scholarly journals Identification of the separate domains in the hepatic glycogen-targeting subunit of protein phosphatase 1 that interact with phosphorylase a, glycogen and protein phosphatase 1

1998 ◽  
Vol 336 (3) ◽  
pp. 699-704 ◽  
Author(s):  
Christopher G. ARMSTRONG ◽  
Martin J. DOHERTY ◽  
Patricia T. W. COHEN
Keyword(s):  
Protein Phosphatase ◽  
Glycogen Synthesis ◽  
Liver Glycogen ◽  
Binding Domain ◽  
Protein Phosphatase 1 ◽  
Hepatic Glycogen ◽  
Storage Site ◽  
C Terminus ◽  
Lysine Residues ◽  
High Affinity Binding Site

Deletion and mutational analyses of the rat liver glycogen-targeting subunit (GL) of protein phosphatase 1 (PP1) have identified three separate domains that are responsible for binding of PP1, glycogen and phosphorylase a. The glycogen-binding domain spans the centre of GL between residues 144 and 231 and appears to be distinct from the glycogen-binding (storage) site of phosphorylase. The regulatory high-affinity binding site for phosphorylase a lies in the 16 amino acids at the C-terminus of GL. The PP1-binding domain is deduced to comprise the -RVXF- motif [Egloff, Johnson, Moorhead, Cohen and Barford (1997) EMBO J. 16, 1876–1887] located at residues 61–64 of GL and preceding lysine residues at positions 56, 57 and 59. A possible approach for increasing glycogen synthesis in certain disorders is discussed.

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

scholarly journals Loss of the hepatic glycogen-binding subunit (GL) of protein phosphatase 1 underlies deficient glycogen synthesis in insulin-dependent diabetic rats and in adrenalectomized starved rats

1998 ◽  
Vol 333 (2) ◽  
pp. 253-257 ◽  
Author(s):  
Martin J. DOHERTY ◽  
Joan CADEFAU ◽  
Willy STALMANS ◽  
Mathieu BOLLEN ◽  
Patricia T. W. COHEN
Keyword(s):  
Protein Phosphatase ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Diabetic Rats ◽  
Catalytic Subunit ◽  
Protein Phosphatase 1 ◽  
Hepatic Glycogen ◽  
Insulin Dependent ◽  
Insulin Dependent Diabetic ◽  
Binding Subunit

Hepatic glycogen synthesis is impaired in insulin-dependent diabetic rats and in adrenalectomized starved rats, and although this is known to be due to defective activation of glycogen synthase by glycogen synthase phosphatase, the underlying molecular mechanism has not been delineated. Glycogen synthase phosphatase comprises the catalytic subunit of protein phosphatase 1 (PP1) complexed with the hepatic glycogen-binding subunit, termed GL. In liver extracts of insulin-dependent diabetic and adrenalectomized starved rats, the level of GL was shown by immunoblotting to be substantially reduced compared with that in control extracts, whereas the level of PP1 catalytic subunit was not affected by these treatments. Insulin administration to diabetic rats restored the level of GL and prolonged administration raised it above the control levels, whereas re-feeding partially restored the GL level in adrenalectomized starved rats. The regulation of GL protein levels by insulin and starvation/feeding was shown to correlate with changes in the level of the GL mRNA, indicating that the long-term regulation of the hepatic glycogen-associated form of PP1 by insulin, and hence the activity of hepatic glycogen synthase, is predominantly mediated through changes in the level of the GL mRNA.

scholarly journals Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis

2017 ◽  
Vol 292 (25) ◽  
pp. 10444-10454 ◽  
Author(s):  
Minal B. Mehta ◽  
Swapnil V. Shewale ◽  
Raymond N. Sequeira ◽  
John S. Millar ◽  
Nicholas J. Hand ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Energy Homeostasis ◽  
Glycogen Synthesis ◽  
Protein Phosphatase 1 ◽  
Regulatory Subunit ◽  
Hepatic Glycogen

scholarly journals Tyr306 near the C-terminus of protein phosphatase-1 affects enzyme stability and inhibitor binding

IUBMB Life ◽  
2011 ◽  
Vol 63 (7) ◽  
pp. 574-581
Author(s):  
Bai J. Wang ◽  
Wei Tang ◽  
Peng Zhang ◽  
Qun Wei
Keyword(s):  
Protein Phosphatase ◽  
Enzyme Stability ◽  
Protein Phosphatase 1 ◽  
Inhibitor Binding ◽  
C Terminus

Plasma glucose concentration determines direct versus indirect liver glycogen synthesis

1986 ◽  
Vol 251 (5) ◽  
pp. E584-E590 ◽  
Author(s):  
C. H. Lang ◽  
G. J. Bagby ◽  
H. L. Blakesley ◽  
J. L. Johnson ◽  
J. J. Spitzer
Keyword(s):  
Plasma Glucose ◽  
Glucose Concentration ◽  
Infusion Rate ◽  
Glycogen Synthesis ◽  
Liver Glycogen ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Hepatic Glycogen ◽  
Glucose Load ◽  
Indirect Pathway

In the present study hepatic glycogenesis by the direct versus indirect pathway was determined as a function of the glucose infusion rate. Glycogen synthesis was examined in catheterized conscious rats that had been fasted 48 h before receiving a 3-h infusion (iv) of glucose. Glucose, containing tracer quantities of [U-14C]- and [6-3H]glucose, was infused at rates ranging from 0 to 230 mumol X min-1 X kg-1. Plasma concentrations of glucose, lactate, and insulin were positively correlated with the glucose infusion rate. Despite large changes in plasma glucose, lactate, and insulin concentrations, the rate of hepatic glycogen deposition (0.46 +/- 0.03 mumol X min-1 X g-1) did not vary significantly between glucose infusion rates of 20 and 230 mumol X min-1 X kg-1. However, the percent contribution of the direct pathway to glycogen repletion gradually increased from 13 +/- 2 to 74 +/- 4% in the lowest to the highest glucose infusion rates, with prevailing plasma glucose concentrations from 9.4 +/- 0.5 to 21.5 +/- 2.1 mM. Endogenous glucose production was depressed (by up to 40%), but not abolished by the glucose infusions. Only a small fraction (7-14%) of the infused glucose load was incorporated into liver glycogen via the direct pathway irrespective of the glucose infusion rate. Our data indicate that the relative contribution of the direct and indirect pathways of hepatic glycogen synthesis are dependent on the glucose load or plasma glucose concentration and emphasize the predominance of the indirect pathway of glycogenesis at plasma glucose concentrations normally observed after feeding.

