All cells constantly receive multiple signals from their environment, including changes in levels of hormones, metabolites, and gases such as NO and oxygen. All of these signals must be integrated. The breakdown of glycogen to glucose (glycogenolysis) provides an excellent example of how cells can integrate their responses to more than one signal. As discussed in Section 15.5, epinephrine stimulation of muscle and liver cells leads to a rise in the second messenger cAMP, which promotes glycogen breakdown (see Figure 15-28a). In both muscle and liver cells, other signaling pathways produce the same cellular response of enhanced glycogenolysis.

In striated muscle cells (see Figure 17-30), stimulation by nerve impulses causes the release of Ca²⁺ ions from the sarcoplasmic reticulum and an increase in the cytosolic Ca²⁺ concentration, which triggers muscle contraction. The rise in cytosolic Ca²⁺ also allows Ca²⁺ binding to the δ subunit of glycogen phosphorylase kinase (GPK)—which is calmodulin—thus activating the kinase catalytic activity of the γ subunit and thereby stimulating the degradation of glycogen to glucose-1-phosphate, which fuels prolonged muscle contraction.

Rises in blood epinephrine concentrations lead to activation of adenylyl cyclase and an increase in cAMP concentrations. Recall that phosphorylation by cAMP-dependent PKA also activates GPK (see Figure 15-28) and that maximal activation of GPK, and therefore glycogenolysis, requires both phosphorylation and Ca²⁺. Thus this key regulator of glycogenolysis is subject to both neural and hormonal regulation in muscle (Figure 15-37a).

In liver cells, hormone-induced activation of the effector protein phospholipase C also regulates glycogen breakdown by generating the second messengers DAG and IP₃. As we have just learned, IP₃ induces an increase in cytosolic Ca²⁺, which activates GPK, as in muscle cells, leading to glycogen degradation. Moreover, the combined effect of DAG and increased Ca²⁺ activates protein kinase C (see Figure 15-34). This kinase then phosphorylates and thereby inhibits glycogen synthase, reducing the rate of glycogen synthesis. Thus we see how multiple intracellular signal transduction pathways interact to regulate an important metabolic process (Figure 15-37b).

Recall that GPK is maximally active when Ca²⁺ ions are bound to the δ (calmodulin) subunit and the α subunit has been phosphorylated by PKA. After neuronal stimulation of muscle cells, GPK is sufficiently active, even if it is nonphosphorylated, to allow degradation of glycogen in the absence of hormone stimulation. Binding of Ca²⁺ to the δ subunit may be essential to the enzymatic activity of GPK. Phosphorylation of the α and also the β subunits by PKA increases the affinity of the δ subunit for Ca²⁺, allowing Ca²⁺ ions to bind to the enzyme at the submicromolar Ca²⁺ concentrations found in resting cells.