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J. Biol. Chem., Vol. 276, Issue 6, 4304-4314, February 9, 2001
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From the Laboratory of Signal Transduction, NIEHS, National
Institutes of Health,
Research Triangle Park, North Carolina 27709
The movement of intracellular monovalent cations
has previously been shown to play a critical role in events leading to
the characteristics associated with apoptosis. A loss of
intracellular potassium and sodium occurs during apoptotic cell
shrinkage establishing an intracellular environment favorable for
nuclease activity and caspase activation. We have now investigated the
potential movement of monovalent ions in Jurkat cells that occur prior
to cell shrinkage following the induction of apoptosis. A rapid
increase in intracellular sodium occurs early after apoptotic stimuli
suggesting that the normal negative plasma membrane potential may
change during cell death. We report here that diverse apoptotic stimuli
caused a rapid cellular depolarization of Jurkat T-cells that occurs
prior to and after cell shrinkage. In addition to the early increase in
intracellular Na+, 86Rb+
studies reveal a rapid inhibition of K+ uptake in response
to anti-Fas. These effects on Na+ and K+ ions
were accounted for by the inactivation of the
Na+/K+-ATPase protein and its activity.
Furthermore, ouabain, a cardiac glycoside inhibitor of the
Na+/K+-ATPase, potentiated anti-Fas-induced
apoptosis. Finally, activation of an anti-apoptotic signal,
i.e. protein kinase C, prevented both cellular
depolarization in response to anti-Fas and all downstream characteristics associated with apoptosis. Thus cellular depolarization is an important early event in anti-Fas-induced apoptosis, and the
inability of cells to repolarize via inhibition of the
Na+/K+-ATPase is a likely regulatory component
of the death process.
Plasma Membrane Depolarization without Repolarization Is an Early
Molecular Event in Anti-Fas-induced Apoptosis*
*
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. Tel.: 919- 541-1564;
Fax: 919-541-1367.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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