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J. Biol. Chem., Vol. 276, Issue 45, 42050-42056, November 9, 2001
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From the Department of Pharmacology, Medical College of Ohio,
Toledo, Ohio 43614
We have shown before that
Na+/K+-ATPase acts as a signal
transducer, through protein-protein interactions, in addition to being an ion pump. Interaction of ouabain with the enzyme of the intact cells
causes activation of Src, transactivation of EGFR, and activation of
the Ras/ERK1/2 cascade. To determine the role of protein kinase C (PKC)
in this pathway, neonatal rat cardiac myocytes were exposed to ouabain
and assayed for translocation/activation of PKC from cytosolic to
particulate fractions. Ouabain caused rapid and sustained stimulation
of this translocation, evidenced by the assay of
Ca2+-dependent and Ca2+-independent
PKC activities and by the immunoblot analysis of the
Role of Protein Kinase C in the Signal Pathways That
Link Na+/K+-ATPase to ERK1/2*
, 
, and 
isoforms of PKC. Dose-dependent stimulation of PKC
translocation by ouabain (1-100 µM) was accompanied by
no more than 50% inhibition of Na+/K+-ATPase
and doubling of [Ca2+]i, changes that do not
affect myocyte viability and are known to be associated with positive
inotropic, but not toxic, effects of ouabain in rat cardiac ventricles.
Ouabain-induced activation of ERK1/2 was blocked by PKC inhibitors
calphostin C and chelerythrine. An inhibitor of phosphoinositide
turnover in myocytes also antagonized ouabain-induced PKC translocation and ERK1/2 activation. These and previous findings indicate that ouabain-induced activation of PKC and Ras, each linked to
Na+/K+-ATPase through Src/EGFR, are both
required for the activation of ERK1/2. Ouabain-induced PKC
translocation and ERK1/2 activation were dependent on the presence of
Ca2+ in the medium, suggesting that the signal-transducing
and ion-pumping functions of Na+/K+-ATPase
cooperate in activation of these protein kinases and the resulting
regulation of contractility and growth of the cardiac myocyte.
*
This work was supported by NHLBI, National Institutes of
Health, Grants HL-36573 and HL-63238 and by institutional funds derived from The Ohio Board of Regents Research Challenge Program. Preliminary accounts of this work have been presented (11, 12).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Pharmacology,
Medical College of Ohio, 3035 Arlington Ave., Toledo, OH 43614-5804. Tel.: 419-383-4182; Fax: 419-383-2871; E-mail: mheck@mco.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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