The binding of hormones, such as glucagon or epinephrine, to plasma membrane G protein–coupled receptors ([GPCR] see p. 94) signals the need for glycogen to be degraded, either to elevate blood glucose levels or to provide energy for exercising muscle.
1. Protein kinase A activation: Binding of glucagon or epinephrine to their specific hepatocyte GPCR, or of epinephrine to a specific myocyte GPCR, results in the G protein–mediated activation of adenylyl cyclase. This enzyme catalyzes the synthesis of cyclic adenosine monophosphate (cAMP), which activates cAMP-dependent protein kinase A (PKA). cAMP binds the two regulatory subunits of tetrameric PKA, releasing two individual catalytic subunits that are active (Fig. 11.9; also see p. 95). PKA then phosphorylates several enzymes of glycogen metabolism, affecting their activity. [Note: When cAMP is removed, the inactive tetramer reforms.] on next page.) catalytic subunit.
2.
Phosphorylase kinase activation: Phosphorylase kinase exists in two forms: an inactive “b” form and an active “a” form. Active PKA phosphorylates the inactive “b” form of phosphorylase kinase, producing the active “a” form (see Fig. 11.9).
3.
Glycogen phosphorylase activation: Glycogen phosphorylase also exists in a dephosphorylated, inactive “b” form and a phosphorylated, active “a” form. Phosphorylase kinase a is the only enzyme that phosphorylates glycogen phosphorylase b to its active “a” form, which then begins glycogenolysis (see Fig. 11.9).
4.
Signal amplification: The cascade of reactions described above activates glycogenolysis. The large number of sequential steps serves to amplify the effect of the hormonal signal (that is, a few hormone molecules binding to their GPCR result in a number of PKA molecules being activated that can each activate many phosphorylase kinase molecules). This causes the production of many active glycogen phosphorylase a molecules that can degrade glycogen.
5.
Phosphorylated state maintenance: The phosphate groups added to phosphorylase kinase and phosphorylase in response to cAMP are maintained because the enzyme that hydrolytically removes the phosphate, protein phosphatase-1 (PP1), is inactivated by inhibitor proteins that are also phosphorylated and activated in response to cAMP (see Fig. 11.9). [Note: PP1 is activated by a signal cascade initiated by insulin (see Fig. 27.7 on p. 311). Because insulin also activates the phosphodiesterase that degrades cAMP, it opposes the effects of glucagon and epinephrine.]
B. Covalent inhibition of glycogenesis
The regulated enzyme in glycogenesis, glycogen synthase, also exists in two forms, the active “a” form and the inactive “b” form. However, in contrast to phosphorylase kinase and phosphorylase, the active form of glycogen synthase is dephosphorylated, whereas the inactive form is phosphorylated at several sites on the enzyme, with the level of inactivation proportional to the degree of phosphorylation (Fig. 11.10). Phosphorylation is catalyzed by several different protein kinases in response to cAMP (for example, PKA and phosphorylase kinase) or other signaling mechanisms (see C. below). Glycogen synthase b can be reconverted to the “a” form by PP1. Figure 11.11 summarizes the covalent regulation of glycogen metabolism.