Glucagon breakdown

Stimulation of glycogen breakdown involves consumption of molecules of ATP at three different steps in the hormone-sensitive adenylyl cyclase cascade (Figure 15.19). Note that the cascade mechanism is a means of chemical amplification, because the binding of just a few molecules of epinephrine or glucagon results in the synthesis of many molecules of cyclic / MP, which, through the action of c/ MP-dependent protein kinase, can activate many more molecules of phosphorylase kinase and even more molecules of phosphorylase. For example, an extracellular level of 10 to 10 M epinephrine prompts the for-... 

Glucagon Gs-cAMP-A kinase glycogen breakdown (muscle), gluconeogenesis (liver)... 

Increased hepatic glycogen breakdown 1 Glucagon Tumour necrosis factor... 

In contrast to glucagon, the peptide hormone insulin (see p. 76) increases glycogen synthesis and inhibits glycogen breakdown. Via several intermediates, it inhibits protein kinase GSK-3 (bottom right for details, see p. 388) and thereby prevents inactivation of glycogen synthase. In addition, insulin reduces the cAMP level by activating cAMP phosphodiesterase (PDE). 

Glucagon stimulates glycogen breakdown and simultaneously inhibits glycogen synthesis in the liver. 

Glucagon or epinephrine decreases [fructose 2,6-bisphosphate]. The hormones do this by raising [cAMP] and bringing about phosphorylation of the bifunctional enzyme that makes and breaks down fructose 2,6-bisphosphate. Phosphorylation inactivates PFK-2 and activates FBPase-2, leading to breakdown of fructose 2,6-bisphosphate. Insulin increases [fructose 2,6-bisphosphate] by activating a phosphoprotein phosphatase that dephosphorylates (activates) PFK-2. 

Glucagon causes an increase in blood glucose concentration in several ways (Table 23-4). Like epinephrine, it stimulates the net breakdown of liver glycogen... 

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. 

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