Phospholipase C-independent activation of glycogen synthase kinase-3β and C-terminal Src kinase by Gαq

It is generally thought that activation of phospholipase Cbeta (PLCbeta) by Galpha(q) accounts for most of the effects of G(q)-coupled receptors. Here we describe a novel effect of Galpha(q) that is independent of the PLCbeta pathway. Expression of the constitutively active Galpha(q) mutant Galpha(q)(Q209L) promoted an increase in glycogen synthase kinase-3beta (GSK-3beta) activity that was associated with increased phosphorylation of Tyr(216) on GSK-3beta. Galpha(q)(Q209L)-AA, a mutant that cannot activate PLCbeta, also induced GSK-3beta activation and phosphorylation of Tyr(216). We speculate that the protein-tyrosine kinase Csk (C-terminal Src kinase), which is also activated by Galpha(q) (Q209L) and Galpha(q)(Q209L)-AA, acts upstream of GSK-3beta. Expression of Csk accentuated the activation of GSK-3beta by Galpha(q)(Q209L), whereas catalytically inactive Csk blocked GSK-3beta activation by Galpha(q)(Q209L). Recombinant Csk phosphorylated and activated GSK-3beta in vitro, and GSK-3beta coprecipitated with Csk from cell lysates. These results suggest that activation of Csk and GSK-3beta by Galpha(q) may contribute to the physiological and pathological effects of G(q)-coupled receptors.