Glycogen synthesis and breakdown are controlled tightly by hormonal action. These involve regulatory kinase cascades, as depicted in Figure 13.18 for glycogen breakdown. Like gluconeogenesis/glycolysis, glycogen synthesis/breakdown is reciprocally regulated. For example, epinephrine inhibits glycogen synthesis at the same time as it promotes glycogen breakdown.

Glycogen synthase is the primary regulatory enzyme in glycogen synthesis. Like glycogen phosphorylase, the enzyme that breaks down glycogen, glycogen synthase exists in phosphorylated and dephosphorylated states. Some of the phosphorylations/dephosphorylations are catalyzed by the same protein kinases and phosphatases that regulate glycogen breakdown. Figure 16.11 illustrates that the cAMP-stimulated kinase regulatory cascade for both glycogen synthesis and breakdown pathways is the same. The primary difference lies in the effect of phosphorylation on the primary regulatory enzymes, glycogen synthase (made less active) and glycogen phorphorylase a (made active).

When glycogen synthase is phosphorylated, its activity depends upon the presence of glucose-6-phosphate. It is thus called the dependent form. The unphosphorylated form of glycogen synthase acts independently of glucose-6-phosphate and is called the independent form.

Note in Figure 16.11 that active protein kinase can phosphorylate glycogen synthase directly, in addition to the phosphorylation by synthase-phosphorylase kinase (also called phosphorylase b kinase).

Dephosphorylation of glycogen synthase and glycogen phosphorylase reverses the effects of phosphorylation. This converts glycogen synthase to the independent form and glycogen phosphorylase to a less active form. The primary enzyme responsible for dephosphorylating the glycogen metabolism enzymes is phosphoprotein phosphatase (PP-1). It is regulated by another protein called phosphoprotein phosphatase inhibitor (PI-1). PI-1 is also phosphorylated by active protein kinase. When phosphorylated, PI-1 inhibits PP-1.

Thus, cAMP stimulates a kinase cascade that phosphorylates the regulatory enzymes of glycogen metabolism. It simultaneously activates PI-1, which converts PP-1 to the inactive form. Conversely, action of insulin stimulates phosphatase activity in cells, completely reversing the kinase cascade and reversing the preferred activities of the glycogen metabolism enzymes.

The bottom line:

1. Epinephrine and glucagon stimulate glycogen breakdown. They do this via stimulating production of cAMP, which activates a kinase (phosphorylation) cascade, which activates glycogen phosphorylase, converts glycogen synthase to the dependent form, and inhibits phosphoprotein phosphatase.

2. Insulin stimulates dephosphorylation, which activates phosphoprotein phosphatase, which reverses the activities of the glycogen metabolism, converting glycogen synthase to the independent form and glycogen phosphorylase to the less active form.

See also: Reciprocal Regulation, Kinase Cascade (from chapter 13), Glycogen Breakdown Regulation,