Gene Structure and Expression of the Targeting Subunit, RGL, of the Muscle-Specific Glycogen-Associated Type 1 Protein Phosphatase, PP1G

Lannér, Carita; Suzuki, Yôichi; Bi, Chen; Zhang, Hong; Cooper, Lori; Bowker-Kinley, Melissa M.; DePaoli‐Roach, Anna A.

doi:10.1006/abbi.2001.2283

Cited by 19 publications

(20 citation statements)

References 49 publications

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“…The activity towards GS phosphorylated in the site 3 region was decreased by 40% in the homozygotes. Although not as pronounced, reductions in R GL , C1, and phosphatase activity were also observed in heart (data not shown), consistent with the ϳ10-fold-lower level of expression of R GL in this tissue (37,60).…”

Section: Resultssupporting

confidence: 70%

“…R GL , also called G M , was the first glycogen-binding subunit of PP1 identified (59), and the corresponding holoenzyme, PP1G/ R GL , consists of the 124-kDa R GL protein (60) in association with C1. R GL is exclusively expressed in skeletal and cardiac muscle (37,60). The NH 2 -terminal 240 amino acids contain binding sites for glycogen and C1 (64), whereas a hydrophobic region between residues 1063 and 1097 in the COOH terminus anchors the protein to membrane (45,60).…”

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confidence: 99%

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Insulin Control of Glycogen Metabolism in Knockout Mice Lacking the Muscle-Specific Protein Phosphatase PP1G/R_GL

Suzuki

Lannér

Kim

et al. 2001

Molecular and Cellular Biology

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142

160

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The regulatory-targeting subunit (R GL , also called G M ) of the muscle-specific glycogen-associated protein phosphatase PP1G targets the enzyme to glycogen where it modulates the activity of glycogen-metabolizing enzymes. PP1G/R GL has been postulated to play a central role in epinephrine and insulin control of glycogen metabolism via phosphorylation of R GL . To investigate the function of the phosphatase, R GL knockout mice were generated. Animals lacking R GL show no obvious defects. The R GL protein is absent from the skeletal and cardiac muscle of null mutants and present at ϳ50% of the wild-type level in heterozygotes. Both the level and activity of C1 protein are also decreased by ϳ50% in the R GL -deficient mice. In skeletal muscle, the glycogen synthase (GS) activity ratio in the absence and presence of glucose-6-phosphate is reduced from 0.3 in the wild type to 0.1 in the null mutant R GL mice, whereas the phosphorylase activity ratio in the absence and presence of AMP is increased from 0.4 to 0.7. Glycogen accumulation is decreased by ϳ90%. Despite impaired glycogen accumulation in muscle, the animals remain normoglycemic. Glucose tolerance and insulin responsiveness are identical in wild-type and knockout mice, as are basal and insulin-stimulated glucose uptakes in skeletal muscle. Most importantly, insulin activated GS in both wild-type and R GL null mutant mice and stimulated a GS-specific protein phosphatase in both groups. These results demonstrate that R GL is genetically linked to glycogen metabolism, since its loss decreases PP1 and basal GS activities and glycogen accumulation. However, PP1G/R GL is not required for insulin activation of GS in skeletal muscle, and rather another GS-specific phosphatase appears to be involved.In recent years, the generality that the activity of the type 1 serine/threonine protein phosphatases (PP1) is dictated by the associated noncatalytic subunits has emerged. These ancillary proteins are thought to target the catalytic component (C1) to distinct subcellular locales in proximity to substrates, to confer specificity, and to regulate activity (10,21,33,41). To date, more than 30 C1-binding polypeptides have been identified that direct the enzyme to a variety of subcellular structures, including glycogen (6,24,25,49,59,60), myosin (2), ribosomes (31), nuclei (4, 13), and neuronal structures (5). A subset of C1-binding proteins includes inhibitory proteins such as inhibitors 1 and 2 (48, 67) and DARPP-32 (46). Four C1-glycogen-targeting subunits are presently known. R GL , also called G M , was the first glycogen-binding subunit of PP1 identified (59), and the corresponding holoenzyme, PP1G/ R GL , consists of the 124-kDa R GL protein (60) in association with C1. R GL is exclusively expressed in skeletal and cardiac muscle (37, 60). The NH 2 -terminal 240 amino acids contain binding sites for glycogen and C1 (64), whereas a hydrophobic region between residues 1063 and 1097 in the COOH terminus anchors the protein to membrane (45,60). Of the other three glycoge...

