M2: Regulation of Glycogen Metabolism in Muscle and Liver L8

Question 1

What are the hormone receptors involved in glycogen control?

Answer 1

1. Insulin Receptor Tyrosine Kinase
2. G alpha-s coupled receptors- Adenylate Cyclase Pathway (second messenger cAMP) (beta adrenergic)
3. G alpha-q coupled receptors- Phosphoinositide pathway (second messengers IP3, DAG, Ca2+) (alpha adrenergic)

Question 2

How is glycogen metabolism regulated when insulin binds a tyrosine kinase receptor?

Answer 2

1. When insulin binds, the receptor subunits on the inside of the cell get autophosphorylated on tyrosine residues.
2. A signal cascade causes protein Kinases to get activated.
3. Protein kinase phosphorylates Glycogen synthase kinase (GSK3beta) which inactivates it. It can no longer inhibit glycogen synthase.

Conclusion: Insulin stimulates synthesis of glycogen.
BTW, we also learned that PP1c is activated by insulin. Which adds to this same effect.

Question 3

What hormone binds to the G alpha-s coupled receptors (Beta adrenergic receptors)? and in which body part?

Answer 3

Epinephrine in the muscle and the liver

Question 4

What is the mechanism for beta adrenergic receptors once they are bound by epinephrine (liver and muscle) or for glucagon receptors once they are bound by glucagon (liver)?

Answer 4

1. Hormone binds to its receptor
2. GDP-bound Ga subunit binds GTP
3. GTP-bound Ga dissociates from Gbg subunits
4. GTP-bound Ga activates adenylate cyclase
5. Adenylate cyclase produces cAMP
6. cAMP activates Protein Kinase A
7. Activated PKA triggers a cellular response

Question 5

What type of receptor is a G alpha-q coupled receptor?

Answer 5

Alpha adrenergic receptor (GPCR).

Question 6

What is the mechanism of activation of G alpha-q coupled receptors?

Answer 6

1. Binding of a ligand to its receptor activates phospholipase C (due to regular GPCR cascade), which hydrolyzes PIP2 to IP3 and diacylglycerol (DAG).
2. IP3 stimulates the release of calcium in the endoplasmic reticulum (into cytosol), thereby activating various cellular processes through calmodulin (delta subunit on phosphorylase kinase).
3. DAG activates protein kinase C, which also modulates various cellular processes (inhibits glycogen synthase).

Question 7

What is the hormonal control of glycogen metabolism at stress or upon contraction of a muscle cell?

Answer 7

1) Epinephrine binds Beta adrenergic receptor (G-alpha s)
2) Release of cAMP & muscle contraction increases calcium release from SR.
3) PKA activated by cAMP:
- inhibits Glycogen synthase
- phosphorylates PP1c inhibitor and GM
- activates Phosphorylase kinase
4) Phosphorylase kinase:
- activates Glycogen phosphorylase
- inhibits Glycogen synthase
4) PP1c dissociates from GM and binds to its inhibitor => PP1c is inhibited
5) Glycogen breakdown = ON
Glycogen synthesis = OFF
6) Glucose generated goes through glycolysis

Question 8

What is the hormonal control of glycogen metabolism upon stress of a liver cell?

Answer 8

Stress hormones (epinephrine) bind to their receptor

Alpha adrenergic receptor:
activates PLC => generates IP3 and DAG
IP3 increases Ca2+ => stimulates Phosphorylase kinase which activates glycogen phosphorylase => degradation
DAG activates PKC => PKC inhibits glycogen synthase

Beta adrenergic receptor:
Generates cAMP => Activates PKA
PKA: - Activates Phosphorylase kinase, which activates glycogen phosphorylase => Degradation
- Inhibits Glycogen synthase => inhibits synthesis
- Inhibits PP1c=> inhibits synthesis

Final: Glucose released to blood through GLUT-2 transporter.

Question 9

What is the hormonal control of glycogen metabolism after a meal on a muscle cell?

Answer 9

1) High blood glucose and high insulin
2) Insulin:
- stimulates glucose uptake via GLUT4
- activates insulin-stimulated protein kinase
3) Insulin-stimulated protein kinase:
- activates PP1c through association with GM
4) Active PP1c:
- dephosphorylates Glycogen synthase (activates)
- inactivates Phosphorylase kinase and glycogen phosphorylase (deactivates them).
4) High [G6P] activates Glycogen synthase
4) Inactive Phosphorylase kinase activates
Glycogen synthase (because it can’t phosphorylate it).
5) Glycogen breakdown = OFF
Glycogen synthesis = ON

Question 10

What is the hormonal control of glycogen metabolism after a meal on a liver cell?

