SIGNALING FROM G-PROTEIN-COUPLED RECEPTORS TO C-JUN KINASE INVOLVES BETA-GAMMA-SUBUNITS OF HETEROTRIMERIC G-PROTEINS ACTING ON A RAS AND RAC1-DEPENDENT PATHWAY

Stimulation of a variety of cell surface receptors enhances the enzyma tic activity of mitogen-activated protein kinases (MAPKs). MAPKs have been classified in three subfamilies: extracellular signal-regulated k inases (ERKs), Stress-activated protein kinases or c-Jun NH2-terminal kinases (SAPKs/JNKs), and p38 kinase. Whereas the pathway linking cell surface receptors to ERKs has been partially elucidated, the mechanis m of activation of JNKs is still poorly understood. Recently, we have shown that stimulation of G protein-coupled receptors can effectively induce JNK in NIH 3T3 cells (Coso, O. A., Chiariello, M., Kalinec, G., Kyriakis, J. M., Woodgett, J., and Gutkind, J. S. (1995) J. Biol. Che m. 270, 5620-5624). In the present study, we have used the transient e xpression in COS-7 cells of m1 and m2 muscarinic receptors (mAChRs) as a model system to study the signaling pathway linking G protein-coupl ed receptors to JNK. We show that stimulation of either muscarinic rec eptor subtype leads to JNK activation; however, this effect was not mi micked by expression of activated forms of alpha(s), alpha(i2), alpha( q), or alpha(13) G protein alpha subunits. In contrast, overexpression of G beta gamma subunits potently induced JNK activity. Furthermore, we show that signaling from mi and m2 mAChRs to JNK involves beta gamm a subunits of heterotrimeric G proteins, acting on a Ras and Rac1-depe ndent pathway.