Volume-sensitive chloride channels involved in apoptotic volume decrease and cell death

J Membr Biol. 2006 Jan;209(1):21-9. doi: 10.1007/s00232-005-0836-6. Epub 2006 Apr 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / pharmacology
  • 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Size / drug effects
  • Chloride Channels / antagonists & inhibitors
  • Chloride Channels / physiology*
  • Humans
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / physiology
  • Staurosporine / pharmacology


  • Chloride Channels
  • 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid
  • Staurosporine
  • 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid