It is now generally accepted that apoptosis in most species and cell types is precisely regulated by the actions of a number of intracellular molecules, derived from both active gene transcription (i.e., proteins) and various metabolic events, including mitochondrial respiration (e.g., reactive oxygen species) and release of proapoptotic factors (e.g., cytochrome c, apoptosis-inducing factor), phospholipid turnover (e.g., ceramide, sphingosine-1-phosphate, diacyl-glycerol), and ion fluxes. Despite the diversity and complexity of the events surrounding the induction of cell death, many genetic and biochemical studies have provided evidence that there likely exists an ordered and evolutionarily conserved pathway by which cells activate, execute, and complete the process of self-destruction.
One universal feature of apoptosis is a loss of cell volume leading to cytoplasmic condensation. Indeed, using glucocorticoid-treated S49-Neo lymphocytes as a model, it was reported that DNA fragmentation only occurred in those cells that exhibited reductions in cell volume and that cell shrinkage in lymphocytes was necessary and sufficient for the initiation of apoptosis. Although the mechanisms underlying reductions in cell volume during apoptosis remain to be elucidated, several studies have directly linked potassium ion efflux from the cell as a precipitating event. For instance, apoptosis induced by treatment of CEM-C7A lymphoblastoid cells with dexametha-sone or of L cells with VP-16 is associated with a net loss of intracellular potassium and a concomitant reduction in cell volume. Activity of potassium ion channels appears to regulate the sensitivity of lymphoid cells to extracellular ATP-induced apoptosis, and cell shrinkage in eosinophils undergoing apoptosis can be inhibited in a dose-dependent manner by the presence of potassium channel blockers.