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Epinephrine and Glucagon Signal the Need for Glycogen Breakdown

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Epinephrine and Glucagon Signal the Need for Glycogen Breakdown
Figure 21.13. Activation of Phosphorylase Kinase. Phosphorylase kinase is activated by hormones that lead to the
phosphorylation of the β subunit and by Ca2+ binding of the δ subunit. Both types of stimulation are required for
maximal enzyme activity.
II. Transducing and Storing Energy
21. Glycogen Metabolism
21.3. Epinephrine and Glucagon Signal the Need for Glycogen Breakdown
Protein kinase A activates phosphorylase kinase, which in turn activates glycogen phosphorylase. What activates protein
kinase A? What is the signal that ultimately triggers an increase in glycogen breakdown?
21.3.1. G Proteins Transmit the Signal for the Initiation of Glycogen Breakdown
Several hormones greatly affect glycogen metabolism. Glucagon and epinephrine trigger the breakdown of glycogen.
Muscular activity or its anticipation leads to the release of epinephrine (adrenaline), a catecholamine derived from
tyrosine, from the adrenal medulla. Epinephrine markedly stimulates glycogen breakdown in muscle and, to a lesser
extent, in the liver. The liver is more responsive to glucagon, a polypeptide hormone that is secreted by the α cells of the
pancreas when the blood-sugar level is low. Physiologically, glucagon signifies the starved state.
How do hormones trigger the breakdown of glycogen? We will briefly review this signal-transduction cascade, already
discussed in Section 15.1 (Figure 21.14).
1. The signal molecules epinephrine and glucagon bind to specific 7TM receptors in the plasma membranes of muscle
and liver cells, respectively. Epinephrine binds to the β-adrenergic receptor in muscle, whereas glucagon binds to the
glucagon receptor. These binding events activate the α subunit of the heteromeric Gs protein. A specific external signal
has been transmitted into the cell through structural changes, first in the receptor and then in the G protein.
2. The GTP-bound form of the α subunit of Gs activates adenylate cyclase, a transmembrane protein that catalyzes the
formation of the secondary messenger cyclic AMP from ATP.
3. The elevated cytosolic level of cyclic AMP activates protein kinase A through the binding of cyclic AMP to the
regulatory subunits, which then dissociate from the catalytic subunits. The free catalytic subunits are now active.
4. Protein kinase A phosphorylates the β subunit of phosphorylase kinase, which subsequently activates glycogen
phosphorylase.
The cyclic AMP cascade highly amplifies the effects of hormones. Hence, the binding of a small number of hormone
molecules to cell-surface receptors leads to the release of a very large number of sugar units. Indeed, the amplification is
so large that much of the stored glycogen would be mobilized within seconds were it not for a counterregulatory system
(Section 21.3.2).
The signal-transduction processes in the liver are more complex than those in muscle. Epinephrine can also elicit
glycogen degradation in the liver. However, in addition to binding to the β-adrenergic receptor, it binds to the 7TM αadrenergic receptor, which then activates phospholipase C and, hence, initiates the phosphoinositide cascade (Section
15.2). The consequent rise in the level of inositol 1,4,5-trisphosphate induces the release of Ca2+ from endoplasmic
reticulum stores. Recall that the δ subunit of phosphorylase kinase is the Ca2+ sensor calmodulin. Binding of Ca2+ to
calmodulin leads to a partial activation of phosphorylase kinase. Stimulation by both glucagon and epinephrine leads to
maximal mobilization of liver glycogen.
21.3.2. Glycogen Breakdown Must Be Capable of Being Rapidly Turned Off
There must be a way to shut down the high-gain system of glycogen breakdown quickly to prevent the wasteful
depletion of glycogen after energy needs have been met. Indeed, another cascade leads to the dephosphorylation and
inactivation of phosphorylase kinase and glycogen phosphorylase. Simultaneously, glycogen synthesis is activated.
The signal-transduction pathway leading to the activation of glycogen phosphorylase is shut down by the process already
described for such pathways employing G proteins and cyclic AMP. The inherent GTPase activity of the G protein
converts the bound GTP into GDP, thereby halting signal transduction. Cells also contain phosphodiesterase activity that
converts cyclic AMP into AMP. Protein kinase A sets the stage for the shutdown of glycogen degradation by adding a
phosphoryl group to the α subunit of phosphorylase kinase after first phosphorylating the β subunit. This addition of a
phosphoryl group renders the enzyme a better substrate for dephosphorylation and consequent inactivation by the
enzyme protein phosphatase 1 (PP1). Protein phosphatase 1 also removes the phosphoryl group from glycogen
phosphorylase, converting the enzyme into the usually inactive b form.
21.3.3. The Regulation of Glycogen Phosphorylase Became More Sophisticated as the
Enzyme Evolved
Analyses of the primary structures of glycogen phosphorylase from human beings, rats, Dictyostelium (slime
mold), yeast, potatoes, and E. coli have enabled inferences to be made about the evolution of this important
enzyme. The 16 residues that come into contact with glucose at the active site are identical in nearly all the enzymes.
There is more variation but still substantial conservation of the 15 residues at the pyridoxal phosphate-binding site.
Likewise, the glycogen-binding site is relatively well conserved in all the enzymes. The high degree of similarity of the
active site, the pyridoxal phosphate-binding site and the glycogen-binding site shows that the catalytic mechanism has
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