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(Received for publication, March 5, 1996, and in revised form, July 12, 1996)
From the We have shown that ethanol inhibits uptake of
adenosine by a specific nucleoside transporter in NG108-15
neuroblastoma × glioma cells and that cAMP-dependent
protein kinase (PKA) activity is required for this inhibition. After
chronic exposure to ethanol, adenosine uptake is no longer inhibited on
rechallenge with ethanol, i.e. transport has become
tolerant to ethanol. Here we show that protein kinase C (PKC)
contributes to ethanol-induced tolerance of adenosine transport.
Activation of PKC by phorbol esters in control cells results in an
ethanol-tolerant phenotype, similar to that produced by chronic ethanol
exposure. In addition, chronic exposure to ethanol increases the
amounts of
Volume 271, Number 46,
Issue of November 15, 1996
pp. 29468-29472
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
,
¶
**
and
¶
**
Ernest Gallo Clinic and Research Center and
the ¶ Department of Neurology,
Department of Cellular and
Molecular Pharmacology and ** Neuroscience Program, University of
California, San Francisco, California 94110
,
, and
PKC. However, reducing PKC activity by
inhibition with chelerythrine during chronic exposure to ethanol or
down-regulation by phorbol esters prevents the development of
ethanol-induced tolerance of adenosine transport. By contrast, the
inhibition of PKA activity produces tolerance to ethanol inhibition of
adenosine uptake. When protein phosphatase inhibitors are present,
inhibiting PKA activity has no effect on ethanol sensitivity of
adenosine uptake, suggesting a role for protein phosphatases in the
regulation of ethanol sensitivity of uptake. Taken together, our
results suggest that PKA and PKC have opposing effects on the ethanol
sensitivity of adenosine transport; PKA activity is required for
ethanol sensitivity, and PKC activation produces tolerance. Based on
these data, we propose that chronic ethanol exposure increases PKC
activity, leading to the activation of a protein phosphatase (1 or 2A). This phosphatase then dephosphorylates a PKA-phosphorylated site, which
is required for ethanol to inhibit adenosine uptake. Therefore, the
sensitivity of adenosine transport to ethanol appears to be maintained
by a balance of PKA and protein phosphatase activities, and PKC may
regulate phosphatase activity.
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