Glycogen Synthesis and Degradation: Hormonal Control

Glycogen Metabolism Regulation

Introduction to Glycogen Metabolism

• Glycogen synthase is the enzyme that catalyzes the rate limiting step during glycogen synthesis.
• Glycogen phosphorylase: Catalyzes the rate limiting step during glycogen degradation or glycogenolysis.

Hormonal Control

• Hormones: insulin, glucagon, and epinephrine regulate glycogen synthesis and degradation.

Insulin

• Insulin: Anabolic hormone that facilitates glucose absorption from the blood into skeletal muscle, adipose tissue, and liver.
• Insulin promotes the synthesis of proteins, triglycerides, nucleic acids, and glycogen.

Cellular Mechanism of Insulin

• Insulin binds to the insulin receptor on hepatocytes and skeletal muscle cells.
• Insulin receptor: A tyrosine kinase transmembrane receptor with two alpha and two beta subunits.
  • Alpha subunits: Extracellular, bind insulin.
  • Beta subunits: Intracellular, contain tyrosine kinase domains.
• Insulin binding: Causes subunit dimerization and activates tyrosine kinase.
• Tyrosine kinase autophosphorylation: Tyrosine kinase phosphorylates tyrosine residues on the insulin receptor.
• IRS-1 activation: Tyrosine kinase activates insulin receptor substrate one (IRS-1) through phosphorylation.
• IRS-1 activates protein phosphatase via an intermediate called PI3K.
• Protein phosphatase activates glycogen synthase by removing a phosphate group (activating it).
• Protein phosphatase inhibits glycogen phosphorylase kinase, inhibiting glycogen phosphorylase and ultimately inhibiting glycogenolysis.
• Overall, insulin promotes glycogenesis and inhibits glycogenolysis.

Other Activating Factors

• Cortisol and Glucose-6-phosphate (G6P) also activate glycogen synthase.
• Cortisol promotes glycogen synthesis in the liver, despite catabolic effects in peripheral tissues.
  • Increases insulin resistance in peripheral tissues, decreasing glucose uptake.
  • This leads to increased blood glucose levels, prompting insulin to direct excess glucose to glycogen synthesis in the liver.
• G6P: High G6P levels indicate abundant glucose, favoring glycogen storage.

Glucagon

• Glucagon: Counteracts insulin.
• Active during fasting, promoting gluconeogenesis and glycogenolysis in the liver.
• Low blood glucose stimulates glucagon release from pancreatic alpha cells.
• Glucagon binds to the glucagon receptor on hepatocytes.
  • Glucagon receptor: G protein-coupled receptor.
  • Binding activates adenylate cyclase, which converts ATP to cAMP.
  • cAMP activates protein kinase A (PKA).

Protein Kinase A Function

• Inactivates glycogen synthase by phosphorylation.
• Activates glycogen phosphorylase kinase by phosphorylation.
• Glycogen phosphorylase kinase activates glycogen phosphorylase, initiating glycogen breakdown.

Epinephrine

• Epinephrine: Produced in response to stress, mobilizing glucose stores for energy; promotes glycogenolysis in the liver and skeletal muscle.
• Epinephrine activates similar pathways to glucagon but binds differently.

Beta Receptors Activation

• Binds to beta receptors on hepatocytes and skeletal muscle, activating the same cAMP/PKA pathway as glucagon.
• PKA activates glycogen phosphorylase kinase, leading to glycogenolysis.

Alpha Receptors Activation

• Binds to alpha receptors on hepatocytes, activating a different pathway.
  • Alpha receptor: Another G protein-coupled receptor.
  • Activates phospholipase C (PLC) instead of adenylate cyclase.
  • PLC converts PIP2 to IP3 and DAG.
  • $PIP<em>2 \rightarrow IP</em>3 + DAG$
  • IP3: Diffuses into the cytosol and binds to IP3 receptors on the endoplasmic reticulum, releasing calcium into the cytosol.
  • Calcium binds to calmodulin, forming the calcium-calmodulin complex.
  • The calcium-calmodulin complex activates glycogen phosphorylase kinase.
  • Glycogen phosphorylase kinase activates glycogen phosphorylase, leading to glycogen breakdown.

AMP Activation

• AMP (Adenosine Monophosphate): Activates glycogen phosphorylase.
• High AMP means low energy availability, signaling the need for more glucose production through glycogenolysis.

Summary

• Glycogen synthase: Rate-limiting enzyme in glycogen synthesis.
• Glycogen phosphorylase: Rate-limiting enzyme in glycogenolysis.
• Insulin, glucagon, and epinephrine regulate these enzymes through signal transduction pathways.
• Insulin promotes glycogen synthesis by activating tyrosine kinase, IRS-1, PI3K, and protein phosphatase.
• Protein phosphatase activates glycogen synthase, inhibiting glycogen phosphorylase kinase.
• Glucagon promotes glycogenolysis by activating adenylate cyclase, cAMP, and protein kinase A.
• Protein kinase A phosphorylates and inactivates glycogen synthase while activating glycogen phosphorylase kinase.
• Epinephrine activates similar pathways to glucagon through beta receptors and activates PLC through alpha receptors, leading to calcium release and activation of glycogen phosphorylase kinase.