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Rac and Cdc42‐dependent regulation of c‐Jun N‐terminal kinases by the δ‐opioid receptor
Author(s) -
Kam Angel Y. F.,
Chan Anthony S. L.,
Wong Yung H.
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01535.x
Subject(s) - microbiology and biotechnology , kinase , proto oncogene tyrosine protein kinase src , receptor tyrosine kinase , tyrosine kinase , g protein coupled receptor kinase , biology , chemistry , signal transduction , g protein coupled receptor
Heptahelical opioid receptors utilize G i 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 NH 2 ‐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.