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Inhibition by glucose 6-phosphate of cyclic AMP-dependent protein kinase phosphorylation of glycogen synthase

C Villar-Palasi1

  • 1Department of Pharmacology, Medical School University of Virginia, Charlottesville 22908.

Biochimica Et Biophysica Acta
|July 20, 1994
PubMed

Insights

Glycogen synthase can activate protein kinase A, but glucose 6-phosphate reduces this activation. This explains how insulin may inhibit protein kinase A activity in muscles.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Metabolism

Background:

  • Cyclic AMP-dependent protein kinase (PKA) regulates glycogen metabolism by phosphorylating and inactivating glycogen synthase.
  • Glycogen synthase itself can modulate PKA activity, suggesting complex feedback mechanisms in glucose homeostasis.

Purpose of the Study:

  • To investigate the interaction between glycogen synthase and PKA.
  • To elucidate the role of glucose 6-phosphate in modulating this interaction.
  • To explain the mechanism behind insulin's effect on PKA activity in skeletal muscle.

Main Methods:

  • Enzyme kinetics studies to assess PKA activity.
  • Investigating the effect of glucose 6-phosphate on PKA-glycogen synthase interaction.
  • Analyzing subunit dissociation of PKA.

Main Results:

  • Glycogen synthase can partially activate PKA in the absence of cyclic AMP, likely via subunit dissociation.
  • Glucose 6-phosphate significantly reduces PKA activation by glycogen synthase at physiological concentrations.
  • This reduction is specific to glycogen synthase as a substrate and PKA as the phosphorylating enzyme.

Conclusions:

  • Glucose 6-phosphate acts as a specific modulator, reducing PKA activation by glycogen synthase.
  • This interaction provides a mechanism for the apparent inhibition of PKA by glucose 6-phosphate, mimicking competitive inhibition with cyclic AMP.
  • The findings support the hypothesis that elevated intracellular glucose 6-phosphate, induced by insulin, contributes to the inhibition of PKA in skeletal muscle.

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