Differential requirement of Gα₁₂, Gα₁₃, Gα₁₃, 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 G₁₂, G₁₃, 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 Gα₁₂ and Gα₁₃. JNK activation was also inhibited by expression of the Gα₁₂/Gα₁₃-specific inhibitor regulator of G protein signaling (RGS) domain of p115RhoGEF and the Gα_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 Gβγ-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 Gα₁₂, Gα₁₃, and Gα_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 Gα_i- and Gβγ-dependent pathways. These results clearly demonstrate that differential pathways activate JNK and ERK.