Lecture 4: Coordinated Regulation of Glycogen Synthesis and Breakdown

Question 1

How is glycogen metabolism regulated?

Answer 1

The glycogen metabolism is regulated at covalent modifications of glycogen synthase and glycogen phosphorylase involving the phosphorylation and dephosphorylation of these enzymes. This occurs when the receptors for certain hormones are activated by hormones binding to their cognate receptor, and elicit so-called signal transduction cascades.

• These cascades modify many aspects of cell behaviour and function – often through eliciting phosphorylation and dephosphorylation of protein targets that can be metabolic enzymes.

Question 2

What stimulates glycogen synthesis and breakdown?

Answer 2

• Breakdown → epinephrine & glucagon
• Synthesis → insulin

Question 3

Glycogen breakdown hormones response?

Answer 3

• epinephrine → response to stress
• glucagon → response to fasting

Question 4

Steps of signal transduction effects on glycogen breakdown

Answer 4

1. Catabolic hormones (1st messenger) acts on cognate receptors.
2. This elicits the production of cyclic AMP (2nd messenger).
3. Cyclic AMP allosterically stimulates protein kinase A (PKA).
4. PKA phosphorylates (non-phosphorylated) phosphorylase kinase.
5. Phosphorylated phosphorylase kinase is active and goes on to phosphorylate (non-phosphorylated, inactive) glycogen phosphorylase making it phosphorylated and active/
6. Active glycogen phosphorylase is next ready to breakdown glycogen.

Question 5

Role of glucagon

Answer 5

Glucagon is released when there is not enough glucose and binds to receptors found on the liver to elicit response to make more glucose

• Stimulates glycogenolysis and gluconeogenesis
• glucagon receptors NOT found on muscle cells

Question 6

How is signal transduction of glycogen an amplification cascade?

Answer 6

One hormone acts on the receptor which causes a change inside the cell that creates a cascade of many changes

Question 7

Difference in carbohydrate metabolism in liver and muscle

Answer 7

• Muscle has a receptor for epinephrine, but it has no receptor for glucagon.
  
  • sensitive to stress but not to glucose levels outside of cell
• The liver can respond to both epinephrine and glucagon.
  
  • sensitive to stress and glucose concentration outside of the cell

Question 8

Response of liver to glucagon

Answer 8

In response to glucagon, the liver makes cAMP that activates cAMP- dependent protein kinase (PKA)-mediated phosphorylation of:

• Pyruvate kinase, which inhibits glycolysis.
• Phosphorylase kinase which activates glycogen phosphorylase and stimulates glycogen breakdown.

Question 9

What happens when blood glucagon levels are high?

Answer 9

glycolysis is decreased → fatigue.

• in uncontrolled diabetes and fasting/starvation

Question 10

Effects of epinephrine and glucagon on glycogenolysis, glycolysis and gluconeogenesis

Answer 10

deduced by first principles: a set of propositions that are consistent with one another

Question 11

What happens when muscle returns to rest after glycogen breakdown?

Answer 11

When the muscle returns to rest, phosphoprotein phosphatase-1 (PP1) removes the phosphoryl groups on phosphorylase kinase and active glycogen phosphorylase, thus slowing down glycogen synthesis.

Question 12

Mechanisms of insulin on glycogen synthesis

Answer 12

Insulin elicits two complementary mechanisms:

1. dephosphorylation of phosphorylated glycogen synthase.
2. phosphorylation of glycogen synthase kinase.

Question 13

Mechanism of insulin on glycogen synthesis

Answer 13

When blood glucose levels are high, insulin signaling stimulates glycogen synthesis.

• Through eliciting a signaling cascade leading to the phosphorylation and deactivation of GSK-3.
• In parallel, insulin activates a protein phosphatase (PP1) which then dephosphorylates and re-activates glycogen synthase.

Question 14

Muscle vs. liver response to insulin

Answer 14

• In response to insulin, muscle GLUT4 translocates to the muscle cell membrane and blood glucose is taken up by muscle → high affinity for glucose (GLUT4 has a Kt = 5 mM).
• Liver expresses GLUT2, which is low affinity for glucose (GLUT2 has a Kt = 66 mM). So, the liver does not takes up glucose from blood unless blood [glucose] is > 66 mM.

This means that the liver does not normally compete with muscle for blood glucose. Rather, the liver makes glucose by gluconeogenesis which is released to the blood once its intrahepatic concentration reaches 66 mM. The release of glucose from the liver increases the concentration of blood glucose, which is taken up by muscle and other tissues as soon as it reaches between 1 and 5 mM

Question 15

Cascade of high blood glucose

Answer 15

Question 16

Cascade of low blood glucose

Answer 16