section 15.2
Glycogen Metabolism
289
Activation of
phosphorylase k in a s e .
Activation of
glycogen phosphorylase
Activation of calmodulin-
dependent multiprotein
kinase
Increased
glycogen
breakdown
,
Inhibition of
‘glycogen synthase
R educed
glycogen
synthesis
FIGURE 15-11
Epinephrine
O u tsid e
P la sm a m em b ran e
Inside
Activation ot
lenvlate cvd asa
CAMP + PR
Activation of cA M P-
- d e p en d e n t protein k in ase -
A TP
A ctivation of
inhibitor-1
A ctivation of
Inhibition of
Inhibition of
p h o sp h o ry lase k in ase *.
....protein p h o s p h a ta s e -1 .
.......
►
g lycogen sy n th ase
A ctivation of
„X
glycogen p h o sp h o ry lase
In c re a se d
glycogen
breakdow n
R ed u ced
glycogen
sy n th esis
Possible mechanism for regulation of glycogen metabolism in skeletal
muscle by changes in cytosolic calcium. Increased glycogen breakdown
may be coordinated with muscle contractions, as indicated here. The actual
control scheme is probably more complicated, since phosphoprotein
phosphatases are also involved. Interactions with cAMP-activated
reactions, which also may complicate regulation, are not included.
Whether glycogen synthase is a substrate for phosphorylase kinase
in vivo
is unclear. [Modified and reproduced with permission from P. Cohen,
Protein phosphorylation and the control of glycogen metabolism in skeletal
muscle.
P h ilo s. Trans. R. Soc. b o n d . (B io l.)
302,
13 (1983).]
FIGURE 15-12
Possible mechanism for regulation of glycogen metabolism in skeletal
muscle by changes in cyclic AMP. The actual control scheme is probably
more complicated, since changes in cytoplasmic calcium concentration are
likely also to be important. Whether glycogen synthase is a substrate for
phosphorylase kinase
in vivo
is unclear (indicated by ?). Dashed arrows
from protein phosphatase
- 1
to glycogen synthase and phosphorylase and
phosphorylase kinase indicate that inhibition of dephosphorylation may
be less important than activation of phosphorylation in changing the
activities of these enzymes. [Modified and reproduced with permission
from P. Cohen, Protein phosphorylation and the control of glycogen
metabolism in skeletal muscle.
P hilos. Trans. R. Soc. L ond. (B io l.)
Integrated Regulation o f Muscle
302
(1983).]
Glycogen Metabolism
Figures 15-11 and 15-12 provide a model for the reg-
ulation of glycogen metabolism in muscle. This model is
consistent with many of the known facts, but alternative
interpretations are equally plausible. Only two of the ex-
ternal stimuli that affect muscle glycogen metabolism are
considered in these figures.
1. Initiation of muscle contraction by action potential
from an
a
motor neuron depolarizes the muscle-cell
membrane and causes an increase in the myoplasmic
[Ca2+] (Chapter 21). The increase in calcium
activates phosphorylase kinase and
Ca
2
+/calmodulin-dependent kinase, which inactivate
glycogen synthase and active glycogen phosphorylase
(Figure 15-11). This step coordinates muscle
contraction with glycogenolysis. These steps are
reversed by one or more phosphatases at the end of
contraction.
2. Binding of epinephrine to an adrenergic receptor
away from a motor end plate on the muscle membrane
causes glycogenolysis to increase and glycogenesis to
decrease. This activates adenylate cyclase, increasing
the cytosolic concentration of cAMP and activating
the cAMP-dependent protein kinase (Figure 15-12).
The net effect
in vivo
is an increase in phosphorylation
of glycogen synthase and phosphorylase. This may
occur in several ways, and the relative importance of
increased phosphorylation compared to decreased
dephosphorylation remains unclear.
Insulin also regulates skeletal muscle glycogen meta-
bolism. Skeletal muscle is the major site of insulin-
stimulated glucose uptake from the bloodstream, most of
which is converted to glycogen. The insulin-induced glu-
cose uptake is mediated by the glucose transporter GLUT4
(Chapter 13). Binding of insulin to its cell surface receptor
initiates a cascade of phosphorylation reactions followed
by dephosphorylation reactions (Chapter 22). Activation
of glycogen synthase occurs by dephosphorylation at sites
phosphorylated by cAMP-dependent kinase and GSK-3.
Protein phosphatase-1 is a key component of the insulin
signaling pathway and it activates glycogen synthase; it
simultaneously inactivates phosphorylase a and phospho-
rylase kinase, promoting glycogen synthesis. Inactivation
of GSK-3 via the protein kinase B pathway has also
