Diverse effects of two allosteric inhibitors on the phosphorylation state of glycogen phosphorylase in hepatocytes.
Two distinct allosteric inhibitors of glycogen phosphorylase, 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and CP-91149 (an indole-2-carboxamide), were investigated for their effects on the phosphorylation state of the enzyme in hepatocytes in vitro. CP-91149 induced inactivation (dephosphorylation) of phosphorylase in the absence of hormones and partially counteracted the phosphorylation caused by glucagon. Inhibition of glycogenolysis by CP-91149 can be explained by dephosphorylation of phosphorylase a. This was associated with activation of glycogen synthase and stimulation of glycogen synthesis. DAB, in contrast, induced a small degree of phosphorylation of phosphorylase. This was associated with inactivation of glycogen synthase and inhibition of glycogen synthesis. Despite causing phosphorylation (activation) of phosphorylase, DAB is a very potent inhibitor of glycogenolysis in both the absence and presence of glucagon. This is explained by allosteric inhibition of phosphorylase a, which overrides the increase in activation state. In conclusion, two potent phosphorylase inhibitors exert different effects on glycogen metabolism in intact hepatocytes as a result of opposite effects on the phosphorylation state of both phosphorylase and glycogen synthase.
Department of Diabetes, The Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne NE2 4HH, U.K.
Theodore
T
Latsis
Birgitte
B
Andersen
Loranne
L
Agius
D000494:Allosteric Regulation; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001089:Arabinose; D005947:Glucose / Q000494:pharmacology; D024981:Glycogen Phosphorylase / Q000378:metabolism*; D006006:Glycogen Synthase / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D050113:Imino Furanoses; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010762:Phosphorylase a / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013402:Sugar Alcohols / Q000494:pharmacology*
D000577:Amides; C110844:CP 91149; D050113:Imino Furanoses; D007211:Indoles; D013402:Sugar Alcohols; C058137:1,4-dideoxy-1,4-iminoarabinitol; D001089:Arabinose; D024981:Glycogen Phosphorylase; D010762:Phosphorylase a; D006006:Glycogen Synthase; D005947:Glucose