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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 2, 2004; DOI: 10.1124/jpet.104.065078

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Received for publication January 5, 2004.
Revised February 18, 2004.
Accepted for publication March 1, 2004.

{kappa}-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

Angel Y.F. Kam 1, Anthony S.L. Chan 1, Yung H. Wong 1*

1 Hong Kong University of Science & Technology

* Address correspondence to: E-mail: boyung{at}ust.hk

Abstract

Opioid peptides exert diverse physiological functions through their cognate receptors. One subtype of opioid receptors, {kappa}-opioid receptor is endogenously expressed in human monocytic THP-1 cells. Stimulation of the THP-1 cells with a {kappa}-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 {kappa}-opioid receptor regulates JNK activity, heterologous expression assays in COS-7 cells were utilized. Overexpression of G{alpha}t in COS-7 cells clearly suppressed {kappa}-opioid receptor-stimulated JNK activity, indicating that the pathway is primarily regulated by G{beta}{gamma}. In both THP-1 and transfected COS-7 cells, pretreatment of the selective Src family kinase inhibitor PP1 abolished the JNK activation, whereas the EGF receptor inhibitor AG1478 failed to do that. Furthermore, the JNK activation in response to {kappa}-opioid receptor was suppressed by an autophosphorylation-resistant mutant of focal adhesion kinase (FAK). Consistently, activated {kappa}-opioid receptor induced Src stimulation, 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 attenuated the agonist-induced activation of JNK. These studies demonstrate that the activation of JNK by {kappa}-opioid receptors is routed via G{beta}{gamma}, Src, FAK, Sos, Rac and Cdc42.


Key words: FAK, G protein, JNK, Src, opioid receptor, signal transduction


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