K+ Channels in Apoptosis

Abstract

A proper rate of programmed cell death or apoptosis is required to maintain normal tissue homeostasis. In disease states such as cancer and some forms of hypertension, apoptosis is blocked, resulting in hyperplasia. In neurodegenerative diseases, uncontrolled apoptosis leads to loss of brain tissue. The flow of ions in and out of the cell and its intracellular organelles is becoming increasingly linked to the generation of many of these diseased states. This review focuses on the transport of K(+) across the cell membrane and that of the mitochondria via integral K(+)-permeable channels. We describe the different types of K(+) channels that have been identified, and investigate the roles they play in controlling the different phases of apoptosis: early cell shrinkage, cytochrome c release, caspase activation, and DNA fragmentation. Attention is also given to K(+) channels on the inner mitochondrial membrane, whose activity may underlie anti- or pro-apoptotic mechanisms in neurons and cardiomyocytes.

A novel paradigm for rapid ABT-737-induced apoptosis involving outer mitochondrial membrane rupture in primary leukemia and lymphoma cells

“…Mitochondrial matrix volume is controlled primarily by potassium fluxes and many studies have implicated potassium channels in regulating apoptosis. 33,34 Furthermore, BCL2 inhibits mitochondrial potassium uptake in some apoptotic models. 35 Thus, the ABT-737-induced MIMP observed in the present study may be related to a loss of BCL2 regulation of potassium fluxes.…”

Salinomycin in cancer: A new mission for an old agent

“…A decrease in intracellular potassium concentration has previously been shown to be essential for the induction of apoptosis in human lymphoma cells (47), suggesting that salinomycin-induced apoptosis is mediated, at least in part, by the ability of salinomycin to deplete cytoplasmic and mitochondrial potassium and/or to interfere with potassium membrane potential. Potassium channels of the mitochondrial and cytoplasmic membrane are overexpressed in many human cancer cells, play pivotal roles in the regulation of tumorigenesis, tumor cell proliferation, cell cycle progression and apoptosis (48)(49)(50), and may constitute novel and promising molecular targets for cancer therapy (51). Now that the potassium ionophore antibiotic salinomycin has been shown to kill human breast cancer stem cells and apoptosisresistant cancer cells in vitro, the investigation of its safety, toxicity, pharmacology and anticancer activity in humans is a challenge for the coming years.…”

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

“…6,7 Inhibition of K þ extrusion by increasing K þ extracellular concentration, or by means of K þ channel blockers, prevents all or the most relevant downstream events from taking place, including AVD and cytochrome c translocation. 28,29 The latter is inhibited even in cells stimulated for apoptosis with insults, whose mechanisms of action do not require caspases for cytochrome c release. This is not a trivial issue because mitochondrial injury has been proposed as the no-return point in the commitment of cells to apoptosis.…”