A Primary Role for K+ and Na+ Efflux in the Activation of Apoptosis*
- From the Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709
Abstract
Cell shrinkage is a major characteristic of apoptosis, but the mechanism and role of this process in cell death are poorly understood. The primary factor that controls volume regulation in all cells is ions, and thus we have examined the movement of ions at the single cell level in lymphocytes during apoptosis. Activation of the death program with several stimuli that act through independent pathways to stimulate apoptosis results in a synchronous shift of cells from a normal cell size to a shrunken cell size. Only the shrunken cells exhibit DNA fragmentation and an approximate 4-fold elevation of caspase-3-like activity. Analysis of K+ and Na+ ion content of individual cells by flow cytometry revealed that the intracellular ionic strength of apoptotic cells decreased substantially from their non-shrunken counterparts. Additionally, we show apoptosis is enhanced under conditions where the intracellular K+ concentration is diminished and that apoptosis is inhibited when K+ efflux is prevented. These data show that the efflux of ions, primarily potassium, plays a necessary and perhaps a pivotal role in the cell death program.
Footnotes
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↵* 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.
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↵‡ Performed this work while a graduate student at the Dept. of Physiology, University of North Carolina, Chapel Hill, NC 27599.
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↵§ To whom correspondence should be addressed. Tel.: 919-541-1564; Fax: 919-541-1367.
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↵1 The abbreviations used are: PBFI-AM, potassium-binding benzofuran isophthalate-acetoxymethyl ester; SBFI-AM, sodium-binding benzofuran isophthalate-acetoxymethyl ester; PI, propidium iodide.
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↵2 C. D. Bortner and J. A. Cidlowski, unpublished results.
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- Received June 10, 1997.
- Revision received September 2, 1997.
