Regulation of Glycogen Synthesis and Degradation

What does glycogen phosphorylase have in MUSCLE

forms and states

b form glycogen phosphorylase

unphosphorylated glycogen phosphorylase and is inactive

a form glycogen phosphorylase

phosphorylated glycogen phosphorylase and is active

What does each form have

two states- T and R

T state

less active

R state

more active

What state does the a form favor

R state

What state foes the b form favor

T state

b-form regulation by low ATP/high AMP

AMP binds to an allosteric regulatory site to stabilize the R-state and glycogen phosphorylase activity is elevated (R-state)

b-form regulation by high ATP

ATP competes with AMP for binding at the regulatory site. ATP stabilizes the T-state (the least active of all forms/states)

Regulation of the b-form by glucose-6-phosphate

Glucose-6-phosphate stabilizes the T-state

Overall explain b-form regulation in muscle

with an abundance of ATP and glucose present, there is no need to degrade glycogen to make glucose, so glycogen phosphorylase activity is reduced (T-state)

What about a-form glycogen phosphorylase in muscle

in the muscle, the a-form (phosphorylated) is not affected by AMP, ATP, and glucose-6-phosphate and is considered to be fully active when phosphorylated

What regulates glycogen phosphorylase in the LIVER

glucose regulates glycogen phosphorylase in the liver

a-form glucose phosphorylase regulation in the liver

With an abundance of glucose present, there is no need to degrade glycogen to make glucose, so glycogen phosphorylase activity is reduced from the R-state to the T-state

Phosphorylase kinase

enzyme that phosphorylates glycogen phosphorylase at Ser-14

Phosphorylate kinase structure

Large complex, 1200 kD, 16 total subunits, 4 tetramers (alpha,beta,gamma,delta)

What is the gamma subunit of phosphorylase kinase

gamma subunit is the catalytic subunit

What are the alpha beta and delta subunits of phosphorylase kinase

the alpha beta and delta subunits are the regulatory subunits

what is the delta-subunit

Ca 2+ binding protein called calmodulin which is an a regulatory protein that stimulates enzymes, such as phosphorylase kinase

What phosphorylates phosphorylase kinase and where

Protein Kinase A (PKA) phosphorylates phosphorylase kinase on the beta-subunit

How does phosphorylation regulate phosphorylase kinase

unphosphorylated phosphorylase kinase is inactive

phosphorylated phosphorylase kinase is active

How does calcium regulate phosphorylase kinase

high Ca2+ concentration leads to maximal activation of phosphorylase kinase which leads to an active glycogen phosphorylase and the subsequent degradation of glycogen to produce glucose

IN LIVER: glycogen phosphorylase

1. Active phosphorylase kinase phosphorylates glycogen phosphorylase

2. Phosphorylated glycogen phosphorylase (the "a" form) is active

3. Glycogen degradation is stimulated

IN LIVER: glycogen synthase

1. PKA phosphorylates glycogen synthase

2. Phosphorylated glycogen synthase (the "b" form) is inactive

3. Glycogen synthesis is inhibited

IN LIVER: glycogen synthase kinase

1. PKB phosphorylates glycogen synthase kinase

2. Phosphorylated glycogen synthase kinase is inactive

3. An inactive GSK cannot phosphorylate glycogen synthase- unphosphorylated glycogen synthase (the "a" form) is active

4. Glycogen synthesis is stimulated

Protein Phosphatase 1 (PP1)

is an enzyme that dephosphorylates phosphorylase kinase, glycogen phosphorylase, and glycogen synthase

What phosphorylates PP1 and where IN MUSCLE

PKA phosphorylates the regulatory subunits of protein phosphatase 1 (PP1) called GM (in muscle)

How does phosphorylation GM affect PP1 and subsequently glycogen synthesis and degradation

Phosphorylated GM leads to PP1 decreased association with substrate

PP1 not associated with it’s substrate cannot dephosphorylate it

Glycogen synthesis is inhibited

Glycogen degradation is stimulated

What happens if PKA phosphorylates the inhibitor proteins of PP1

Phosphorylated inhibitor proteins of PP1 inhibit PP1 activity

Glycogen synthesis is inhibited

Glycogen degradation is stimulated

What happens to PP1 when glucose is low

inactive PP1 is associated with the phosphorylated phosphorylase a (only when in the R-state) on the GL protein. The interaction of phosphorylated phosphorylase a (R-state) inhibits PP1 activity

Glycogen synthesis is inhibited

Glycogen degradation is stimulated

Mechanism of glucose elevation on PP1

1. Glucose induces the transition in phosphorylated phosphorylase a from R- to T- state

2. The phosphorylated phosphorylase a T-state leaves the inhibitory complex, allowing PP1 to become active

What can active PP1 do

dephosphorylate phosphorylase a, converting it to the inactive b-form-glycogen degradation is reduced

dephosphorylate glycogen synthase, converting it to the active a-form-glycogen synthesis is stimulated