Apoptosis, cell volume regulation and volume-regulatory chloride channels.

Apoptosis occurs in response to various stimuli under physiological and pathological circumstances. A major hallmark of the programmed cell death is normotonic shrinkage of cells. Induction of the apoptotic volume decrease (AVD) was found to precede cytochrome c release, caspase-3 activation and DNA laddering. A broad-spectrum caspase inhibitor blocked these biochemical apoptotic events but failed to block the AVD. The normotonic AVD induction was coupled to facilitation of the regulatory volume decrease (RVD), which is attained by parallel operation of Cl- and K+ channels, under hypotonic conditions. Both the AVD induction and RVD facilitation were prevented by application of a blocker of volume-regulatory Cl- or K+ channels. Furthermore, apoptotic cell death was rescued by channel blocker-induced prevention of AVD. Thus, it is concluded that the AVD is produced under normotonic conditions by a mechanism similar, though without preceding swelling, to RVD and represents an early prerequisite to apoptotic events leading to cell death. It was previously reported that hypertonic stress triggers apoptosis in cell types that lack the regulatory volume increase (RVI) mechanism. Taken together, it is suggested that 'disordered' or altered cell volume regulation is associated with apoptosis.