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Vol. 305, Issue 2, 531-540, May 2003
Opioid Receptor by
Agonists: Etorphine and Levorphanol Reduced Dynorphin A- and
U50,488H-Induced Internalization and Phosphorylation
Department of Pharmacology and Center for Substance Abuse Research,
Temple University School of Medicine, Philadelphia, Pennsylvania
We previously observed that
(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide
(U50,488H) promoted internalization and phosphorylation of the
FLAG-tagged human 
opioid receptor (FLAG-hkor) stably expressed in
Chinese hamster ovary (CHO) cells. In this study, we compared
regulation of the FLAG-hkor expressed in CHO cells by U50,488H,
dynorphin A, etorphine, and levorphanol, which were potent full
agonists as determined by stimulation of guanosine
5'-O-(3-[35S]thio)triphosphate
binding. Using fluorescence flow cytometry, we found that dynorphin
A(1-17), like U50,488H, promoted internalization of the FLAG-hkor in a
time- and dose-dependent manner. The antagonists naloxone and
norbinaltorphimine, having no effect on FLAG-hkor internalization,
effectively blocked dynorphin A(1-17)- and U50,488H-induced internalization. Interestingly, the full agonists etorphine and levorphanol did not cause internalization of the FLAG-hkor but significantly reduced dynorphin A(1-17)- and U50,488H-induced internalization in a dose-dependent manner. Immunofluorescence staining
of FLAG-hkor yielded similar results. Dynorphin A(1-17) and U50,488H
enhanced phosphorylation of FLAG-hkor to a greater extent than
etorphine, but levorphanol did not increase FLAG-hkor phosphorylation.
Etorphine or levorphanol decreased dynorphin- or U50,488H-induced
phosphorylation. It is likely that conformations of the hkor required
for phosphorylation and initiation of internalization are different
from those for activation of G proteins. We also examined whether the
four agonists had differential effects on superactivation of adenylate
cyclase. Pretreatment with U50,488H, dynorphin A(1-17), or etorphine
enhanced forskolin-stimulated adenylate cyclase activity to ~200 to
250% of the control, whereas levorphanol pretreatment did not result
in significant adenylate cyclase superactivation. Thus, the degree of
superactivation caused by an agonist is unrelated to its ability to
promote internalization of the hkor.
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