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(Received for publication, August 22, 1996, and in revised form, December 30, 1996)
From the Department of Pathology and Cell Biology, Thomas Jefferson
University, Philadelphia, Pennsylvania 19107
The key signal transduction enzyme protein kinase
C (PKC) contains a hydrophobic binding site for alcohols and
anesthetics (Slater, S. J., Cox, K. J. A., Lombardi, J. V., Ho, C.,
Kelly, M. B., Rubin, E., and Stubbs, C. D. (1993) Nature
364, 82-84). In this study, we show that interaction of
n-alkanols and general anesthetics with PKC
Volume 272, Number 10,
Issue of March 7, 1997
pp. 6167-6173
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
results in
dramatically different effects on membrane-associated compared with
lipid-independent enzyme activity. Furthermore, the effects on
membrane-associated PKC differ markedly depending on whether
activity is induced by diacylglycerol or phorbol ester and also on
n-alkanol chain length. PKC contains two distinct
phorbol ester binding regions of low and high affinity for the
activator, respectively (Slater, S. J., Ho, C., Kelly, M. B., Larkin,
J. D., Taddeo, F. J., Yeager, M. D., and Stubbs, C. D. (1996)
J. Biol. Chem. 271, 4627-4631). Short chain
n-alkanols competed for low affinity phorbol ester binding
to the enzyme, resulting in reduced enzyme activity, whereas high
affinity phorbol ester binding was unaffected. Long chain
n-alkanols not only competed for low affinity phorbol ester
binding but also enhanced high affinity phorbol ester binding.
Furthermore, long chain n-alkanols enhanced phorbol ester
induced PKC activity. This effect of long chain
n-alkanols was similar to that of diacylglycerol, although the n-alkanols alone were weak activators of the enzyme.
The cellular effects of n-alkanols and general anesthetics
on PKC-mediated processes will therefore depend in a complex manner on
the locality of the enzyme (e.g. cytoskeletal or
membrane-associated) and activator type, apart from any
isoform-specific differences. Furthermore, effects mediated by
interaction with the region on the enzyme possessing low affinity for
phorbol esters represent a novel mechanism for the regulation of PKC
activity.
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