Abstract
Apoptosis is an essential process in organ development, tissue homeostasis, somatic cell turnover, and the pathogenesis of degenerative diseases. Apoptotic cell death occurs in response to a variety of stimuli in physiological and pathological circumstances. Efflux of K+ and Cl− leads to apoptotic volume decrease (AVD) of the cell. Both mitochondrion-mediated intrinsic, and death receptor-mediated extrinsic, apoptotic stimuli have been reported to rapidly activate Cl− conductances in a large variety of cell types. In epithelial cells and cardiomyocytes, the AVD-inducing anion channel was recently determined to be the volume-sensitive outwardly rectifying (VSOR) Cl− channel which is usually activated by swelling under non-apoptotic conditions. Blocking the VSOR Cl− channel prevented cell death in not only epithelial and cardiac cells, but also other cell types, by inhibiting the induction of AVD and subsequent apoptotic events. Ischemia-reperfusion-induced apoptotic death in cardiomyocytes and brain neurons was also prevented by Cl− channel blockers. Furthermore, cancer cell apoptosis induced by the anti-cancer drug cisplatin was recently found to be associated with augmented activity of the VSOR Cl− channel and to be inhibited by a Cl− channel blocker. The apoptosis-inducing VSOR Cl− channel is distinct from ClC-3 and its molecular identity remains to be determined.
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Acknowledgements
The authors are grateful to E.L. Lee for reading the manuscript, to M. Ohara for technical assistance, and to T. Okayasu for secretarial assistance. This work was supported by a Grant-in-Aid for Scientific Research from MEXT of Japan and by a grant from the Salt Science Foundation.
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Okada, Y., Shimizu, T., Maeno, E. et al. Volume-sensitive Chloride Channels Involved in Apoptotic Volume Decrease and Cell Death. J Membrane Biol 209, 21–29 (2006). https://doi.org/10.1007/s00232-005-0836-6
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DOI: https://doi.org/10.1007/s00232-005-0836-6