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Vol. 63, Issue 3, 478-488, March 2003

Differential Requirement of Galpha 12, Galpha 13, Galpha q, and Gbeta gamma for Endothelin-1-Induced c-Jun NH2-Terminal Kinase and Extracellular Signal-Regulated Kinase Activation

Ken Arai, Yoshiko Maruyama, Motohiro Nishida, Shihori Tanabe, Shuichi Takagahara, Tohru Kozasa, Yasuo Mori, Taku Nagao, and Hitoshi Kurose

Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.A., Y.M., M.N., S.Tan., S.Tak., T.N., H.K.); Division of Molecular and Cellular Physiology, Center for Integrative Bioscience, National Institute for Physiological Sciences, Okazaki, Japan (M.N., Y.,M.); and Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois (T.K.)

In the present study, we examined the roles of G12, G13, Gq, and Gi 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 Gbeta gamma -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-Gi uncoupler, and GRK2-ct. Thus, ERK was activated by Galpha i- and Gbeta gamma -dependent pathways. These results clearly demonstrate that differential pathways activate JNK and ERK.


Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics



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