Dual roles of plasmalemmal chloride channels in induction of cell death.
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.
Okada
Yasunobu
Y
Department of Cell Physiology, National Institute for Physiological Sciences, 444-8585 Okazaki, Japan. okada@nips.ac.jp
Maeno
Emi
E
Shimizu
Takahiro
T
Manabe
Kenichi
K
Mori
Shin-Ichiro
S
Nabekura
Takashi
T
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology*; D048429:Cell Size; D018118:Chloride Channels / Q000502:physiology*; D006801:Humans; D007038:Hypotonic Solutions; D008564:Membrane Potentials / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D018118:Chloride Channels; D007038:Hypotonic Solutions