TY - JOUR T1 - Regulation of c-Jun N-Terminal Kinase by the ORL<sub>1</sub>Receptor through Multiple G Proteins JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1094 LP - 1100 VL - 295 IS - 3 AU - Anthony S. L. Chan AU - Yung H. Wong Y1 - 2000/12/01 UR - http://jpet.aspetjournals.org/content/295/3/1094.abstract N2 - 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 Gi proteins, and partially contributed by a PTX-insensitive component. Among all known PTX-insensitive G proteins, Gz, 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. The American Society for Pharmacology and Experimental Therapeutics ER -