ADP and glucose as possible synergistic partners in the stimulation of liver glycogen synthase activation.
Glucose administered either intravenously or orally causes liver glycogen synthase activation independent of a rise in circulating insulin. In vitro, physiological concentrations of glucose stimulate synthase phosphatase activity but only in the presence of a second effector which reduced the A0.5 for glucose. Caffeine and certain methylxanthines have been in vitro models for a putative natural effector. The present study demonstrates that, in vitro, ADP also reduced the A0.5 for glucose comparable to the effect of caffeine. The maximum stimulation by glucose in the presence of caffeine or ADP was comparable. The effect of ADP was specific among the major nucleoside diphosphates. However, the A0.5 for ADP was greater than the normal liver concentration which does not change in response to either glucose or insulin administration. The effect of ADP appeared distinct from that of the methylxanthines since it was observed that at near saturating concentrations of ADP and of glucose, stimulation was increased by addition of theophylline. Similarly, addition of adenosine, a natural cell constituent, caused increased stimulation. Subsequently, it was shown that adenosine reduced the A0.5 for ADP to a nearly physiological concentration. Thus, while ADP is not the inducible putative effector which has been predicted it may be part of an intracellular amplification system for glycogen synthase activation which increases the sensitivity to an induced effector. The present work suggests that the effective concentration of the natural ligand may be less than originally anticipated. This work also suggests that the putative effector could be structurally related to adenosine. Phosphorylase phosphatase activity known to be stimulated by ADP and glucose is further stimulated by the combination which may be acting in synergy.
Gilboe
D P
DP
Veterans Administration Medical Center, Minneapolis, Minnesota 55417.
D000241:Adenosine / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000818:Animals; D003565:Cytidine Diphosphate / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation; D005947:Glucose / Q000494:pharmacology*; D006006:Glycogen Synthase / Q000378:metabolism*; D006007:Glycogen-Synthase-D Phosphatase / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013806:Theophylline / Q000494:pharmacology; D014530:Uridine Diphosphate / Q000494:pharmacology
D006153:Guanosine Diphosphate; D014530:Uridine Diphosphate; D000244:Adenosine Diphosphate; D003565:Cytidine Diphosphate; D013806:Theophylline; D006006:Glycogen Synthase; D006007:Glycogen-Synthase-D Phosphatase; D005947:Glucose; D000241:Adenosine