Phosphorylase kinase, glucagon

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-... 

Glycogen phosphorylase isoenzymes have been isolated from liver, brain and skeletal muscle. All forms are subject to covalent control with conversion of the inactive forms (GP-b) to the active forms (GP-a) by phosphorylation on specific serine residues. This phosphorylation step, mediated by the enzyme phosphorylase kinase, is initiated by glucagon stimulation of the hepatocyte. Indeed, the same cAMP cascade which inhibits glycogen synthesis simultaneously stimulates glycogenolysis, giving us an excellent example of reciprocal control. 

Correct answer = B. Epinephrine and glucagon both cause increased glycogen degradation in the liver. Therefore, glycogen phosphorylase activity is increased, whereas glycogen synthase activity is decreased. Both cAMP-dependent protein kinase and its substrate, phosphorylase kinase, are also activated. 

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. 

Glucagon decreases cholesterol synthesis in isolated hepatocytes [131,132] apparently because it reduces the fraction of hydroxymethylglutaryl-CoA reductase in the active form [131,132], This is due to an increase in reductase kinase activity [133], However, there is no evidence that cAMP-dependent protein kinase phos-phorylates either the reductase, reductase kinase or reductase kinase kinase [134], It has been proposed that the phosphorylation state of these enzymes is indirectly controlled through changes in the activity of protein phosphatase I [132,134], This phosphatase can dephosphorylate and activate the reductase [134,135] and its activity can be controlled by a heat stable inhibitor (inhibitor 1), the activity of which is increased by cAMP-dependent phosphorylation [136,137], Since the phosphorylated forms of acetyl-CoA carboxylase, ATP-citrate lyase, pyruvate kinase, phos-phorylase, phosphorylase kinase and glycogen synthase are also substrates for protein phosphatase I [135], this mechanism could also contribute to their phosphorylation by glucagon. 

C. Glucagon in the liver and epinephrine in both the liver and muscle cause cAMP to rise, activating protein kinase A. Protein kinase A phosphorylates and activates phosphorylase kinase, which in turn phosphorylates and activates phosphorylase. These phosphorylation reactions require ATP. 

Liver glycogen phosphorylase exists in an inactive, de-phosphorylated form and in at least one active, phospho-rylated form. Conversion of phosphorylase b to phosphorylase a is catalyzed by phosphorylase kinase, which is activated by vasopressin, angiotensin II, and a-adrenergic agonists (mediated by Ca +) and by glucagon (which elevates cAMP). Glucagon activation of phosphorylase is in some way antagonized by insulin. 

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