-1 Striated Muscle Glycogen-targeting Subunit and Activation of Glycogen Synthase

2000 ◽  
Vol 275 (21) ◽  
pp. 15940-15947 ◽  
Author(s):  
Jun Liu ◽  
David L. Brautigan
Keyword(s):  
Muscle Glycogen ◽  
Protein Phosphatase ◽  
Striated Muscle ◽  
Glycogen Synthase ◽  
Protein Phosphatase 1

scholarly journals Disruption of the striated muscle glycogen-targeting subunit of protein phosphatase 1: influence of the genetic background

2007 ◽  
Vol 40 (2) ◽  
pp. 47-59 ◽  
Author(s):  
James Paterson ◽  
Ian R Kelsall ◽  
Patricia T W Cohen
Keyword(s):  
Skeletal Muscle ◽  
Glucose Transport ◽  
Muscle Glycogen ◽  
Protein Phosphatase ◽  
Striated Muscle ◽  
Protein Phosphatase 1 ◽  
Phosphorylase Kinase ◽  
Donor Strain ◽  
Key Factor

A prediabetic phenotype of glucose intolerance, insulin resistance and obesity was observed at ∼12 months of age in mice homozygous for a null allele of the major skeletal muscle glycogen-targeting subunit GM of protein phosphatase 1 (PP1) and derived from a 129/Ola donor strain. In this study, backcrossing of these mice (termed obese mice) onto two different genetic backgrounds gave rise to lean, glucose-tolerant, insulin-sensitive mice (termed lean mice), indicating that at least one variant gene in the 129/Ola background, not present in the C57BL/6 or 129s2/sV background, is required for the development of the prediabetic phenotype of obese mice. Slightly elevated AMP-activated protein kinase α2 activity in the skeletal muscle of lean C57BL/6 mice was also observed to a lesser extent in the obese mice. Normal or slightly raised in vivo glucose transport in lean C57BL/6 mice compared with decreased glucose transport in the obese mice supports the tenet that adequate transport of glucose may be a key factor in preventing the development of the prediabetic phenotype. The pH 6.8/pH 8.6 activity ratio of phosphorylase kinase was increased in lean C57BL/6 mice compared with controls indicating that phosphorylase kinase is an in vivo substrate of PP1-GM.

scholarly journals Identification of the substrate recruitment mechanism of the muscle glycogen protein phosphatase 1 holoenzyme

2018 ◽  
Vol 4 (11) ◽  
pp. eaau6044 ◽  
Author(s):  
Ganesan Senthil Kumar ◽  
Meng S. Choy ◽  
Dorothy M. Koveal ◽  
Michael K. Lorinsky ◽  
Scott P. Lyons ◽  
...  
Keyword(s):  
Muscle Glycogen ◽  
Protein Phosphatase ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Molecular Data ◽  
Protein Phosphatase 1 ◽  
Regulatory Subunit ◽  
Dual Function ◽  
Carbohydrate Binding ◽  
Amino Terminal

Glycogen is the primary storage form of glucose. Glycogen synthesis and breakdown are tightly controlled by glycogen synthase (GYS) and phosphorylase, respectively. The enzyme responsible for dephosphorylating GYS and phosphorylase, which results in their activation (GYS) or inactivation (phosphorylase) to robustly stimulate glycogen synthesis, is protein phosphatase 1 (PP1). However, our understanding of how PP1 recruits these substrates is limited. Here, we show how PP1, together with its muscle glycogen–targeting (GM) regulatory subunit, recruits and selectively dephosphorylates its substrates. Our molecular data reveal that the GM carbohydrate binding module (GMCBM21), which is amino-terminal to the GM PP1 binding domain, has a dual function in directing PP1 substrate specificity: It either directly recruits substrates (i.e., GYS) or recruits them indirectly by localization (via glycogen for phosphorylase). Our data provide the molecular basis for PP1 regulation by GM and reveal how PP1-mediated dephosphorylation is driven by scaffolding-based substrate recruitment.

Regulation of glycogen synthase and protein phosphatase-1 by hexosamines

Diabetes ◽  
1996 ◽  
Vol 45 (3) ◽  
pp. 322-327 ◽  
Author(s):  
E. D. Crook ◽  
D. A. McClain
Keyword(s):  
Protein Phosphatase ◽  
Glycogen Synthase ◽  
Protein Phosphatase 1

scholarly journals N-Acetyl-β-D-glucopyranosylamine 6-phosphate is a specific inhibitor of glycogen-bound protein phosphatase 1

1997 ◽  
Vol 328 (2) ◽  
pp. 695-700 ◽  
Author(s):  
Mary BOARD
Keyword(s):  
Phosphatase Activity ◽  
Protein Phosphatase ◽  
Glycogen Phosphorylase ◽  
Glycogen Synthase ◽  
Specific Inhibitor ◽  
Competitive Inhibitor ◽  
Protein Phosphatase 1 ◽  
P Concentration ◽  
Glucose Analogue ◽  
Stimulation Of

