Glycogen metabolism phosphorylase kinase

Fig. 7.18. Regulation of glycogen metabolism in muscle. Phosphorylase kinase stands at the center of regulation of glycogen metabolism. Phosphorylase kinase may exist in an active, phosphorylated form and an inactive, unphosphorylated form. Phosphorylation of phosphorylase kinase is triggered by hormonal signals (e.g. adrenahne) and takes place via an activation of protein kinase A in the cAMP pathway. In the absence of hormonal stimulation, phosphorylase kinase can also be activated by an increase in cytosolic Ca. The active phosphorylase kinase stimulates glycogen degradation and inhibits glycogen synthesis, in that, on the one side, it activates glycogen phosphorylase by phosphorylation, and on the other side, it inactivates glycogen synthase by phosphorylation.

Glycogen and its enzymes are compartmentalized. Glycogen granules are only present in astrocytes of adult animals but are found in both astrocytes and neurons of immature animals. Of the enzymes involved in glycogen metabolism, glycogen phosphorylase is found in astrocytes only. Under steady-state conditions, it is probable that less than 10% of phosphorylase in brain is in the unphosphorylated b form (requiring AMP). This form is probably not very active at the low AMP concentrations present when intracellular glucose is sufficient to maintain ATP synthesis. Brain phosphorylase b kinase is activated indirectly by cAMP and by the molar concentrations... 

Metabolic Effects of Mutant Enzymes Predict and explain the effect on glycogen metabolism of each of the following defects caused by mutation (a) loss of the cAMP-binding site on the regulatory subunit of protein kinase A (PKA) (b) loss of the protein phosphatase inhibitor (inhibitor 1 in Fig. 15-40) (c) overexpression of phosphorylase b kinase in liver (d) defective glucagon receptors in liver. 

Two key regulatory enzymes involved in the control of glycogen metabolism were first recognized as targets of cAMP and cAMP-dependent protein kinase in liver and skeletal muscle. These are phosphorylase b kinase and glycogen synthase. The molecular details of the phosphorylation and regulation of these enzymes are better understood in muscle than in liver since the liver enzymes have only recently been purified to homogeneity in the native form. However, it appears that they share many key features in common. 

It is not intended to discuss in this review the conditions involving well-recognized defects in enzymes concerned in muscle glycogen metabolism, which have been dealt with adequately in a previous volume (S22). A recent addition to this category, however, is described by Hug et al. (H13), who were unable to find any detectable activity of the cyclic 3, 5 -AMP dependent phosphorylase kinase kinase in the muscle of a girl patient. 

Protein phosphatase-1 (Mg +/ATP-dependent phosphatase multisubstrate protein phosphatase M.W. of catalytic subunit is 35,000 major enzyme in regulation of glycogen metabolism in skeletal muscle dephosphorylates glycogen phosphorylase, jS-subunit of phosphorylase kinase, and at least three sites of glycogen synthase regulated by inhibitor-1, inhibitor-2, and GSK-3 -t- Mg +- ATP). 

Whether glycogen synthase is a substrate for phosphorylase kinase in vivo is unclear. [Modified and reproduced with permission from P. Cohen, Protein phosphorylation and the control of glycogen metabolism in skeletal muscle. Philos. Trans. R. Soc. Land. (Biol.) 302, 13 (1983).]... 

When bound to calcium, calmodulin plays a special role as an integral subunit of the glycogen metabolism enzyme, phosphorylase b kinase. Hence, the glycogenolysis cascade depends on intracellular calcium concentration as well as on cyclic AMP levels. This dependence is particularly... 

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. 

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