Abstract

Nociceptin is an endogenous peptide that produces its biological effects by binding to the opioid receptor-like (ORL₁) receptor. It has been shown that activation of ORL₁receptor 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 ORL₁receptor 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, G₁₂, G₁₄, and G₁₆ seemed to have functional coupling with the ORL₁ receptor in terms of JNK activation. Stimulation of the endogenous ORL₁ 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 ORL₁ receptor on JNK, and the subsequent activation of c-Jun and activating transcription factor-2.