FUNCTIONAL SELECTIVITY OF ORPHANIN FQ FOR ITS RECEPTOR COEXPRESSED WITH POTASSIUM CHANNEL SUBUNITS IN XENOPUS-LAEVIS OOCYTES

An opioid-like receptor has been cloned by several groups of researche rs and recently shown to be activated by an endogenous heptadecapeptid e termed orphanin FQ (or nociceptin). We isolated the corresponding mo use cDNA and coexpressed it in Xenopus laevis oocytes with the potassi um channel subunits Kir3.1 (GIRK1) and Kir3.4 (CIR, rcKATP). Orphanin FQ evoked potassium currents, with 50% of the maximal effect at simila r to 1 nM; [Tyr(1)]orphanin FQ was equally effective, and des-Phe-orph anin FQ was without activity. Dynorphin A, dynorphin(1-9), dynorphin(1 -13), and alpha-neoendorphin were >100 times less potent, and other ag onists active at mu-, delta-, and kappa-opioid receptors had no effect . Naloxone (1 mu M) and norbinaltorphimine (1 mu M) had no antagonist action. Conversely, oocytes expressing kappa receptors responded to dy norphin (half-maximal concentration, 0.3 nM) but not to orphanin FQ. T hus, both kappa and orphanin FQ receptors readily couple to potassium channels, but the highly selective activation by dynorphin and orphani n FQ is consistent with distinct functional pathways in vivo.