1. BIOC 460 - DR. TISCHLER LECTURE 32
GLYCOGEN METABOLISM:
HORMONAL REGULATION

2. OBJECTIVES
1. Steps by which cyclic AMP-mediated hormonal regulation activates phosphorylase kinase and glycogen phosphorylase.
2. Events associated with reversal of the cyclic AMP-mediated cascade - roles of GTPase activity of the s-subunit, phosphodiesterase, protein phosphatase-1.
3. Features in regulation of glycogen synthase by covalent modification
4. Regulation of the activity of protein phosphatase-1.
5. Mechanisms by which insulin facilitates the activation of glycogen synthase to promote glycogen storage.

3. Glucagon or epinephrine inactive enzyme
G-protein
adenylyl cyclase
- inactive
adenylyl cyclase -active
ATP ADP OH
Glycogen
synthase-i OP
Glycogen
synthase-d
ATP cAMP
Protein
kinase-A
Protein kinase-A OP
Phosphorylase
kinase-a OH
Phosphorylase
kinase-b
ATP ADP OP
Glycogen
phosphorylase-a HO
Glycogen
phosphorylase-b
ATP ADP
Pi + Glucosen Glucosen-1 +
(Glycogen) Glucose-1-P
Figure 1. Cascade for the control of glycogenolysis and glycogenesis

4. phosphodiesterase (+insulin)
G-protein
Adenylyl cyclase
Adenylyl cyclase
cAMP  AMP
phosphodiesterase (+insulin)
active enzyme
cAMP
loss
Protein kinase-A
Protein kinase-A
inactive enzyme OP
Phosphorylase kinase-a HO
Phosphorylase kinase-b
-Pi
Glycogen synthase-d OP
protein
phosphatase
activated via insulin
signal transduction
-Pi OH
Glycogen synthase-i
-Pi OP
Glycogen phosphorylase-a OH
Glycogen phosphorylase-b
Figure 2. Reversal of phosphorylation events initiated by protein kinase A.

5. Figure 3. Regulation of protein phosphatase-1. Fed state
OPins
PP-1
OHpka
fully-activated complex
RGI
Signal via receptor tyrosine kinase
[1]
ATP
ADP
[2]
activated
insulin-sensitive
protein kinase
Insulin
binds to
receptor o
OHins
PP-1
OHpka
low activity form
RGI
glycogen
Figure 3. Regulation of protein phosphatase-1. Fed state

6. Figure 3. Regulation of protein phosphatase-1 – starvation/stress
OHins
PP-1
OHpka
low activity form
RGI
ADP
ATP
[4]
Signal via
G-protein
[3]
activated
protein kinase A
glucagon or epinephrine
binds to
receptor
OHins
OPpka
RGI o
RGI
PP-1
PP-1
minimally active form
PP-1
PP-1
activated PKA
PP-1 OP I I OH OP I OP I
PP-1 OP I OP I
ADP
ATP
[5]
inactive form
[6]
inactive form
active form
Figure 3. Regulation of protein phosphatase-1 – starvation/stress

7. Figure 4. Insulin inactivates glycogen synthase kinase-3.
Insulin signal
mediated by IRS, p85, PI-3 kinase, PIP3, PKB
ATP ADP OH
Glycogen
synthase
kinase-3
(active) OP
Glycogen
synthase
kinase-3
(inactive)
Inactive glycogen synthase kinase-3 leads to active glycogen synthase
Figure 4. Insulin inactivates glycogen synthase kinase-3.

8. Mechanisms by Which Insulin Facilitates the Activation of Glycogen Synthase to Promote Glycogen Storage
PP-1 removes the phosphate from phosphorylase kinase so that it cannot phosphorylate glycogen synthase
Phosphodiesterase degrades cyclic AMP so PKA becomes inactive and unable to phosphorylate glycogen synthase
Insulin promotes dephosphorylation (activation) of glycogen synthase through activation of protein phosphatase-1
4) Insulin prevents phosphorylation of glycogen synthase inactivating glycogen synthase kinase-3