Phosphorylase kinase glycogenolysis

Glycogenolysis increases in muscle several hundred-fold immediately after the onset of contraction. This involves the rapid activation of phosphorylase by activation of phosphorylase kinase by Ca +, the same signal as that which initiates contraction in response to nerve stimulation. Muscle phosphorylase kinase has four... 

Not only is phosphorylase activated by a rise in concentration of cAMP (via phosphorylase kinase), but glycogen synthase is at the same time converted to the inactive form both effects are mediated via cAMP-dependent protein kinase. Thus, inhibition of glycogenolysis enhances net glycogenesis, and inhibition of glycogenesis enhances net glycogenolysis. Furthermore,... 

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. 

Since phosphorylase kinase not only activates phosphorylase, but also phospho-rylates glycogen synthase thereby decreasing its activity, the regulation of phosphorylase kinase by calcium may also provide a mechanism for co-ordinating the rates of glycogenolysis and glycogen synthesis during muscle contraction. 

Ca + is required for phosphorylase activation in fat bodies of both P, americana (25) and discoidalis (personal observation). Addition of Ca + elevates fat body phosphorylase kinase activity in P. americana (33). and calmodulin inhibitors suppress CC-stimulated trehalose production by the fat body in vitro. However, direct addition of calmodulin to fat body phosphorylase kinase also suppresses the kinase activity. It is proposed that Ca + interacts directly with a calmodulin-like subunit of phosphorylase kinase to activate the enzyme, and the presence of exogenous calmodulin competes with the enzymic subunit for available Ca + (33). These results suggest that the HGHs may influence adipocyte Ca + levels related to phosphorylase activation to promote glycogenolysis for trehalose synthesis. Possibly, HGH-mediated fat body Ca levels may interact with polyphosphoinositides, diacyl glycerol and protein kinase C as second messengers for endocrine message transduction and phosphorylase activation. 

Initiation of muscle contraction by action potential from an a motor neuron depolarizes the muscle-cell membrane and causes an increase in the myoplasmic [Ca " ] (Chapter 21). The increase in calcium activates phosphorylase kinase and Ca +/calmoduIin-dependent kinase, which inactivate glycogen synthase and active glycogen phosphorylase (Figure 15-11). This step coordinates muscle contraction with glycogenolysis. These steps are reversed by one or more phosphatases at the end of contraction. 

Another advantage of a cascade is the possibility of intervening anywhere along the cascade, not only at the initiation. In the case of the phosphorylase cascade, phosphorylase kinase in the inactive (i.e., nonphosphorylated) form can be activated allosterically by calcium, thus causing phosphorylase kinase to catalyze the phosphorylation of phosphorylase to the active form, causing increased glycogenolysis. One of the subunits of phosphorylase kinase is a polypeptide known as calmodulin. This polypeptide occurs in many proteins that require or have Ca2+ as an effector. This polypeptide in phosphorylase kinase results in the ca2+ activation of this enzyme. The binding of Ca2+ by the calmodulin subunit of phosphorylase kinase also facilitates a more rapid phosphorylation of this enzyme by the cAMP-dependent protein kinase. 

The liver is also affected by epinephrine in this case, the a-1 receptors are activated by epinephrine. This will cause an increase in intracellular liver Ca2+, via IP3, an allosteric activator of phosphorylase kinase which will catalyze the phosphorylation of phosphorylase and thereby activation. This increase in active phosphorylase will rapidly increase glycogenolysis and provide hexosphosphates, which in the case of liver are not used primarily for glycolysis but, via the action of glucose-6-phosphatase, augment the blood glucose levels (Fig. 16.10). 

Glycogen phosphorylase has been purified from adult A. suum muscle (3). The dephosphorylated enzyme, which requires AMP for activity, can be phosphorylated and activated by rabbit muscle phosphorylase kinase. Kinetic data and the observation that phosphorylase is not at equilibrium with its substrates and products, indicate that phosphorylase catalyzes the rate-limiting step of glycogenolysis in A. suum muscle. Phosphorylase activity correlates well with the rate of glycogenolysis observed in vivo... 

Fig. 28.10. Activation of muscle glycogen phosphorylase during exercise. Glycogenolysis in skeletal muscle is initiated by muscle contraction, neural impulses, and epinephrine. LAMP produced from the degradation of ATP during muscular contraction allosterically activates glycogen phosphorylase b. 2. The neural impulses that initiate contraction release Ca from the sarcoplasmic reticulum. The Ca binds to calmodulin, which is a modifier protein that activates phosphorylase kinase. 3. Phosphorylase kinase is also activated through phosphorylation by protein kinase A. The formation of cAMP and the resultant activation of protein kinase A are initiated by the binding of epinephrine to plasma membrane receptors.

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