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Dual roles of plasmalemmal chloride channels in induction of cell death

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Abstract

Even under anisotonic conditions, most cells can regulate their volume by mechanisms called regulatory volume decrease (RVD) and increase (RVI) after osmotic swelling or shrinkage, respectively. In contrast, the initial processes of necrosis and apoptosis are associated with persistent swelling and shrinkage. Necrotic volume increase (NVI) is initiated by uptake of osmolytes, such as Na+, Cl− and lactate, under conditions of injury, hypoxia, ischaemia, acidosis or lactacidosis. Persistence of NVI is caused by dysfunction of RVD due to impairment of volume-sensitive Cl− channels under conditions of ATP deficiency or lactacidosis. Both lactacidosis-induced RVD dysfunction and necrotic cell death are prevented by pretreatment of cells with the vacuolating cytotoxin-A (VacA) toxin protein purified from Helicobacter pylori, which forms a lactacidosis-resistant anion channel. Apoptotic volume decrease (AVD) is triggered by activation of K+ and Cl− conductances following stimulation with a mitochondrion-mediated or death receptor-mediated apoptosis inducer. Apoptotic cell death can be prevented by blocking the Cl− channels but not the K+-Cl− cotransporters. Thus, the volume regulatory anion channel plays, unless impaired, a cell-rescuing role in the necrotic process by ensuring RVD after swelling induced by necrotic insults, whereas normotonic activation of the anion channel plays a cell-killing role in the apoptotic process by triggering AVD following stimulation with apoptosis inducers.

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Acknowledgements

We thank TL Cover for reading the manuscript and providing the VacA protein, RZ Sabirov for reading the manuscript, M Ohara, K Shigemoto and C Kondo for technical assistance, and T Okayasu for secretarial assistance. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by support from the Salt Science Foundation.

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  1. Department of Cell Physiology, National Institute for Physiological Sciences, 444-8585, Okazaki, Japan

    Yasunobu Okada, Emi Maeno, Takahiro Shimizu, Kenichi Manabe, Shin-ichiro Mori & Takashi Nabekura

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Okada, Y., Maeno, E., Shimizu, T. et al. Dual roles of plasmalemmal chloride channels in induction of cell death. Pflugers Arch - Eur J Physiol 448, 287–295 (2004). https://doi.org/10.1007/s00424-004-1276-3

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