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CELLULAR AND MOLECULAR

-Opioid Receptor Signals through Src and Focal Adhesion Kinase to Stimulate c-Jun N-Terminal Kinases in Transfected COS-7 Cells and Human Monocytic THP-1 Cells

Department of Biochemistry, Molecular Neuroscience Center, and Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

Opioid peptides exert diverse physiological functions through their cognate receptors. One subtype of the opioid receptors, -opioid receptor, is endogenously expressed in human monocytic THP-1 cells. Stimulation of the THP-1 cells with a -opioid receptor-selective agonist exerted a G_i-dependent activation of c-Jun N-terminal kinase (JNK). To further investigate the signaling mechanism by which the -opioid receptor regulates JNK activity, heterologous expression assays in COS-7 cells were utilized. Overexpression of G_t in COS-7 cells clearly suppressed -opioid receptor-stimulated JNK activity, indicating that the pathway is primarily regulated by G. In both THP-1 and transfected COS-7 cells, pretreatment of the selective Src family kinase inhibitor pyrazolopyrimidine PP1 abolished the JNK activation, whereas the epidermal growth factor receptor inhibitor AG1478 [N-(3-chlorophenyl)-6,7-dimethoxy-4-quinazolinanine] failed to do that. Furthermore, the JNK activation in response to -opioid receptor was suppressed by an autophosphorylation-resistant mutant of focal adhesion kinase (FAK). Consistently, activated -opioid receptor induced Src stimulation and FAK autophosphorylation and promoted the formation of Src-FAK complex. The participation of small GTPases as well as a guanine nucleotide exchange factor was also implicated because dominant-negative mutants of Rac, Cdc42, and Son-of-sevenless (Sos) attenuated the agonist-induced activation of JNK. These studies demonstrate that the activation of JNK by -opioid receptors is routed via G, Src, FAK, Sos, Rac, and Cdc42.

Address correspondence to: Prof. Yung H. Wong, Department of Biochemistry, the Molecular Neuroscience Center, and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong. E-mail: boyung{at}ust.hk

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