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?

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 secreted by the α cells of the pancreas when the blood-sugar level is low. Physiologically, glucagon signifies the starved state (Figure 21.15).

How do hormones trigger the breakdown of glycogen? They initiate a cyclic AMP signal-transduction cascade, already discussed in Section 14.1 (Figure 21.16).

The cyclic AMP cascade highly amplifies the effects of hormones. 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, much of the stored glycogen would be mobilized within seconds were it not for a counterregulatory system.

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 α-adrenergic receptor, which then initiates the phosphoinositide cascade (Section 14.2) that induces the release of Ca²⁺ from endoplasmic reticulum stores. Recall that the δ subunit of phosphorylase kinase is the Ca²⁺ sensor calmodulin. The 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.

It is crucial that the high-gain system of glycogen breakdown be terminated quickly to prevent the wasteful depletion of glycogen after energy needs have been met. When glucose needs have been satisfied, phosphorylase kinase and glycogen phosphorylase are dephosphorylated and inactivated. Simultaneously, glycogen synthesis is activated.

The signal-transduction pathway leading to the activation of glycogen phosphorylase is shut down automatically when secretion of the initiating hormone ceases. The inherent GTPase activity of the G protein converts the bound GTP into inactive GDP, and phosphodiesterases always present in the cell convert cyclic AMP into AMP. Protein phosphatase 1 (PP1) removes the phosphoryl groups from phosphorylase kinase, thereby inactivating the enzyme. Finally, PP1 also removes the phosphoryl group from glycogen phosphorylase, converting the enzyme into the usually inactive b form.

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 well conserved in all the enzymes. The high degree of similarity among these three sites shows that the catalytic mechanism has been maintained throughout evolution.

Differences arise, however, when we compare the regulatory sites. The simplest type of regulation would be feedback inhibition by glucose 6-phosphate. Indeed, the glucose 6-phosphate regulatory site is highly conserved among most of the phosphorylases. The crucial amino acid residues that participate in regulation by phosphorylation and nucleotide binding are well conserved only in the mammalian enzymes. Thus, this level of regulation was a later evolutionary acquisition.

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