Amino acid sequence and expression of the hepatic glycogen-binding (GL -subunit of protein phosphatase-1

FEBS Letters ◽  
1995 ◽  
Vol 375 (3) ◽  
pp. 294-298 ◽  
Author(s):  
Martin J. Doherty ◽  
Greg Moorhead ◽  
Nick Morrice ◽  
Philip Cohen ◽  
Patricia T.W. Cohen
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Hepatic Glycogen

Mechanism of delayed hepatic glycogen synthesis after an oral galactose load vs. an oral glucose load in adult rats

1992 ◽  
Vol 263 (1) ◽  
pp. E42-E49 ◽  
Author(s):  
C. B. Niewoehner ◽  
B. Neil
Keyword(s):  
Glucose Concentration ◽  
Glycogen Synthesis ◽  
Liver Glycogen ◽  
Hepatic Glycogen ◽  
Oral Glucose ◽  
Glucose Load ◽  
Adult Rats ◽  
Glycogen Accumulation ◽  
Glucose Administration

We have compared the effects of administration of oral galactose or glucose (1 g/kg) to 24-h fasted rats to examine the mechanism by which galactose regulates its own incorporation into liver glycogen in vivo. Liver glycogen increased to a maximum more slowly after galactose than after glucose administration (0.14 vs. 0.29 mumol.g liver-1.min-1). Glycogen accumulation after the galactose load was 70% of that after the glucose load (149 vs. 214 mumol), and the net increase in liver glycogen represented the same proportion (24 vs. 22%) of added carbohydrate after urinary loss of galactose was accounted for. Slower glycogen accumulation after galactose vs. glucose loading could not be explained by galactosuria, by differences in the active forms of synthase or phosphorylase, by end product (glycogen) inhibition of synthase phosphatase, or by different concentrations of the known allosteric effectors of synthase R plus I and phosphorylase a. Similar increases in glucose 6-phosphate were observed after both hexoses. AMP and ADP increased only transiently after galactose administration, and ATP, UTP, and Pi concentrations were unchanged. The UDP-glucose concentration decreased, whereas the UDP-galactose concentration increased two- to threefold after galactose but not glucose administration. The UDP-glucose pyrophosphorylase reaction is inhibited competitively by UDP-galactose. This could explain the decreased UDP-glucose concentration and the reduced rate of glycogen synthesis after galactose was given.

Hepatic glycogen accurately reflected by acetaminophen glucuronide in dogs refed after fasting

1995 ◽  
Vol 269 (4) ◽  
pp. E766-E773 ◽  
Author(s):  
K. I. Rother ◽  
W. F. Schwenk
Keyword(s):  
Glycogen Synthesis ◽  
Liver Glycogen ◽  
Hepatic Glycogen ◽  
Indirect Pathway ◽  
Isotopic Tracers ◽  
Glucose Flux ◽  
Liver Biopsies ◽  
The Mean ◽  
Acetaminophen Glucuronide ◽  
Group 2

To validate a method to “biochemically biopsy” the immediate precursor of intrahepatic glycogen [uridyl diphosphate (UDP)-glucose] using acetaminophen and to assess how fasting affects the direct and indirect pathways of glycogen synthesis, dogs were fasted overnight (group 1, n = 5) or for 2.5 days (group 2, n = 5) and then given a 4-h duodenal infusion of unlabeled glucose, [3-3H]glucose, and [U-14C]lactate to label hepatic glycogen via the direct and indirect pathways, respectively, and [1-13C]galactose to measure intrahepatic UDP-glucose flux. After 3 h for equilibration, acetaminophen was given and urine was collected for acetaminophen glucuronide. Multiple liver biopsies were obtained. The mean 3H/14C ratios of glucose derived from glycogen (10.4 +/- 4.1 and 1.1 +/- 0.3 for groups 1 and 2, respectively) and glucose derived from acetaminophen glucuronide (11.5 +/- 4.0 and 1.0 +/- 0.1 for groups 1 and 2, respectively) were similar. Fasting significantly increased UDP-glucose flux, the rate of glycogen synthesis, and the contribution of the indirect pathway. We conclude that, in dogs, 1) no functional hepatic zonation exists with regard to acetaminophen glucuronidation and liver glycogen synthesis and 2) with appropriate choice of isotopic tracers and study design, UDP-glucose flux can accurately reflect rates of hepatic glycogen synthesis.

scholarly journals The Inhibitor-1 C Terminus Facilitates Hormonal Regulation of Cellular Protein Phosphatase-1

2004 ◽  
Vol 279 (47) ◽  
pp. 48904-48914 ◽  
Author(s):  
Douglas C. Weiser ◽  
Suzanne Sikes ◽  
Shi Li ◽  
Shirish Shenolikar
Keyword(s):  
Protein Phosphatase ◽  
Hormonal Regulation ◽  
Cellular Protein ◽  
Protein Phosphatase 1 ◽  
C Terminus
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