Regulating Glycogen Metabolism

Mammalian glycogen stores glucose in times of plenty (after feeding, a time of high glucose levels) and supplies glucose in times of need (during fasting or in “fight-or-flight” situations). In muscle, glycogen provides fuel for muscle contraction. In contrast, liver glycogen is largely converted to glucose that exits liver cells and enters the bloodstream for transport to other tissues that require it [The Cori Cycle]. Both the mobilization and synthesis of glycogen are regulated by hormones.

The regulation of glycogen metabolism is a good way to introduce the idea of signal transduction. This is a very popular part of modern biochemistry. It's basically a way in which signals from outside the cell are transduced through a chain of molecules to affect a particular biochemical reaction. In this case, we'll examine how the hormones glucagon, epinephrine, and insulin regulate glycogen synthesis and glycogen degradation.

Let's look at glycogen synthesis. Glycogen synthase is the enzyme responsible for adding UDP-glucose to a growing chain of glycogen. There are two forms of this enzyme. The inactive form is called glycogen synthase b and it is phosphorylated (P). The active form is called glycogen synthase a and it does not carry a phosphate group. The activity of glycogen synthase is controlled by covalent modification just like pyruvate dehydrogenase [Regulating Pyruvate Dehydrogenase].

The phosphorlation of enzymes is performed by kinases. In this case it's a very common cellular kinase called protein kinase A (PKA). The complete name of the enzyme is cyclic AMP-dependent protein kinase A because its activity is regulated by a messenger molecule known as cyclic AMP (cAMP). Cyclic AMP is made from ATP by the enzyme adenylyl cyclase and it is degraded by the action of an enzyme called phosphodiesterase

When cAMP is present inside the cell it binds to protein kinase A and activates it so that it can phosphorylate glycogen synthase. This shuts down glycogen synthesis by deactivating the enzyme. The key to hormonal regulation is the effect of the hormones on the production of cAMP. This takes place on the cell surface when the hormone binds to a cell surface receptor molecule.

Insulin, glucagon, and epinephrine are the principal hormones that control glycogen metabolism in mammals. Insulin, a 51-residue protein is synthesized by the cells of the pancreas. It is secreted when the concentration of glucose in the blood increases. Thus, high levels of insulin are associated with the fed state of an animal. Insulin stimulates glycogen synthesis in the liver. This makes sense since high concentrations of glucose indicate that it's time to store it as glycogen.

Glucagon, a peptide hormone containing 29 amino acid residues, is secreted by the cells of the pancreas in response to a low blood glucose concentration. Glucagon restores the blood glucose concentration to a steady-state level by stimulating glycogen degradation. Only liver cells are rich in glucagon receptors, so glucagon is extremely selective in its target. The effect of glucagon is opposite that of insulin, and an elevated glucagon concentration is associated with the fasted state.

The adrenal glands release the catecholamine epinephrine (also known as adrenaline) in response to neural signals that trigger the fight-or-flight response. Epinephrine stimulates the breakdown of glycogen to glucose 1-phosphate, which is converted to glucose 6-phosphate. The increase in intracellular glucose 6-phosphate increases both the rate of glycolysis in muscle and the amount of glucose released into the bloodstream from the liver. Note that epinephrine triggers a response to a sudden energy requirement; glucagon and insulin act over longer periods to maintain a relatively constant concentration of glucose in the blood.

Epinephrine binds to β-adrenergic receptors of liver and muscle cells and to α1-adrenergic receptors of liver cells. The binding of epinephrine to β-adrenergic receptors or of glucagon to its receptors activates the adenylyl cyclase signaling pathway. The second messenger, cyclic AMP (cAMP), then activates protein kinase A.

For now let's just take it as a given that glucagon and epinephrine trigger cAMP synthesis and this leads to shutting down of glycogen synthesis.


In addition to blocking glycogen synthesis, these hormones stimulate glycogen degradation. The glycogen degradation enzyme is called glycogen phosphorylase and it comes in two forms. Glycogen phosphorylase a is the active form and it's phosphorylated (it has an attached phosphate group). Glycogen phosphorylase b is the unphosphorylated form of the enzyme and it's inactive. Note the reciprocal relationship of the glycogen synthase and glycogen degradation enzymes. When both are phosphorylated, glycogen degradation is active and glycogen synthesis is not. When both are dephosphorylated, glycogen synthesis is active and glycogen degradation is blocked. This suggests a similar mechanism of regulation for the two enzymes.

The phosphorylation of glycogen phosphorulase is carried out by a kinase enzyme. In this case it's a specific kinase called phosphorylase kinase. Phosphorylase kinase is itself subject to activation by phosphorylation. The kinase that does this is our friend protein kinase A. Thus, epinephrine and glucagon will stimulate glycogen degradation in addition to stopping glycogen synthesis.



For every kinase there's a phosphatase that removes phosphate groups from proteins. Recall that insulin is released when glucose levels in the blood are high. The effect of insulin is the exact opposite of the effect of glucagon and epinephrine. Insulin binds to a cell surface receptor and triggers a pathway that leads to activation of protein phosphatase-1. This enzyme dephosphorylates the three enzymes shown above leading to activation of glycogen synthesis and deactivation of glycogen degradation. Insulin causes glucose to be stored as glycogen.



These kinds of kinase/phosphatase cascades are very common in eukaryotes. Believe it or not, this is one of the simpler examples.

Now, let's return to the effect of the hormone on cAMP synthesis. This is the key part of any signaling pathway and it's best illustrated by using a general model based on cAMP production. (There are other types of signaling pathways.)



The details aren't important unless you're seriously into signaling—like 50% of all biochemistry graduate students these days. Hormone binds to a cell surface receptor. The signal is transferred through the cell membrane to the inside part of the receptor molecule. This interacts with a G protein so that when hormone binds, the G protein is activated.

G protein then diffuses to the membrane bound adenylyl cyclase molecule and, when the two proteins connect, the activity of adenylyl cyclase is stimulated and cAMP is produced. This leads to activation of protein kinase A. The stimulatory effect of the signal transduction pathway is transient because cAMP is rapidly degraded by phosphodiesterase. Thus, hormone must usually be continuously present in order to get stimulation.

There are other hormones that inhibit cAMP production by activating different G proteins (G_i) that block adenylyl cyclase.

[©Laurence A. Moran. Some of the text is from Principles of Biochemistry 4th ed. ©Pearson/Prentice Hall]