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Vol. 54, Issue 6, 949-953, December 1998
Department of Biochemistry, State University of New York, Health
Science Center at Brooklyn, Brooklyn, New York 11203 (S.C., L.W.,
A.R.G.) and
Department of Pharmacological and Physiological Sciences,
University of Chicago, Chicago, Illinois 60637 (W.-J.T.)
Despite the demonstration that chronic morphine increases
phosphorylation of multiple substrate proteins, their identity has, for
the most part, remained elusive. Thus far, chronic morphine has not
been shown to increase the phosphorylation of any identified effector
protein. This is the first demonstration that persistent activation of
opioid receptors has profound effects on phosphorylation of adenylyl
cyclase (AC). A dramatic increase in phosphorylation of AC (type II
family) was observed in ileum longitudinal muscle myenteric plexus
preparations obtained from chronic morphine-treated guinea pigs.
Analogous results were obtained when AC was immunoprecipitated using
two differentially directed AC antibodies. The magnitude of the
augmented AC phosphorylation was substantially attenuated by
chelerythrine, a protein kinase C-selective inhibitor. These results
suggest the potential relevance of increased phosphorylation (protein
kinase C-mediated) of AC to opioid tolerant/dependent mechanisms.
Because phosphorylation of AC isoforms (type II family) can
significantly increase their stimulatory responsiveness to Gs
and G
, this mechanism could
underlie, in part, the predominance of opioid AC stimulatory signaling
observed in opioid tolerant/dependent tissue. Moreover, in light of the
fact that many G protein-coupled receptors signal through common
effector proteins, this effect provides a mechanism for divergent
consequences of chronic morphine treatment and could explain the well
documented complexity of changes that accompany the opioid
tolerant/dependent state.
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