Dual roles of plasmalemmal chloride channels in induction of cell death

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.

TMEM16 Proteins Produce Volume-regulated Chloride Currents That Are Reduced in Mice Lacking TMEM16A

“…33% hypotonicity. Tissues were mounted into a microperfused Ussing chamber with a circular aperture of 0.785 mm 2 . Luminal and basolateral sides of the epithelium were perfused continuously at a rate of 5 ml/min.…”

“…It has been reported earlier that cell shrinkage due to opening of ion channels not only occurs during hypotonic swelling, but also in normotonic solution, when cells go into apoptotic cell death (2,29). AVD is an initial step during apoptosis, which can be induced by compounds such as staurosporin (29).…”

“…External hypotonicity leads to cell swelling and subsequent activation of volume-regulated chloride and potassium channels, to release intracellular ions and to re-shrink the cells, a process termed regulatory volume decrease (RVD) 3 (1). Volume-regulated chloride currents (I Cl,swell ) have dual functions during cell proliferation as well as apoptotic volume decrease (AVD), preceding apoptotic cell death (2). Although I Cl,swell is activated in swollen cells to induce RVD, AVD takes place under normotonic conditions to shrink cells (3,4).…”

Apoptotic volume decrease as a geometric determinant for cell dismantling into apoptotic bodies

“…1 We also speculate that AVD is an early process during apoptosis 10 partly because extrusion of volume out of the cell is an energy-consuming process. 34 In fact, energy-depleted cells swell rather than shrink and dye through necrosis rather than apoptosis. 35,36 Necrotic volume increase is caused by dysfunction of regulatory volume response due to impairment of volume-sensitive Cl À channels under conditions of ATP deficiency.…”

“…35,36 Necrotic volume increase is caused by dysfunction of regulatory volume response due to impairment of volume-sensitive Cl À channels under conditions of ATP deficiency. 34 In the course of apoptosis, the cell's energetic status must be preserved initially to some extent in order for the apoptotic machinery to work properly. 18,37,38 A rapid energetic crisis aborts apoptosis and turns cell death into a necrotic-like phenotype.…”