Phospholipase C-independent Activation of Glycogen Synthase Kinase-3β and C-terminal Src Kinase by Gαq

Abstract It is generally thought that activation of phospholipase Cβ (PLCβ) by Gαq accounts for most of the effects of Gq-coupled receptors. Here we describe a novel effect of Gαq that is independent of the PLCβ pathway. Expression of the constitutively active Gαq mutant Gαq(Q209L) promoted an increase in glycogen synthase kinase-3β (GSK-3β) activity that was associated with increased phosphorylation of Tyr216 on GSK-3β. Gαq(Q209L)-AA, a mutant that cannot activate PLCβ, also induced GSK-3β activation and phosphorylation of Tyr216. We speculate that the protein-tyrosine kinase Csk (C-terminal Src kinase), which is also activated by Gαq(Q209L) and Gαq(Q209L)-AA, acts upstream of GSK-3β. Expression of Csk accentuated the activation of GSK-3β by Gαq(Q209L), whereas catalytically inactive Csk blocked GSK-3β activation by Gαq(Q209L). Recombinant Csk phosphorylated and activated GSK-3β in vitro, and GSK-3β coprecipitated with Csk from cell lysates. These results suggest that activation of Csk and GSK-3β by Gαq may contribute to the physiological and pathological effects of Gq-coupled receptors.