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Section: Resultssupporting

confidence: 70%

mentioning

confidence: 99%

Insulin Control of Glycogen Metabolism in Knockout Mice Lacking the Muscle-Specific Protein Phosphatase PP1G/R_GL

Suzuki

Lannér

Kim

et al. 2001

Molecular and Cellular Biology

Self Cite

142

160

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“…Little is known about the metabolic factors that regulate these scaffolding proteins. A recent study suggests that insulin does not regulate RGL protein levels in skeletal muscle (31). Another study shows that PTG mRNA expression can be induced by neurotransmitters such as noradrenaline and vasoactive intestinal peptide in primary culture of mouse cortical astrocytes (2).…”

Section: Discussionmentioning

confidence: 99%

Muscle-Specific Deletion of the Glut4 Glucose Transporter Alters Multiple Regulatory Steps in Glycogen Metabolism

Kim

Peroni

Aschenbach

et al. 2005

Molecular and Cellular Biology

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Mice with muscle-specific knockout of the Glut4 glucose transporter (muscle-G4KO) are insulin resistant and mildly diabetic. Here we show that despite markedly reduced glucose transport in muscle, muscle glycogen content in the fasted state is increased. We sought to determine the mechanism(s). Basal glycogen synthase activity is increased by 34% and glycogen phosphorylase activity is decreased by 17% (P < 0.05) in muscle of muscle-G4KO mice. Contraction-induced glycogen breakdown is normal. The increased glycogen synthase activity occurs in spite of decreased signaling through the insulin receptor substrate 1 (IRS-1)-phosphoinositide (PI) 3-kinase-Akt pathway and increased glycogen synthase kinase 3␤ (GSK3␤) activity in the basal state. Hexokinase II is increased, leading to an approximately twofold increase in glucose-6-phosphate levels. In addition, the levels of two scaffolding proteins that are glycogen-targeting subunits of protein phosphatase 1 (PP1), the muscle-specific regulatory subunit (RGL) and the protein targeting to glycogen (PTG), are strikingly increased by 3.2-to 4.2-fold in muscle of muscle-G4KO mice compared to wild-type mice. The catalytic activity of PP1, which dephosphorylates and activates glycogen synthase, is also increased. This dominates over the GSK3 effects, since glycogen synthase phosphorylation on the GSK3-regulated site is decreased. Thus, the markedly reduced glucose transport in muscle results in increased glycogen synthase activity due to increased hexokinase II, glucose-6-phosphate, and RGL and PTG levels and enhanced PP1 activity. This, combined with decreased glycogen phosphorylase activity, results in increased glycogen content in muscle in the fasted state when glucose transport is reduced.A fundamental action of insulin is to control the plasma glucose concentration by stimulating glucose uptake into muscle and adipose cells and inhibiting hepatic glucose output (13). The stimulatory effect of insulin on glucose transport and glycogen synthesis involves a series of cellular events (26,49). Dysregulation of any of these steps could result in insulin resistance, which is a major risk factor in the development of type 2 diabetes (26,49). The binding of insulin to its receptor generates intracellular signals that stimulate Glut4 translocation. The nature of the signaling intermediates that mediate this process is under intense investigation (57). It is likely that defects in signaling account for resistance to insulin-stimulated glucose transport in muscle in cases of type 2 diabetes (25,42,48).The relative importance of glucose transport compared to that of glycogen synthase activity in regulating the rate of glycogen synthesis has been debated over many years (32,44). Attention has focused on the importance of glucose transporters in determining the rate of glycogen synthesis (22,46). Studies with transgenic mice overexpressing the glucose transporters Glut1 or Glut4 in skeletal muscle support the notion that increasing glucose transport is sufficient to increase glycogen...

