Cl-channels in apoptosis.
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.
Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany.
Podchanart
P
Wanitchakool
Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany.
Jiraporn
J
Ousingsawat
Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany.
Lalida
L
Sirianant
Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Nanna
N
MacAulay
Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany.
Rainer
R
Schreiber
Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany. karl.kunzelmann@ur.de.
Karl
K
Kunzelmann
D000818:Animals; D000075368:Anoctamins; D017209:Apoptosis; D002453:Cell Cycle; D018118:Chloride Channels / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D055724:Electrophysiological Phenomena; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009995:Osmosis; D010539:Permeability; D049294:Phospholipid Transfer Proteins / Q000378:metabolism; D014867:Water / Q000378:metabolism
C555078:ANO6 protein, human; D000075368:Anoctamins; D018118:Chloride Channels; C485976:LRRC8A protein, human; D008565:Membrane Proteins; D049294:Phospholipid Transfer Proteins; D014867:Water; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
Anoctamin; Apoptosis; CFTR; Ca2+-activated chloride channels; Cell death; Chloride channel; LRRC8A; RVD; TMEM16A; TMEM16F; TMEM16J; TMEM16K; Volume regulation