Regulation of glycogen synthase in rat hepatocytes - Evidence for multiplesignaling pathways

We examined the signaling pathways regulating glycogen synthase (GS) in pri mary cultures of rat hepatocytes. The activation of GS by insulin and gluco se was completely reversed by the phosphatidylinositol 3-kinase inhibitor w ortmannin. Wortmannin also inhibited insulin-induced phosphorylation and ac tivation of protein kinase B/Akt (PKB/Akt) as well as insulin-induced inact ivation of GS kinase-3 (GSK-3), consistent with a role for the phosphatidyl inositol 3-kinase/PKB-Akt/GSK-3 axis in insulin-induced GS activation. Alth ough wortmannin completely inhibited the significantly greater level of GS activation produced by the insulin-mimetic bisperoxovanadium 1,10-phenanthr oline (bpV-(phen)), there was only minimal accompanying inhibition of bpV(p hen)-induced phosphorylation and activation of PKB/Akt, and inactivation of GSK-3. Thus, PKB/Akt activation and GSK-3 inactivation may be necessary bu t are not sufficient to induce GS activation in rat hepatocytes, Rapamycin partially inhibited the GS activation induced by bpV(phen) but not that eff ected by insulin. Both insulin- and bpV(phen)-induced activation of the aty pical protein kinase C (zeta/lambda) (PKC (zeta/lambda)) was reversed by wo rtmannin, Inhibition of PKC (zeta/lambda) with a pseudosubstrate peptide ha d no effect on GS activation by insulin, but substantially reversed GS acti vation by bpV(phen). The combination of this inhibitor with rapamycin produ ced an additive inhibitory effect on bpV(phen)-mediated GS activation. Take n together, our results indicate that the signaling components mammalian ta rget of rapamycin and PKC (zeta/lambda) as well as other yet to be defined effector(s) contribute to the modulation of GS in rat hepatocytes.