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

It is generally thought that activation of phospholipase Cβ (PLCβ) by Gα_q accounts for most of the effects of G _q-coupled receptors. Here we describe a novel effect of Gα _q that is independent of the PLCβ pathway. Expression of the constitutively active Gα_q mutant Gα_q(Q209L) promoted an increase in glycogen synthase kinase-3β (GSK-3β) activity that was associated with increased phosphorylation of Tyr²¹⁶ on GSK-3β. Gα_q(Q209L)-AA, a mutant that cannot activate PLCβ, also induced GSK-3β activation and phosphorylation of Tyr ²¹⁶. We speculate that the protein-tyrosine kinase Csk (C-terminal Src kinase), which is also activated by Gα_q(Q209L) and Gα_q(Q209L)-AA, acts upstream of GSK-3β. Expression of Csk accentuated the activation of GSK-3β by Gα_q(Q209L), whereas catalytically inactive Csk blocked GSK-3β activation by Gα_q(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 Gα _q may contribute to the physiological and pathological effects of G_q-coupled receptors.