Hormonal Effects of Glucagon Are Mediated by Cyclic AMP

Glucagon itself never enters the liver cells, so it must somehow trigger an event to occur on the cytosolic side of the plasma membrane. A breakthrough in our understanding of 

Cyclic AMP triggers a cascade of reactions that ultimately lead to glycogen breakdown. The immediate action of cAMP is to activate a protein kinase that phosphorylates a number of proteins, including phosphorylase kinase. Phosphorylation of phosphorylase kinase converts it from an inactive to an active form, which catalyzes the conversion of phosphorylase b to phosphorylase a (see chapter 9). The cascade of effects triggered by glucagon is shown in figure 12.29. 

The same cAMP-dependent protein kinase that is responsible for phosphorylating phosphorylase kinase also catalyzes the phosphorylation of glycogen synthase. Whereas phosphorylation of glycogen phosphorylase leads to increased activity, the phosphorylation of glycogen synthase decreases its activity. As a result when glycogen breakdown is stimulated in response to glucagon, glycogen synthesis is inhibited. In this way the simultaneous operation of both enzymes associated with pseudocycle la is prevented. 

When the systemic need has been satisfied there should be a way of reversing the hormone triggered process. All of the effects we have seen are promptly reversed when the need for them has ended. Cyclic AMP is hydrolyzed to 5 -AMP by an enzyme called cyclic AMP phosphodiesterase, and protein phosphatases catalyze the hydrolytic re- 

Synthesis of cyclic AMP. A catalytic site on adenylate cyclase ( B) removes a proton from the C-3 oxygen, which then attacks the a-phosphate and displaces the pyrophosphate group. This reaction occurs on the inner plasma membrane (see fig. 12.29). 

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