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J. Biol. Chem., Vol. 283, Issue 52, 36071-36087, December 26, 2008

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Glutathione Depletion and Disruption of Intracellular Ionic Homeostasis Regulate Lymphoid Cell Apoptosis^*

From the Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

Intracellular glutathione (GSH) depletion is an important hallmark of apoptosis. We have recently shown that GSH depletion by its extrusion regulates apoptosis independently of excessive reactive oxygen species accumulation. However, the mechanisms by which GSH depletion regulates apoptosis are still unclear. Because disruption of intracellular ionic homeostasis, associated with apoptotic volume decrease (AVD), is necessary for the progression of apoptotic cell death, we sought to evaluate the relationship between GSH transport and ionic homeostasis during Fas ligand (FasL)-induced apoptosis in Jurkat cells. GSH depletion in response to FasL was paralleled by distinct degrees of AVD identified by differences in cellular forward scatter and electronic impedance analysis. Inhibition of GSH efflux prevented AVD, K⁺ loss, and the activation of two distinct ionic conductances, mediated by Kv1.3 and outward rectifying Cl^– channels. Reciprocally, stimulation of GSH loss accelerated the loss of K⁺_, AVD, and consequently the progression of the execution phase of apoptosis. Although high extracellular K⁺ inhibited FasL-induced apoptosis, GSH depletion was largely independent of K⁺ loss. These results suggest that deregulation of GSH and ionic homeostasis converge in the regulation of apoptosis in lymphoid cells.

Received for publication, September 11, 2008 , and in revised form, October 20, 2008.

^* This work was supported, in whole or in part, by a National Institutes of Health grant (intramural research program of the NIEHS). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Laboratory of Signal Transduction, NIEHS, National Institutes of Health, P. O. Box 12233, 111 TW Alexander Dr., Research Triangle Park, NC 27709. Tel.: 919-541-1564; Fax: 919-541-1367; E-mail: cidlows1{at}mail.nih.gov.

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