Vol. 295, Issue 3, 1094-1100, December 2000

Regulation of c-Jun N-Terminal Kinase by the ORL₁ Receptor through Multiple G Proteins¹

Anthony S. L. Chan and Yung H. Wong

Department of Biochemistry and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

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 ORL₁ 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 ORL₁ 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, 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.