2.4.5. Glycogen III Flashcards
Regulation of glycogen degradation
Hormones that use 3’,5’-cyclic AMP (cAMP) as a second messenger stimulate a mechanism, resulting in the phosphorylation of enzymes
Glycogen degradation is stimulated, and synthesis is inhibited when the enzymes of glycogen metabolism are phosphorylated
Action of Glucagon and Epinephrine
Glucagon acts on liver cells and epinephrine (adrenaline) acts on both liver and muscle cells to stimulate glycogen degradation
These hormones via G-proteins activate adenylate cyclase (aka adenyl or adenylyl cyclase) in the cell membrane, which converts ATP to cAMP
Action of cAMP
cAMP activates protein kinase A, which consists of two regulatory and two catalytic subunits
cAMP binds to the regulatory (inhibitory) subunits, releasing the catalytic subunits in an active form
Action of protein kinase A
Phosphorylates glycogen synthase, causing it to be less active, thus decreasing the glycogen synthesis
Phosphorylates “phosphorylase kinase” which phosphorylates “phosphorylase b,” converting it to its active form “phosphorylase a”
Action of phosphorylase a
cleaves glucose residues from the nonreducing ends of glycogen chains, producing G1P, which is oxidized or, in the liver, converted to blood glucose
The cAMP cascade
The cAMP-activated process is a cascade in which the initial hormonal signal is amplified many times:
- One hormone molecules, by activating the enzyme adenylate cyclase, produces many molecules of cAMP, which activate protein kinase A
- One active protein kinase A molecule phosphorylates many phosphorylase kinase molecules, which convert many molecules of phosphorylase b to phosphorylase a
- One molecule of phosphorylase a produces many molecules of G1P from glycogen
- The net result is that one hormone molecule can generate tens of thousands of molecules of G1P, which forms G6P (oxidation of G6P generates hundreds of thousands of molecules of ATP)
Additional regulatory mechanisms in muscle
AMP and Ca stimulate glycogen breakdown in muscle
- Phosphorylase b is activated by the rise in AMP, which occurs during muscle contraction (ATP → AMP + 2Pi)
- Phosphorylase kinase is activated by Ca, which is released from the SR during muscle contraction (Ca binds to calmodulin, which serves as a subunit of phosphorylase kinase; the conformational change induced by calcium binding to calmodulin is sufficient to activate the non-phosphorylated form of phosphorylase kinase)
Regulation of glycogen synthesis
Insulin, which is elevated after a meal, stimulates the synthesis of glycogen in liver and muscle
Factors that promote glycogen synthesis in the liver
In the fed states, glycogen degradation decreases because glucagon is low, and the cAMP cascade is not activated
- cAMP is converted to AMP by a cell membrane phosphodiesterase
- As cAMP decreases, the regulatory subunits rejoin the catalytic subunits of protein kinase A, and the enzyme is inactivated
- Dephosphorylation of phosphorylase kinase and phosphorylase a causes these enzymes to be inactivated. Insulin causes the activation of phosphatases that dephosphorylate these enzymes
PP-1
A key phosphatase that is regulated by a protein inhibitor (which is activated by phosphorylation by protein kinase A)
The inhibitor, when phosphorylated, binds to and inhibits PP-1 activity
The PP-1:inhibitor complex allows for slow hydrolysis of the phosphorylated inhibitor by PP-1; when the inhibitor is dephosphorylated, it no longer has affinity for PP-1 and falls out of the complex, leading to fully active PP-1
Factors that promote glycogen synthesis in muscle
After a meal, muscle will have low levels of cAMP, AMP, and Ca if it is not contracting and epinephrine is low
Consequently, muscle glycogen degradation will or occur
Two actions of insulin in muscle
- Stimulates glycogen synthesis by mechanisms similar to those in the liver
- Stimulates the transport of glucose into muscle cells, providing increased substrate for glycogen synthesis
Insulinomas and glucagonomas
Rare neuroendocrine tumors of the pancreas that can episodically release large amounts of either insulin or glucagon, respectively
Insulinomas lead to hypoglycemia due to the stimulation of glucose transport into the muscle and fat cells
Glucagonomas lead to hyperglycemia as the liver is instructed to release glucose via glycogenolysis and gluconeogenesis
Rate determining step of glycogenesis
Glycogen synthase
Regulated by:
G6P (+), Insulin (+), Cortisol (+), Epinephrine (-), Glucagon (-)
What does insulin bind?
Tyrosine kinase dimer receptor, which activates glycogen synthase and protein phosphatase, which inhibits glycogen phosphorylase
