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Vol. 52, Issue 6, 993-999, 1997
Institute of Pharmacology, Toxicology and Pharmacy, University of
Munich, D-80539 München, Germany
Chronic opioid treatment of stably µ-opioid receptor transfected
human mammary epidermoid A431 carcinoma cells (clone A431/µ13) results in sensitization of adenylyl cyclase (AC), a cellular adaptation associated with drug dependence. Up-regulation of AC is
characterized by significantly increased levels of both basal and
post-receptor-stimulated effector activities, which develop without any
apparent change in the quantity of stimulatory G proteins and the
maximum catalytic activity of AC. Here, we report that detergent
extracts from membranes of chronically morphine-treated (10 µM; 2 days) A431/µ13 cells display higher stimulatory
AC activities as assessed in the S49cyc
reconstitution assay. This finding is most likely due to an increased functional activity of Gs
because the addition of
exogenous G
subunits, which per se
stimulate AC in S49cyc membranes, failed to
affect the difference in reconstitutive AC activity. Moreover, both
chemical depalmitoylation by hydroxylamine and inhibition of
palmitoyl-CoA transferase in vivo by tunicamycin treatment increased the reconstitutive activity of detergent extracts and eliminated the differences between native and opioid-dependent cells, indicating that the increase in stimulatory activity is due to
depalmitoylation of Gs. Indeed, metabolic labeling studies with [3H]palmitic acid revealed that chronic
opioid treatment reduces considerably the fraction of palmitoylated
Gs in the plasma membrane. Furthermore, high affinity
[3H]forskolin binding experiments demonstrated that
depalmitoylated Gs is able to associate directly with AC
during the state of opioid dependence even without preceding receptor
activation. These results suggest that post-translational
palmitoylation of Gs provides a potential regulator of
transmembrane signaling. Moreover, accumulation of the depalmitoylated
form of Gs in the plasma membrane as reported herein may
contribute to the increase in stimulatory AC signaling, as is
characteristic for the state of opioid dependence.
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