U01.01.123 Glycogen regulation by insulin and glucagon/epinephrine

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Learning Objectives

  • Explain the reciprocal regulation of Glycogen Synthase and Glycogen Phosphorylase.
  • Differentiate between the signaling pathways of Glucagon, Epinephrine, and Insulin.
  • Identify the role of Calcium-Calmodulin in muscle glycogenolysis during contraction.
  • Understand the importance of Protein Phosphatase-1 in the fed state.

1. Hormonal Control of Glycogen

Glycogen metabolism is tightly regulated to ensure that the body either stores energy (fed state) or releases glucose (fasted/stress state).

  • The Fasted State (Glucagon/Epinephrine):
    • Glucagon (liver) and Epinephrine (liver/muscle) bind to G-protein-coupled receptors, increasing cAMP.
    • cAMP activates Protein Kinase A (PKA).
    • PKA phosphorylates enzymes. In glycogen metabolism, Phosphorylation = Activation of Breakdown and Inhibition of Synthesis.
  • The Fed State (Insulin):
    • Insulin binds to its Tyrosine Kinase receptor.
    • This activates Protein Phosphatase-1 (PP1).
    • PP1 dephosphorylates enzymes. Dephosphorylation = Activation of Synthesis and Inhibition of Breakdown.

2. The Glycogen “Switch.”

Regulation occurs through two key enzymes that act like a see-saw. They are never fully active at the same time.

Enzyme State Effect of Phosphorylation
Glycogen Synthase Synthesis Inactivated (Glycogenesis ↓)
Glycogen Phosphorylase Breakdown Activated (Glycogenolysis ↑)

Activity

Memory Hook: Phosphorylation by PKA Pull apart (breaks down) glycogen.

3. Muscle-Specific Regulation

Muscles do not respond to glucagon; they respond to local signals to ensure energy is available during exercise.

  • Calcium-Calmodulin: During muscle contraction, $Ca^{2+}$ is released from the sarcoplasmic reticulum. $Ca^{2+}$ binds to calmodulin, which directly activates Glycogen Phosphorylase Kinase without needing cAMP or PKA.
  • AMP: In extreme exercise, ↑ AMP levels directly activate Glycogen Phosphorylase.

Activity

Clinical Notes & Corrections:

  • Liver vs. Muscle: Remember that Glucagon does not affect muscle glycogen because muscles lack glucagon receptors. Epinephrine, however, works on both.
  • Epinephrine (Liver): In the liver, Epinephrine can act via α-1 receptors to increase intracellular Ca^{2+}, providing a second pathway for glycogenolysis alongside the β-receptor/cAMP pathway.

Activity