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“…For the purpose of conformity, we suggest that the G subunits are differentiated by a capital subscript, which refers to their gene name, except for G M and G L where the subscript refers to the tissues (striated muscle and liver, respectively) where they are expressed most abundantly (Table 2). With the exception of G M and G L , the G subunits are expressed ubiquitously, albeit at variable levels (20,110,215). G L displays a remarkable species-dependent distribution in that it is absent from sketal muscle of rats while it is highly expressed in human skeletal muscle (263).…”

Section: The Mammalian G Subunitsmentioning

confidence: 99%

Functional Diversity of Protein Phosphatase-1, a Cellular Economizer and Reset Button

Ceulemans

Bollen

2004

Physiological Reviews

599

584

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Ceulemans, Hugo, and Mathieu Bollen. Functional Diversity of Protein Phosphatase-1, a Cellular Economizer and Reset Button. Physiol Rev 84: 1–39, 2004; 10.1152/physrev.00013.2003.—The protein serine/threonine phosphatase protein phosphatase-1 (PP1) is a ubiquitous eukaryotic enzyme that regulates a variety of cellular processes through the dephosphorylation of dozens of substrates. This multifunctionality of PP1 relies on its association with a host of function-specific targetting and substrate-specifying proteins. In this review we discuss how PP1 affects the biochemistry and physiology of eukaryotic cells. The picture of PP1 that emerges from this analysis is that of a “green” enzyme that promotes the rational use of energy, the recycling of protein factors, and a reversal of the cell to a basal and/or energy-conserving state. Thus PP1 promotes a shift to the more energy-efficient fuels when nutrients are abundant and stimulates the storage of energy in the form of glycogen. PP1 also enables the relaxation of actomyosin fibers, the return to basal patterns of protein synthesis, and the recycling of transcription and splicing factors. In addition, PP1 plays a key role in the recovery from stress but promotes apoptosis when cells are damaged beyond repair. Furthermore, PP1 downregulates ion pumps and transporters in various tissues and ion channels that are involved in the excitation of neurons. Finally, PP1 promotes the exit from mitosis and maintains cells in the G1or G2phases of the cell cycle.

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Gene Structure and Expression of the Targeting Subunit, RGL, of the Muscle-Specific Glycogen-Associated Type 1 Protein Phosphatase, PP1G

Cited by 19 publications

References 49 publications

Insulin Control of Glycogen Metabolism in Knockout Mice Lacking the Muscle-Specific Protein Phosphatase PP1G/R_GL

Insulin Control of Glycogen Metabolism in Knockout Mice Lacking the Muscle-Specific Protein Phosphatase PP1G/R_GL

Muscle-Specific Deletion of the Glut4 Glucose Transporter Alters Multiple Regulatory Steps in Glycogen Metabolism

Functional Diversity of Protein Phosphatase-1, a Cellular Economizer and Reset Button

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Gene Structure and Expression of the Targeting Subunit, RGL, of the Muscle-Specific Glycogen-Associated Type 1 Protein Phosphatase, PP1G

Cited by 19 publications

References 49 publications

Insulin Control of Glycogen Metabolism in Knockout Mice Lacking the Muscle-Specific Protein Phosphatase PP1G/RGL

Insulin Control of Glycogen Metabolism in Knockout Mice Lacking the Muscle-Specific Protein Phosphatase PP1G/RGL

Muscle-Specific Deletion of the Glut4 Glucose Transporter Alters Multiple Regulatory Steps in Glycogen Metabolism

Functional Diversity of Protein Phosphatase-1, a Cellular Economizer and Reset Button

Contact Info

Product

Resources

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Insulin Control of Glycogen Metabolism in Knockout Mice Lacking the Muscle-Specific Protein Phosphatase PP1G/R_GL

Insulin Control of Glycogen Metabolism in Knockout Mice Lacking the Muscle-Specific Protein Phosphatase PP1G/R_GL