Cell shrinkage and monovalent cation fluxes: Role in apoptosis

Abstract

The loss of cell volume or cell shrinkage has been a morphological hallmark of the programmed cell death process known as apoptosis. This isotonic loss of cell volume has recently been term apoptotic volume decrease or AVD to distinguish it from inherent volume regulatory responses that occurs in cells under anisotonic conditions. Recent studies examining the intracellular signaling pathways that result in this unique cellular characteristic have determined that a fundamental movement of ions, particularly monovalent ions, underlie the AVD process and plays an important role on controlling the cell death process. An efflux of intracellular potassium was shown to be a critical aspect of the AVD process, as preventing this ion loss could protect cells from apoptosis. However, potassium plays a complex role as a loss of intracellular potassium has also been shown to be beneficial to the health of the cell. Additionally, the mechanisms that a cell employs to achieve this loss of intracellular potassium vary depending on the cell type and stimulus used to induce apoptosis, suggesting multiple ways exist to accomplish the same goal of AVD. Additionally, sodium and chloride have been shown to play a vital role during cell death in both the signaling and control of AVD in various apoptotic model systems. This review examines the relationship between this morphological change and intracellular monovalent ions during apoptosis.

Kv1.1 and Kv1.3 channels contribute to the degeneration of retinal ganglion cells after optic nerve transection in vivo

“…Neurons can express multiple K þ channel types and their normal activity is clearly not toxic. However, apoptosis in several cell types is accompanied by an 'AVD', increased K þ currents and a decrease in cytoplasmic K þ concentration [11][12][13] (recently reviewed by Yu 14 ), which is considered crucial for both triggering (e.g., caspase 8) and effector (e.g., caspase 3) molecules for apoptosis. 12,13,23 The limited information on channel identity points to involvement of different K þ channels in different cell types.…”

“…Kv1.3 is apparently responsible for the increased K þ efflux underlying lymphocyte apoptosis. 11,12,19,20,37 Other K þ channels implicated in apoptosis are Kir1.1 in hippocampal neurons, 22 Kv2.1 in cortical neurons, 23 TASK-3 in cerebellar granule cells 18 and Kv1.5 in smooth muscle cells. 21 It is intriguing that we found contributions of both Kv1.1 and Kv1.3 to RGC degeneration.…”

“…This 'apoptotic volume decrease' (AVD) precedes mitochondrial depolarization, apoptosome formation and cell fragmentation, and is considered a triggering event. [11][12][13][14] The concomitant decrease in cytoplasmic K þ concentration can activate molecules in the apoptotic cascade. Consequently, one experimental strategy has been to target K þ channels; an approach that is beginning to be investigated for RGCs (Diem et al, 15 this study).…”

“…RGC death occurs by apoptosis, as shown by the presence of fragmented nuclei and DNA, caspase 3 activation and apoptotic bodies. 3,9,10 Apoptosis in several cell types is accompanied by increased K þ currents, depletion of cytoplasmic K þ and by cell shrinkage (reviewed by Lang et al, 11 Bortner and Cidlowski, 12 Burg et al, 13 Yu 14 ). This 'apoptotic volume decrease' (AVD) precedes mitochondrial depolarization, apoptosome formation and cell fragmentation, and is considered a triggering event.…”

Convergent Ca 2+ and Zn 2+ signaling regulates apoptotic Kv2.1 K + currents

“…The released Zn 2+ , in turn, triggers p38 MAPK-and Src-dependent Kv2.1 channel insertion into the plasma membrane, resulting in a prominent increase in delayed rectifier K + currents in dying neurons, with no change in activation voltage, ∼3 h following a brief exposure to the stimulus (20)(21)(22)(23)(24)(25)(26). The increase in Kv2.1 channels present in the membrane mediates a pronounced loss of intracellular K + , likely accompanied by Cl − (27,28), that facilitates apoptosome assembly and caspase activation (20,(29)(30)(31)(32)(33)(34).…”