Regulation of c-Jun N-terminal kinase by the ORL(1) receptor through multiple G proteins.

Nociceptin is an endogenous peptide that produces its biological effects by binding to the opioid receptor-like (ORL(1)) receptor. It has been shown that activation of ORL(1) receptor leads to inhibition of the adenylyl cyclase activity, but stimulation of the extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases. In this report, we demonstrate that activation of the G protein-coupled ORL(1) receptor in transfected COS-7 cells leads to stimulation of the JNK subgroup of mitogen-activated protein kinases in a Ras/Rac-dependent manner, and it was insensitive to wortmannin. This increased JNK activity was mainly mediated by PTX-sensitive G(i) proteins, and partially contributed by a PTX-insensitive component. Among all known PTX-insensitive G proteins, G(z), G(12), G(14), and G(16) seemed to have functional coupling with the ORL(1) receptor in terms of JNK activation. Stimulation of the endogenous ORL(1) receptor in NG108-15 cells also led to activation of a PTX-sensitive JNK activity in a wortmannin-insensitive manner. The induced JNK activation is accompanied by the active phosphorylation of c-Jun and activating transcription factor-2. This is the first report that demonstrates the stimulatory effect of ORL(1) receptor on JNK, and the subsequent activation of c-Jun and activating transcription factor-2.