Elongation of Outer Transmembrane Domain Alters Function of Miniature K+ Channel Kcv

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.