Rac and Cdc42-dependent regulation of c-Jun N-terminal kinases by the δ-opioid receptor
Article first published online: 13 JAN 2003
Journal of Neurochemistry
Volume 84, Issue 3, pages 503–513, February 2003
How to Cite
Kam, A. Y. F., Chan, A. S. L. and Wong, Y. H. (2003), Rac and Cdc42-dependent regulation of c-Jun N-terminal kinases by the δ-opioid receptor. Journal of Neurochemistry, 84: 503–513. doi: 10.1046/j.1471-4159.2003.01535.x
- Issue published online: 13 JAN 2003
- Article first published online: 13 JAN 2003
- Received April 15, 2002; revised manuscript received October 15, 2002; accepted October 17, 2002.
- δ-opioid receptor;
- EGF receptor;
- small GTPases;
Heptahelical opioid receptors utilize Gi proteins to regulate a multitude of effectors including the classical adenylyl cyclases and the more recently discovered mitogen-activated protein kinases (MAPKs). The c-Jun NH2-terminal kinases (JNKs) belong to one of three subgroups of MAPKs. In NG108-15 neuroblastoma × glioma hybrid cells that endogenously express δ-opioid receptors, δ-agonist dose-dependently stimulated JNK activity in a pertussis toxin-sensitive manner. By using COS-7 cells transiently transfected with the cDNAs of δ-opioid receptor and hemagglutinin (HA)-tagged JNK, we delineated the signaling components involved in this pathway. Sequestration of Gβγ subunits by transducin suppressed the opioid-induced JNK activity. The possible involvement of the small GTPases was also examined. Expression of dominant negative mutants of Rac and Cdc42 blocked the opioid-induced JNK activation, and a partial inhibition was observed in the presence of the dominant negative mutant of Ras. In contrast, the dominant negative mutant of Rho did not affect the opioid-induced JNK activation. In addition, the receptor-mediated JNK activation was dependent on Src family tyrosine kinases, but independent of phosphatidylinositol-3 kinase and EGF receptor tyrosine kinases. Collectively, these results demonstrate functional regulation of JNK by the δ-opioid receptor, and this pathway requires Gβγ, Src kinases and the small GTPases Rac and Cdc42.