24.3 Epinephrine and Glucagon Signal the Need for Glycogen Breakdown

Protein kinase A activates phosphorylase kinase, which in turn activates glycogen phosphorylase. How is protein kinase A activated? What is the signal that ultimately triggers an increase in glycogen breakdown?

G Proteins Transmit the Signal for the Initiation of Glycogen Breakdown

As already mentioned, glucagon and epinephrine trigger the breakdown of glycogen. Muscular activity or its anticipation leads to the release of epinephrine, which markedly stimulates glycogen breakdown in muscle and, to a lesser extent, in the liver. The liver is more responsive to glucagon, which signifies the starved state (Figure 24.10).

Figure 24.10: The hormonal control of glycogen breakdown. The left side of the illustration shows the hormonal response to fasting. Glucagon stimulates glycogen breakdown in the liver when blood glucose is low. The right side of the illustration shows the hormonal response to exercise. epinephrine enhances glycogen breakdown in muscle and the liver to provide fuel for muscle contraction.

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How do hormones trigger the breakdown of glycogen? They initiate a cyclic AMP (cAMP) signal-transduction cascade, already discussed in Chapter 13 (Figure 24.11). This cascade leads to the activation of phosphorylase in four steps:

  1. The signal molecules epinephrine and glucagon bind to specific seven-transmembrane (7TM) receptors in the plasma membranes of target cells. Epinephrine binds to the β-adrenergic receptor in muscle, whereas glucagon binds to the glucagon receptor in the liver. These binding events activate the Gas protein.

  2. The GTP-bound subunit of Gas activates the transmembrane protein adenylate cyclase. This enzyme catalyzes the formation of the second messenger cAMP from ATP.

  3. The elevated cytoplasmic concentration of cAMP activates protein kinase A.

  4. Protein kinase A phosphorylates phosphorylase kinase, which subsequently activates glycogen phosphorylase.

Figure 24.11: The regulatory cascade for glycogen breakdown. Glycogen degradation is stimulated by hormone binding to 7TM receptors. Hormone binding initiates a G-protein-dependent signal-transduction pathway that results in the phosphorylation and activation of glycogen phosphorylase.

The cAMP 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 in the body would be mobilized within seconds were it not for the regulatory elements that will be discussed shortly.

The signal-transduction processes in the liver are more complex than those in muscle. Epinephrine can elicit glycogen degradation in the liver. However, in addition to binding to the β-adrenergic receptor as it does in skeletal muscle, it binds to the 7TM α-adrenergic receptor, which then initiates the phosphoinositide cascade 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.

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Glycogen Breakdown Must Be Rapidly Turned Off When Necessary

There must be a rapid way to shut down glycogen breakdown 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 (Chapter 25).

The signal-transduction pathway leading to the activation of glycogen phosphorylase is shut down automatically when the initiating hormone is no longer present. The inherent GTPase activity of the G protein converts the bound GTP into inactive GDP, and phosphodiesterases always present in the cell convert cAMP into AMP, which does not activate PKA. Protein phosphatase 1 (PP1) removes the phosphoryl groups from phosphorylase kinase, thereby inactivating the enzyme. Finally, protein phosphatase 1 also removes the phosphoryl group from glycogen phosphorylase, converting the enzyme into the usually inactive b form.

!bio! BIOLOGICAL INSIGHT: Glycogen Depletion Coincides with the Onset of Fatigue

Although most of us have experienced fatigue, it is a multifaceted and difficult condition to define. There are metabolic, neurological, and psychological components to fatigue, but a common definition is simply the inability to maintain the required energy output. Figure 24.12 A shows the decrease in glycogen content of the vastus lateralis muscle (a component of the quadriceps) of cyclists who were exercising at 80% of their maximum workload as a function of time. Muscle glycogen phosphorylase was activated through allosteric mechanisms and by hormonally induced covalent modification to such an extent that, after 75 minutes, all of the glycogen in the vastus lateralis muscle was consumed. Moreover, glycogen depletion coincided with the onset of fatigue, or the inability to maintain the required effort. In other words, the cyclists “hit the wall” or “bonked” (Figure 24.12B). However, these experiments do not show that glycogen depletion causes fatigue; correlation does not mean causation. Some experiments suggest that the increase in ADP concentration resulting from glycogen depletion may be a more direct cause of the fatigue. It is fascinating that an explanation for such a common feeling still eludes scientists and demonstrates once again the scope of how little we know and the opportunities for more exciting research.

Figure 24.12: Glycogen depletion as a result of exercise. (A) Glycogen content of the vastus lateralis decreases as a function of time at 80% effort. (B) The French cyclist Tony Gallopin slumps in exhaustion after winning a stage in the 2014 edition of the Tour de France.

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