Dual regulation of glycogen synthase kinase-3 beta by the alpha(1A)-adrenergic receptor

Catecholamines, acting through adrenergic receptors, play an important role in modulating the effects of insulin on glucose metabolism. Insulin activa tion of glycogen synthesis is mediated in part by the inhibitory phosphoryl ation of glycogen synthase kinase-3 (GSK-3). In this study, catecholamine r egulation of GSK-3 beta was investigated in Rat-1 fibroblasts stably expres sing the alpha (1A)-adrenergic receptor. Treatment of these cells with eith er insulin or phenylephrine (PE), an al-adrenergic receptor agonist, induce d Ser-9 phosphorylation of GSK-3 beta and inhibited GSK-3 beta activity. In sulin-induced GSK-3 beta phosphorylation is mediated by the phosphatidylino sitol 3-kinase/Akt signaling pathway. PE treatment does not activate phosph atidylinositol 3-kinase or Akt (Ballou, L. M., Cross, M. E., Huang, S., McR eynolds, E. M., Zhang, B. X., and Lin, R. Z. (2000) J. Biol. Chem. 275, 480 3-4809), but instead inhibits insulin-induced Akt activation and GSK-3 beta phosphorylation. Experiments using protein kinase C (PKC) inhibitors sugge st that phorbol ester-sensitive novel PKC and Go 6983-sensitive atypical PK C isoforms are involved in the PE-induced phosphorylation of GSK-3 beta. In deed, PE treatment of Rat-1 cells increased the activity of atypical PKC ze ta, and expression of PKC zeta in COS-7 cells stimulated GSK-3 beta Ser-9 p hosphorylation. In addition, PE-induced GSK-3 beta phosphorylation was redu ced in Rat-1 cells treated with a cell-permeable PKC zeta pseudosubstrate p eptide inhibitor. These results suggest that the alpha (1A)-adrenergic rece ptor regulates GSK-3 beta through two signaling pathways. One pathway inhib its insulin-induced GSK-3 beta phosphorylation by blocking insulin activati on of Akt. The second pathway stimulates Ser-9 phosphorylation of GSK3 beta , probably via PKC.