PT  - JOURNAL ARTICLE
AU  - Angel Y. F. Kam
AU  - Anthony S. L. Chan
AU  - Yung H. Wong
TI  - κ-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
AID  - 10.1124/jpet.104.065078
DP  - 2004 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 301--310
VI  - 310
IP  - 1
4099  - http://jpet.aspetjournals.org/content/310/1/301.short
4100  - http://jpet.aspetjournals.org/content/310/1/301.full
SO  - J Pharmacol Exp Ther2004 Jul 01; 310
AB  - Opioid peptides exert diverse physiological functions through their cognate receptors. One subtype of the opioid receptors, κ-opioid receptor, is endogenously expressed in human monocytic THP-1 cells. Stimulation of the THP-1 cells with a κ-opioid receptor-selective agonist exerted a Gi-dependent activation of c-Jun N-terminal kinase (JNK). To further investigate the signaling mechanism by which the κ-opioid receptor regulates JNK activity, heterologous expression assays in COS-7 cells were utilized. Overexpression of Gαt in COS-7 cells clearly suppressed κ-opioid receptor-stimulated JNK activity, indicating that the pathway is primarily regulated by Gβγ. 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 κ-opioid receptor was suppressed by an autophosphorylation-resistant mutant of focal adhesion kinase (FAK). Consistently, activated κ-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 κ-opioid receptors is routed via Gβγ, Src, FAK, Sos, Rac, and Cdc42. The American Society for Pharmacology and Experimental Therapeutics