Previous work has shown that the C-1-substituted glucose-analogue N-acetyl-β-D-glucopyranosylamine (1-GlcNAc) is a competitive inhibitor of glycogen phosphorylase (GP) and stimulates the inactivation of this enzyme by GP phosphatase. In addition to its effects on GP, 1-GlcNAc also prevents the glucose-led activation of glycogen synthase (GS) in whole hepatocytes. Such an effect on GS was thought to be due to the formation of 1-GlcNAc-6-P by the action of glucokinase within the hepatocyte [Board, Bollen, Stalmans, Kim, Fleet and Johnson (1995) Biochem. J. 311, 845-852]. To investigate this possibility further, a pure preparation of 1-GlcNAc-6-P was synthesized. The effects of the phosphorylated glucose analogue on the activity of protein phosphatase 1 (PP1), the enzyme responsible for dephosphorylation and activation of GS, are reported. During the present study, 1-GlcNAc-6-P inhibited the activity of the glycogen-bound form of PP1, affecting both the GSb phosphatase and GPa phosphatase activities. A level of 50% inhibition of GSb phosphatase activity was achieved with 85 μM 1-GlcNAc-6-P in the absence of Glc-6-P and with 135 μM in the presence of 10 mM Glc-6-P. At either Glc-6-P concentration, 500 μM 1-GlcNAc-6-P completely inhibited activity. The Glc-6-P stimulation of the GPa phosphatase activity of PP1 was negated by 1-GlcNAc-6-P but there was no inhibition of the basal rate in the absence of Glc-6-P. 1-GlcNAc-6-P inhibition was specific for the glycogen-bound form of PP1 and did not inhibit the GSb phosphatase activity of the cytosolic form of the enzyme. The present work explains our previous observations on the inactivating effects on GS of incubating whole hepatocytes with 1-GlcNAc. These observations have their basis in the inhibition of glycogen-bound PP1 by 1-GlcNAc-6-P. A novel inhibitor of PP1, specific for the glycogen-bound form of the enzyme, is presented.

The level of the glycogen targetting regulatory subunit R5 of protein phosphatase 1 is decreased in the livers of insulin-dependent diabetic rats and starved rats

2001 ◽  
Vol 360 (2) ◽  
pp. 449-459 ◽  
Author(s):  
Gareth J. BROWNE ◽  
Mirela DELIBEGOVIC ◽  
Stefaan KEPPENS ◽  
Willy STALMANS ◽  
Patricia T. W. COHEN
Keyword(s):  
Phosphatase Activity ◽  
Protein Phosphatase ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Diabetic Rats ◽  
Protein Phosphatase 1 ◽  
Regulatory Subunit ◽  
Hepatic Glycogen ◽  
Insulin Dependent ◽  
Insulin Dependent Diabetic

Hepatic glycogen synthesis is impaired in insulin-dependent diabetic rats owing to defective activation of glycogen synthase by glycogen-bound protein phosphatase 1 (PP1). The identification of three glycogen-targetting subunits in liver, GL, R5/PTG and R6, which form complexes with the catalytic subunit of PP1 (PP1c), raises the question of whether some or all of these PP1c complexes are subject to regulation by insulin. In liver lysates of control rats, R5 and R6 complexes with PP1c were found to contribute significantly (16 and 21% respectively) to the phosphorylase phosphatase activity associated with the glycogen-targetting subunits, GL–PP1c accounting for the remainder (63%). In liver lysates of insulin-dependent diabetic and of starved rats, the phosphorylase phosphatase activities of the R5 and GL complexes with PP1c were shown by specific immunoadsorption assays to be substantially decreased, and the levels of R5 and GL were shown by immunoblotting to be much lower than those in control extracts. The phosphorylase phosphatase activity of R6–PP1c and the concentration of R6 protein were unaffected by these treatments. Insulin administration to diabetic rats restored the levels of R5 and GL and their associated activities. The regulation of R5 protein levels by insulin was shown to correspond to changes in the level of the mRNA, as has been found for GL. The in vitro glycogen synthase phosphatase/phosphorylase phosphatase activity ratio of R5-PP1c was lower than that of GL–PP1c, suggesting that R5–PP1c may function as a hepatic phosphorylase phosphatase, whereas GL–PP1c may be the major hepatic glycogen synthase phosphatase. In hepatic lysates, more than half the R6 was present in the glycogen-free supernatant, suggesting that R6 may have lower affinity for glycogen than R5 and GL

Wortmannin inhibits insulin-stimulated activation of protein phosphatase 1 in rat cardiomyocytes

1999 ◽  
Vol 276 (5) ◽  
pp. H1520-H1526 ◽  
Author(s):  
Jane P. de Luca ◽  
Alice K. Garnache ◽  
Jill Rulfs ◽  
Thomas B. Miller
Keyword(s):  
Protein Phosphatase ◽  
Glycogen Synthase ◽  
Protein Phosphatase 1 ◽  
Rat Cardiomyocytes ◽  
Major Function ◽  
Pi3k Inhibitors ◽  
Protein Levels ◽  
Pi3k Activity ◽  
Insulin Dependent ◽  
Phosphatase Activation

A major function of insulin in target tissues is the activation of glycogen synthase. Phosphatidylinositol 3-kinase (PI3K) has been implicated in the insulin-induced activation of glycogen synthase, although the true function of this enzyme remains unclear. Data presented here demonstrate that the PI3K inhibitors wortmannin and LY-294002 block the insulin-stimulated activation of protein phosphatase 1 (PP1) in rat ventricular cardiomyocytes. This loss of phosphatase activation mimics that seen in diabetic cardiomyocytes, in which insulin stimulation fails to activate both PP1 and glycogen synthase. Interestingly, in diabetic cells, insulin stimulated PI3K activity to 300% of that in untreated controls, whereas this activity was increased by only 77% in normal cells. PI3K protein levels, however, were similar in normal and diabetic cells. Our results indicate that PI3K is involved in the stimulation of glycogen synthase activity by insulin through the regulation of PP1. The inability of insulin to stimulate phosphatase activity in diabetic cells, despite a significant increase in PI3K activity, suggests a defect in the insulin signaling pathway that contributes to the pathology of insulin-dependent diabetes.

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