Cloning, gene expression and signal transduction of opioid kappa-receptor

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Here we report the evidence for a novel type of opioid kappa-receptor inhibiting G-protein activity in the guinea pig cerebellum. In guinea pig cerebellar membranes, kappa-agonists inhibit the high-affinity GTPase activity in concentrations lower than those for stimulation of this activity, possibly through known 7-transmembrane type of opioid kappa-receptor. The inhibitory activity was found to be attributed to the direct inhibition of GTP-GDP exchange activity on Gil reconstituted into membranes. Taken into consideration the finding that kappa-receptor agonists inhibit phospholipase C through an inhibition of Gil activity, we attempted to clone this metabostatic receptor which inhibits currents mediated through Gil and phospholipase C in Xenopus oocytes. In Xenopus oocytes coinjected with RNAs of metabotropic glutamate receptor (or muscarinic M2 receptor) and Gila, the kappa-receptor agonists inhibits these metabotropic receptor-mediated currents. These inhibitory effects were completely antagonized by norBNI,an opioid kappa-receptor antagonist. Using conventional strategies, we cloned a novel type of metabostatic kappa-receptor which has no apparent transmembrane domain.