Dynorphin A as a Potential Endogenous Ligand for Four Members of the Opioid Receptor Gene Family1

Abstract

Dynorphin A is an endogenous opioid peptide that activates thekappa opioid receptor (KOR) with high potency. Some studies also showed that the distribution and functional activity of dynorphin A are not completely correlated with those of KOR, suggesting that dynorphin A may interact with other receptors. To investigate the possibility that dynorphin A may serve as an agonist for other opioid receptors, we took the advantage of the cloning of the three major types of opioid receptors, mu (MOR),delta (DOR) and KOR, and examined their affinity for and their activation by dynorphin A. We used mammalian cells transfected with each of the cDNA clones for the human receptors hMOR, hDOR, hKOR and showed that dynorphin A displaced [³H]-diprenorphine binding with K_i values in the nanomolar range at all three receptors. We also showed that, when hMOR, hDOR or hKOR was coexpressed with a G protein-activated potassium channel inXenopus oocytes, dynorphin A induced a potassium current with EC₅₀ values in the nanomolar range for all three receptors. Furthermore, we showed that the human hORLl, an opioid receptor-like receptor that has been identified as a novel member of the opioid receptor gene family, displayed dynorphin A binding and functional activation. These results indicate that dynorphin A is capable of binding to and functional activation of all members of the opioid receptor family, suggesting that, as a potential endogenous agonist, its activity in humans may involve interaction with other members of the opioid receptor family in addition tokappa receptors.