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Plasma membrane ion channels in suicidal cell death

https://doi.org/10.1016/j.abb.2006.12.028Get rights and content

Abstract

The machinery leading to apoptosis includes altered activity of ion channels. The channels contribute to apoptotic cell shrinkage and modify intracellular ion composition. Cl channels allow the exit of Cl, osmolytes and HCO3- leading to cell shrinkage and cytosolic acidification. K+ exit through K+ channels contributes to cell shrinkage and decreases intracellular K+ concentration, which in turn favours apoptotic cell death. K+ channel activity further determines the cell membrane potential, a driving force for Ca2+ entry through Ca2+ channels. Ca2+ may enter through unselective cation channels. An increase of cytosolic Ca2+ may stimulate several enzymes executing apoptosis. Specific ion channel blockers may either promote or counteract suicidal cell death. The present brief review addresses the role of ion channels in the regulation of suicidal cell death with special emphasis on the role of channels in CD95 induced apoptosis of lymphocytes and suicidal death of erythrocytes or eryptosis.

Section snippets

Anion channels, osmolyte transport and pH regulation

Activation of Cl channels during apoptosis has first been observed following stimulation of CD95 in Jurkat cells [35]. Subsequently, Cl channel activation has been described in TNFα or staurosporine induced apoptosis of various cell types [20], [36]. In Jurkat cells the same channels serve regulatory cell volume decrease following osmotic cell swelling [37]. Activation of those Cl channels by cell swelling [37] or stimulation of CD95 [35] requires the Src-like kinase Lck56. The kinase is

K+ channels

In several cell types, apoptosis is stimulated by activation of K+ channels [40], [68] and inhibited by K+ channel blockers [69], [70] or increase of extracellular K+ concentration [70], [71], [72]. Activation of K+ channels leads to hyperpolarization of the cell membrane, which increases the electrical driving force for Cl exit into the extracellular space. Thus, as indicated above, enhanced activity of K+ channels and Cl channels leads to cellular loss of KCl with osmotically obliged water

Ca2+ and unselective cation channels

Jurkat lymphocyte apoptosis following CD95 triggering is paralleled by inhibition of ICRAC[114], [115], a channel involved in the activation and proliferation of a wide variety of cells [116], [117], [118], [119], [120]. Thus, in the early phase of CD95 triggering, cytosolic Ca2+ activity rather decreases in Jurkat T lymphocytes [115]. On the other hand, sustained increase of cytosolic Ca2+ activity may trigger apoptosis of a variety of nucleated cells [22], [116], [117], [121], [122] and

Conclusions

Ion channels in the plasma membrane play a decisive role in the machinery eventually leading to suicidal cell death. They influence the apoptotic signalling by modifying intracellular ion concentrations and cell volume. The role of individual channels depends on the cell type, the physiological condition, the time course and the intensity of channel activation. Much has to be learned prior to a full understanding of the complex interplay between channel activity and apoptosis signalling.

Acknowledgments

The authors acknowledge the meticulous preparation of the manuscript by Lejla Subasic. The work of the authors was supported by the Deutsche Forschungsgemeinschaft, Nr. La 315/4-3, La 315/6-1, Le 792/3-3, DFG Schwerpunkt Intrazelluläre Lebensformen La 315/11-1, and Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (Center for Interdisciplinary Clinical Research) 01 KS 9602.

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