PROTEIN-KINASE-C INVOLVEMENT IN HOMOLOGOUS DESENSITIZATION OF DELTA-OPIOID RECEPTOR-COUPLED TO G(I1)-PHOSPHOLIPASE C ACTIVATION IN XENOPUS OOCYTES

We have developed the coexpression system of both delta-opiold recepto r (DOR1) and M(2)-muscarinic receptor (M(2)) which mediate agonist-evo ked currents due to common post-receptor mechanisms including G(i1) an d phospholipase C (PLC) activation in Xenopus oocytes reconstituted wi th G(i1)alpha. The DOR1-currents by 100 nM D-Ser(2)-leu-enkephalin-Thr (6) (DSLET) were selectively desensitized by 10 nM phorbol 12-myristat e 13-acetate (PMA). The PMA-desensitization of DSLET-currents was abol ished in the presence of calphostin C, a protein kinase C inhibitor, o r reversed by an intracellular injection of calcineurin, a protein pho sphatase 2B. When a higher concentration (3 mu M) of DSLET was used, D SLET-currents were rapidly desensitized by repeated challenges of DSLE T itself. However, repeated challenges of 10 mu M ACh caused no influe nce on such DSLET- or M(2)-currents. The desensitization of DSLET-curr ents was selectively reversed by protein kinase C inhibitors. Similar results were also obtained with various delta-opioid agonists. These r esutis suggest that protein kinase C is involved in the homologous des ensitization of delta-opioid receptors.