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Vol. 285, Issue 1, 28-36, April 1998
Department of Pharmacology, Temple University School of Medicine,
Philadelphia, Pennsylvania
In this study, we examined whether the human kappa
opioid receptor stably expressed in Chinese hamster ovary cells
underwent desensitization and down-regulation after prolonged exposure
to the agonist (
)U50,488H. Pretreatment with ()U50,488H led to a
reduction in the magnitude of increase in [35S]GTP
S
binding by the subsequent application of ()U50,488H. The extent of
desensitization was related to duration of exposure and ()U50,488H
concentration. Pretreatment with ()U50,488H also reduced the potency
of ()U50,488H in inhibiting forskolin-stimulated adenylate cyclase.
In membranes of ()U50,488H-pretreated cells, the affinity of
()U50,488H was lower than that in the untreated control, and GTPS
had no effect on ()U50,488H affinity, consistent with the notion of
uncoupling of the receptor-G protein complex by ()U50,488H treatment.
Down-regulation of the kappa opioid receptor also
occurred on exposure to ()U50,488H. Higher ()U50,488H concentrations and/or longer incubation periods were required for
down-regulation than for desensitization. The degree of down-regulation depended on the agonist concentration and incubation time.
()U50,488H-induced desensitization and down-regulation were blocked
by naloxone. (+)U50,488H, an inactive stereoisomer, did not cause
desensitization or down-regulation. These results indicate that both
processes were receptor-mediated. After incubation with ()U50,488H
and removal of ()U50,488H, both ()U50,488H-induced
[35S]GTPS binding and receptor number returned to the
control level, which indicates that both processes were reversible.
Thus, desensitization and down-regulation of the kappa
opioid receptor occur after agonist exposure and represent two
different adaptation mechanisms.
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