Answer 10

1) Insulin:
Inhibits Glycogen synthase kinase (GSK3b)
=> Releases inhibition of Glycogen synthase
=> Activates glycogen synthesis
Glucose:
enters through GLUT 2, binds and inactivates Glycogen phosphorylase

2) Active PP1c:
Dephosphorylates Glycogen synthase
=> releases inhibition of Glycogen synthase
=> activates glycogen synthesis
Inactivates Glycogen phosphorylase
=> stops glycogen breakdown
Inactivates Phosphorylase kinase
=> releases inhibition of Glycogen synthase
=> activates glycogen synthesis

Question 11

What is the hormonal control of glycogen metabolism during low blood glucose on a liver cell?

Answer 11

Glucagon binds to its receptor (G-alpha-s GPCR)
Generates cAMP => Activates PKA
PKA: - Activates Phosphorylase kinase, which activates glycogen phosphorylase => Degradation
- Inhibits Glycogen synthase => inhibits synthesis
- Inhibits PP1c => inhibits synthesis
Glucose released to blood through GLUT 2 transporter.

Question 12

What are the 3 glycogen storage diseases?

Answer 12

1. Von Gierke’s disease (G6P phosphatase liver deficiency)
2. McArdle’s disease (Glycogen phosphorylase muscle deficiency)
3. Hers’ disease (Glycogen phosphorylase liver deficiency)

Question 13

Describe von Gierke’s disease.

Answer 13

G6P phosphatase is deficient in the liver. This causes the accumulation of G6P in the ER lumen downstreamn of glycogen mobilization. This traps G6P which allosterically inhibits glycogen phosphorylase by turning it into its most inactive form (Tb). This impairs glycogen breakdown in the liver.

Result: accumulation of glycogen and inability to increase blood glucose in response to glucagon or epinephrine.

Question 14

What are the symptoms to von Gierke’s disease?

Answer 14

• massive liver enlargement (bc of glycogen storage increase),
• hypoglycemia (low blood sugar) bc you can’t release glucose from glycogen
• failure to thrive

Question 15

What is a treatment for von Gierke’s disease?

Answer 15

1. inhibit glucose uptake by liver

2. increase blood glucose by surgical transpostion of portal vein (portal vein feeds the liver from the intestines).

Question 16

Describe McArdle’s disease.

Answer 16

Individual is deficient in glycogen phosphorylase in the muscle. Glycogen phosphorylase Catalyzes glycogen breakdown to G1P.

Glycogen breakdown is impaired: reduced fuel for glycolysis to keep up with the metabolic demand.

Question 17

What are the symptoms of McArdle’s disease?

Answer 17

Painful cramps during exercise.

Elevated ADP levels during exercise. If patients continue exercise, cramps subside.

Question 18

Describe Hers’ disease.

Answer 18

Individual is deficient in glycogen phosphorylase in the liver. Glycogen phosphorylase Catalyzes glycogen breakdown to G1P.

Glycogen breakdown is impaired in the liver: reduced fuel for glycolysis to keep up with the metabolic demand.

Question 19

What are the symptoms of Hers’ disease?

Answer 19

Symptoms: hypoglycemia due to the fact that glycogen phosphorylase cannot respond to the need for glucose production by the liver.

Question 20

What is the main goal of the cori cycle?

Answer 20

To help prevent lactic acidosis in muscle and helps maintain energy during exercise.

Question 21

Describe what is happening in the cori cycle when a person is exercising?

Answer 21

1. In the muscle during exercise glycogen is broken down to maintain high levels of ATP. Glycolysis results in the reduction of NAD+ to NADH. If NADH levels in the cytosol build up, that will feedback and inhibit glycolysis. So the way you can maintain glycolytic rate, is you have to remove NADH. The cell does this by reducing pyruvate to make lactate. When you produce lactate from pyruvate, electrons from NADH get put onto pyruvate and you make NAD+. This allows glycolysis to continue.
2. You don’t want lactate to build up in muscles bc it could cause cramps and burning in muscles when exercising. So cori cycle allows lactate to be released to blood and lactate is turned into glucose through gluconeogenesis in the liver. The glucose can be exported into blood by Glut-2, then be taken in by the muscle.
3. Cycle restarts.