Muscle glycogenolysis. Regulation of the cyclic interconversion of phosphorylase a and phosphorylase b.
Regulation of glycogenolysis in skeletal muscle is dependent on a network of interacting enzymes and effectors that determine the relative activity of the enzyme phosphorylase. That enzyme is activated by phosphorylase kinase and inactivated by protein phosphatase-1 in a cyclic process of covalent modification. We present evidence that the cyclic interconversion is subject to zero-order ultrasensitivity, and the effect is responsible for the "flash" activation of phosphorylase by Ca2+ in the presence of glycogen. The zero-order effect is observable either by varying the amounts of kinase and phosphatase or by modifying the ratio of their activities by a physiological effector, protein phosphatase inhibitor-2. The sensitivity of the system is enhanced in the presence of the phosphorylase limit dextrin of glycogen which lowers the Km of phosphorylase kinase for phosphorylase. The in vitro experimental results are examined in terms of physiological conditions in muscle, and it is shown that zero-order ultrasensitivity would be more pronounced under the highly compartmentalized conditions found in that tissue. The sensitivity of this system to effector changes is much greater than that found for allosteric enzymes. Furthermore, the sensitivity enhancement increases more rapidly than energy consumption (ATP) as the phosphorylase concentration increases. Energy effectiveness is shown to be a possible evolutionary factor in favor of the development of zero-order ultrasensitivity in compartmentalized systems.
Meinke
M H
MH
Department of Biochemistry, University of Minnesota, Minneapolis 55455.
Edstrom
R D
RD
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation; D006003:Glycogen / Q000378:metabolism*; D007700:Kinetics; D009132:Muscles / Q000201:enzymology*; D010764:Phosphorylase Kinase / Q000378:metabolism; D010762:Phosphorylase a / Q000378:metabolism*; D010763:Phosphorylase b / Q000378:metabolism*; D011817:Rabbits
D006003:Glycogen; D010762:Phosphorylase a; D010763:Phosphorylase b; D010764:Phosphorylase Kinase; D002118:Calcium