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Cl− channels in apoptosis

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Abstract

A remarkable feature of apoptosis is the initial massive cell shrinkage, which requires opening of ion channels to allow release of K+, Cl−, and organic osmolytes to drive osmotic water movement and cell shrinkage. This article focuses on the role of the Cl− channels LRRC8, TMEM16/anoctamin, and cystic fibrosis transmembrane conductance regulator (CFTR) in cellular apoptosis. LRRC8A-E has been identified as a volume-regulated anion channel expressed in many cell types. It was shown to be required for regulatory and apoptotic volume decrease (RVD, AVD) in cultured cell lines. Its presence also determines sensitivity towards cytostatic drugs such as cisplatin. Recent data point to a molecular and functional relationship of LRRC8A and anoctamins (ANOs). ANO6, 9, and 10 (TMEM16F, J, and K) augment apoptotic Cl− currents and AVD, but it remains unclear whether these anoctamins operate as Cl− channels or as regulators of other apoptotic Cl− channels, such as LRRC8. CFTR has been known for its proapoptotic effects for some time, and this effect may be based on glutathione release from the cell and increase in cytosolic reactive oxygen species (ROS). Although we find that CFTR is activated by cell swelling, it is possible that CFTR serves RVD/AVD through accumulation of ROS and activation of independent membrane channels such as ANO6. Thus activation of ANO6 will support cell shrinkage and induce additional apoptotic events, such as membrane phospholipid scrambling.

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Acknowledgments

Supported by DFG SFB699-A7/A12, DFG KU756/12-1, and Volkswagenstiftung AZ 87 499. We thank Dr. Johan Heemskerk and Dr. Eduard Bevers (Department of Cell Biochemistry of Thrombosis and Hemostasis Biochemistry, Cardiovascular Research Institute Maastricht; CARIM), for supplying the B-lymphocyte cell lines. HCT116 control cells and HCT116 cells lacking expression of LRRC8A were generously provided by Dr. F. Voss/Prof. Dr. T. Jentsch (FMP, Berlin). The assistance by Mss. B. Wild, P. Seeberger, and E. Tartler is gratefully acknowledged.

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  1. Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany

    Podchanart Wanitchakool, Jiraporn Ousingsawat, Lalida Sirianant, Rainer Schreiber & Karl Kunzelmann

  2. Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Nanna MacAulay

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  1. Podchanart Wanitchakool
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  2. Jiraporn Ousingsawat
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Correspondence to Karl Kunzelmann.

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Special Issue: Ion Channels, Transporters and Cancer.

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Wanitchakool, P., Ousingsawat, J., Sirianant, L. et al. Cl− channels in apoptosis. Eur Biophys J 45, 599–610 (2016). https://doi.org/10.1007/s00249-016-1140-3

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