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Role of mPKCI, a Novel µ-Opioid Receptor Interactive Protein, in Receptor Desensitization, Phosphorylation, and Morphine-Induced Analgesia

Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Baltimore, Baltimore Maryland (W.G., H.W., J.B.W.); and Herbert Irving Comprehensive Cancer Center, College of Physician and Surgeons, Columbia University, New York, New York (T.S., I.B.W.)

The human µ-opioid receptor (HµOR) is a G-protein coupled receptor that mediates analgesia, euphoria and other important central and peripheral neurological functions. In this study, we found in a yeast two-hybrid screen that a protein kinase C-interacting protein (PKCI) specifically interacts with the C terminus of HµOR. The interaction of PKCI with HµOR was recapitulated in Chinese hamster ovary cells that express the full-length HµOR and PKCI proteins. The affinity of HµOR for an opioid ligand and its ability to mediate the activation of a G-protein were not altered by their interaction. However, the association of PKCI with HµOR reduced agonist-induced inhibition of adenylyl cyclase and suppressed HµOR desensitization partially at the G protein level and completely at the adenylyl cyclase level. Furthermore, PMA-induced, but not DAMGO-induced, HµOR phosphorylation was partially inhibited by the coexpression of PKCI, suggesting that PKCI exerts a selective regulatory effect on HµOR signaling. This effect was specific to the µ-opioid receptor because -opioid receptor desensitization was unaffected by PKCI. In addition, behavioral studies revealed that both basal and morphine-induced analgesia were significantly enhanced in the mutant mice that lacked expression of PKCI gene, and these mice developed a greater extent of tolerance to morphine analgesia. Taken together, these results suggest that PKCI functions as a negative regulator in HµOR desensitization, phosphorylation, and in mediating morphine analgesia.

Address correspondence to: Jia Bei Wang, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Baltimore, 20 N Pine Street, Baltimore MD 21201. E-mail: jwang{at}rx.umaryland.edu

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