Differential requirement of Gα12, Gα13, Gαq, and Gβγ for endothelin-1-induced c-Jun NH2-terminal kinase and extracellular signal-regulated kinase activation

In the present study, we examined the roles of G(12), G(13), G(q), and G(i) in endothelin-1-induced hypertrophic responses. Endothelin-1 stimulation activated extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) in cultured rat neonatal myocytes. The activation of JNK, but not ERK, was inhibited by the expression of carboxyl terminal regions of Galpha(12) and Galpha(13). JNK activation was also inhibited by expression of the Galpha(12)/Galpha(13)-specific inhibitor regulator of G protein signaling (RGS) domain of p115RhoGEF and the Galpha(q)-specific inhibitor RGS domain of the G protein-coupled receptor kinase 2 (GRK2-RGS). JNK activation was not, however, inhibited by expression of the carboxyl terminal region of G protein-coupled receptor kinase 2 (GRK2-ct), which is a Gbetagamma-sequestering polypeptide. Additionally, JNK activation but not ERK activation was inhibited by the expression of C3 exoenzyme that inactivates small GTPase Rho. These results suggest that JNK activation by Galpha(12), Galpha(13), and Galpha(q) is involved in Rho. On the other hand, ERK activation was inhibited by pertussis toxin treatment, the receptor-G(i) uncoupler, and GRK2-ct. Thus, ERK was activated by Galpha(i)- and Gbetagamma-dependent pathways. These results clearly demonstrate that differential pathways activate JNK and ERK.