Differential requirement of G alpha12, G alpha13, G alphaq, and G beta gamma 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 NH(2)-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 G alpha(12) and G alpha(13). JNK activation was also inhibited by expression of the G alpha(12)/G alpha(13)-specific inhibitor regulator of G protein signaling (RGS) domain of p115RhoGEF and the G alpha(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 G beta 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 G alpha(12), G alpha(13), and G alpha(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 G alpha(i)- and G beta gamma-dependent pathways. These results clearly demonstrate that differential pathways activate JNK and ERK.
Arai
Ken
K
Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
Maruyama
Yoshiko
Y
Nishida
Motohiro
M
Tanabe
Shihori
S
Takagahara
Shuichi
S
Kozasa
Tohru
T
Mori
Yasuo
Y
Nagao
Taku
T
Kurose
Hitoshi
H
D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism*; D004789:Enzyme Activation; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004268:DNA-Binding Proteins; D019332:Endothelin-1; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins