Regulation of muscle glycogen phosphorylase dimer:

1
Regulation of muscle glycogen phosphorylase
dimer Glycogen Pi ? Glucose-1-phosphate
GP-a and GP-b are interconvertible by
phosphorylation/dephosphorylation Phosphorylase
b kinase and PP1 phosphatase are regulatory
enzymes Phosphorylase b kinase is regulated by
(i) AMP, (ii) Ca2, (iii) hormonally AMP
regulation low energy charge, trigger
glycogen breakdown ATP blocks AMP allosteric
site when at high levels Ca2 regulation
phosphorylase-b kinase has calmodulin domain
Ca2 activates kinase to phosphorylate GP
Ca2 signals muscle contraction
2
Hormone activation of phosphorylase b
kinase Enzyme cascade amplifies a small
initial signal Signal transduction through
G-proteins and cAMP second messenger
3
active
Conformational change

• Liver GP is directly regulated by the glucose
  level in the cell
• High glucose levels turn off glycogen breakdown
  through
• phosphatase PP1 activity
• Insulin acts indirectly through a signaling
  pathway to the
• same end (insulin secreted in response to
  too-high glucose)
• Like muscle GP, liver GP is also activated both
  hormonally
• and allosterically

4
GLYCOGEN SYNTHASE REGULATION
GSK3 is one of at least 11 protein kinases
that regulate GS
Casein kinase II priming by other phosphor.
Phosphoprotein phosphatase bound in glycogen
particle
Synthesize less glycogen signals low blood
sugar
Synthesize more glycogen insulin signals
high blood sugar
5
HOW GSK3 WORKS
GSK3 recognizes the phosphate group on glycogen
synthase (GS) that was added by casein kinase
II. Ser residues to be phosphorylated are 4 aa
apart enzyme reads the spacing, then moves
processively across the glycogen synthase
surface -GSK3 is itself phosphorylated by PKB at
a site mimicking the GS substrate
site -Phosphorylated GSK3 is then trapped in an
inactive conformation -PP1, which
dephosphorylates GS, also dephosphorylates
GSK3 -(GSK3 also mediates signaling by other
nutrients/growth factors)
6
INSULIN CASCADE

• Cascade branches at IRS-1
• PI-3K is another target
• of phosphorylated IRS-1
• PI-3K phosphorylates the
• membrane lipid phosphatidyl-
• inositol 4,5-bisphosphate
• (PIP2) to the 3,4,5 triphosphate
• (PIP3) Fig. 10.9

Text p 441-442

• Insulin receptor insulin interaction triggers a
  cascase of events inside the cell
• The result is to inactivate the regulatory kinase
  GSK3
• When GSK3 is inactive, glycogen synthase is
  dephosphorylated and active
• More glycogen is made in response to the higher
  blood glucose levels

7
INSULIN CASCADE
Side-reaction of insulin-triggered pathway
GLUT4 transporter is opened up allowing more
glucose to enter the cell.
8
CENTRAL ROLE FOR PP1 IN GLYCOGEN METABOLISM

• PP1 removes phosphoryl groups from GP, GS and
  phosphorylase kinase
• PP1 is bound in a complex with its targets with
  assistance from the
• glycogen targeting protein GM
• Epinephrine-signaled phosphorylation of an
  inhibitor protein inactivates
• PP1 by forming a complex with PP1
• Insulin-triggered phosphorylation of GM site 1
  activates PP1
• Epinephrine-triggered phosphorylation of GM site
  2 causes GM dissociation
• and deactivation of PP1 by dissociation of PP1
  from the particle

9
MAP OF CARBOHYDRATE REGULATION IN LIVER
Trigger high blood glucose
Trigger low blood glucose
Role of liver cell supply glucose to the
blood for circulation to other tissues
10
REGULATION OF CARBOHYDRATE METABOLISM
DIFFERENCES IN LIVER AND MUSCLE

• Muscle
• Glycogen breakdown serves
• only its own needs
• Very high ATP demand
• supported by glycolysis
• No gluconeogenesis pathway

• Glucagon, triggered by low blood sugar, does not
  influence muscle
• Epinephrine, triggered by stress response (fight
  or flight) has different
• effects in liver vs. muscle
• Glycolysis decreases in liver and increases in
  muscle
• Breakdown of glycogen increases in both tissues,
  but for different purposes

Muscle insulin response increased glycogen
synthesis (as in liver), by same paths Muscle
insulin response recruits additional GLUT4 to
take up more blood glucose
11
HOW GLYCOLYSIS CAN GO UP IN MUSCLE IN RESPONSE TO
EPINEPHRINE
PKA is activated, but the muscle isozyme of
pyruvate kinase is not phosphorylated Glycogen
breakdown at the bottom of the cascade is
preserved