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Vol. 58, Issue 2, 388-398, August 2000
Department of Pharmacology, 6-120 Jackson Hall, University of
Minnesota, Minneapolis, Minnesota
Previously, we reported that the time course for the rapid
phosphorylation rate of µ-opioid receptor expressed in human
embryonic kidney (HEK)293 cells did not correlate with the slow
receptor desensitization rate induced by
[D-Ala2,N-MePhe4,Gly-ol5]-enkephalin
(DAMGO). However, others have suggested that receptor phosphorylation is the trigger for µ-opioid receptor desensitization. In this study, we demonstrated the relatively slow rate of receptor desensitization could be attributed partially to the recycling of
internalized receptor as determined by fluorescence-activated cell-sorting analysis. However, the blockade of the endocytic and Golgi transport events in HEK293 cells with monensin and brefeldin A did not increase the initial rate of receptor desensitization. But
the desensitization rate was increased by reduction of the µ-opioid
receptor level with 
-furnaltrexamine (FNA). The reduction of the
receptor level with 1 µM FNA significantly increased the rate of
etorphine-induced receptor desensitization. By blocking the ability of
receptor to internalize with 0.4 M sucrose, a significant degree of
receptor being rapidly desensitized was observed in HEK293 cells
pretreated with FNA. Hence, µ-opioid receptor is being
resensitized during chronic agonist treatment. The significance of
resensitization of the internalized receptor in affecting receptor desensitization was demonstrated further with human neuroblastoma SHSY5Y cells that expressed a low level of µ-opioid receptor. Although DAMGO could not induce a rapid desensitization in these cells,
in the presence of monensin and brefeldin A, DAMGO desensitized the
µ-opioid receptor's ability to regulate adenylyl cyclase with a
t1/2 = 9.9 ± 2.1 min and a maximal
desensitized level at 70 ± 4.7%. Furthermore, blockade of
receptor internalization with 0.4 M sucrose enhanced the DAMGO-induced
receptor desensitization, and the inclusion of monensin prevented the
resensitization of the µ-opioid receptor after chronic agonist
treatment in SHSY5Y cells. Thus, the ability of the µ-opioid receptor
to resensitize and to recycle, and the relative efficiency of the
receptor to regulate adenylyl cyclase activity, contributed to the
observed slow rate of µ-opioid receptor desensitization in HEK293 cells.
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