Regulation of C-jun N-terminal kinase by the ORL1 receptor through multiple G proteins

Nociceptin is an endogenous peptide that produces its biological effects by binding to the opioid receptor-like (ORL1) receptor. It has been shown tha t activation of ORL1 receptor leads to inhibition of the adenylyl cyclase a ctivity, but stimulation of the extracellular signal-regulated kinase and p 38 subgroups of mitogen-activated protein kinases. In this report, we demon strate that activation of the G protein-coupled ORL1 receptor in transfecte d 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 w ortmannin. This increased JNK activity was mainly mediated by PTX-sensitive G(i) proteins, and partially contributed by a PTX-insensitive component. A mong all known PTX-insensitive G proteins, G(z),G(12),G(14), and G(16) seem ed to have functional coupling with the ORL1 receptor in terms of JNK activ ation. Stimulation of the endogenous ORL1 receptor in NG108-15 cells also l ed to activation of a PTX-sensitive JNK activity in a wortmannin-insensitiv e manner. The induced JNK activation is accompanied by the active phosphory lation of c-Jun and activating transcription factor-2. This is the first re port that demonstrates the stimulatory effect of ORL1 receptor on JNK, and the subsequent activation of c-Jun and activating transcription factor-2.