Regulation and critical role of potassium homeostasis in apoptosis

Programmed cell death or apoptosis is broadly responsible for the normal homeostatic removal of cells and has been increasingly implicated in mediating pathological cell loss in many disease states. As the molecular mechanisms of apoptosis have been extensively investigated a critical role for ionic homeostasis in apoptosis has been recently endorsed. In contrast to the ionic mechanism of necrosis that involves Ca2+ influx and intracellular Ca2+ accumulation, compelling evidence now indicates that excessive K+ efflux and intracellular K+ depletion are key early steps in apoptosis. Physiological concentration of intracellular K+ acts as a repressor of apoptotic effectors. A huge loss of cellular K+, likely a common event in apoptosis of many cell types, may serve as a disaster signal allowing the execution of the suicide program by activating key events in the apoptotic cascade including caspase cleavage, cytochrome c release, and endonuclease activation. The pro-apoptotic disruption of K+ homeostasis can be mediated by over-activated K+ channels or ionotropic glutamate receptor channels, and most likely, accompanied by reduced K+ uptake due to dysfunction of Na+, K+-ATPase. Recent studies indicate that, in addition to the K+ channels in the plasma membrane, mitochondrial K+ channels and K+ homeostasis also play important roles in apoptosis. Investigations on the K+ regulation of apoptosis have provided a more comprehensive understanding of the apoptotic mechanism and may afford novel therapeutic strategies for apoptosis-related diseases. (C) 2003 Elsevier Ltd. All rights reserved.