Ions, the Movement of Water and the Apoptotic Volume Decrease

The movement of water across the cell membrane is a natural biological process that occurs during growth, cell division, and cell death. Many cells are known to regulate changes in their cell volume through inherent compensatory regulatory mechanisms. Cells can sense an increase or decrease in their cell volume, and compensate through mechanisms known as a regulatory volume increase (RVI) or decrease (RVD) response, respectively. The transport of sodium, potassium along with other ions and osmolytes allows the movement of water in and out of the cell. These compensatory volume regulatory mechanisms maintain a cell at near constant volume. A hallmark of the physiological cell death process known as apoptosis is the loss of cell volume or cell shrinkage. This loss of cell volume is in stark contrast to what occurs during the accidental cell death process known as necrosis. During necrosis, cells swell or gain water, eventually resulting in cell lysis. Thus, whether a cell gains or loses water after injury is a defining feature of the specific mode of cell death. Cell shrinkage or the loss of cell volume during apoptosis has been termed apoptotic volume decrease or AVD. Over the years, this distinguishing feature of apoptosis has been largely ignored and thought to be a passive occurrence or simply a consequence of the cell death process. However, studies on AVD have defined an underlying movement of ions that result in not only the loss of cell volume, but also the activation and execution of the apoptotic process. This review explores the role ions play in controlling not only the movement of water, but the regulation of apoptosis. We will focus on what is known about specific ion channels and transporters identified to be involved in AVD, and how the movement of ions and water change the intracellular environment leading to stages of cell shrinkage and associated apoptotic characteristics. Finally, we will discuss these concepts as they apply to different cell types such as neurons, cardiomyocytes, and corneal epithelial cells.

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Absence of volume regulatory mechanisms contributes to the rapid activation of apoptosis in thymocytes

AJP Cell Physiology ◽

10.1152/ajpcell.1996.271.3.c950 ◽

1996 ◽

Vol 271 (3) ◽

pp. C950-C961 ◽

Cited By ~ 173

Author(s):

C. D. Bortner ◽

J. A. Cidlowski

Keyword(s):

Cell Death ◽

Cell Volume ◽

Cell Types ◽

Lymphoid Cells ◽

Regulatory Mechanisms ◽

Death Process ◽

Nuclear Condensation ◽

Hypertonic Medium ◽

Rapid Induction ◽

Induced Apoptosis

A common event that occurs during apoptosis is a loss of cell volume, but little information is available on its role in the cell death process. Lymphocytes undergo apoptosis in response to glucocorticoids and exhibit cell shrinkage, nuclear condensation, internucleosomal DNA fragmentation, and apoptotic body formation. Interestingly, only cells that exhibit a loss in cell volume degrade their DNA. To determine if physical shrinkage was sufficient to initiate apoptosis, S49 Neo lymphocytes were cultured in hypertonic medium. The normal osmolarity (approximately 300 mosM) of tissue culture medium was increased to either 550 or 800 mosM, using impermeant sugars such as mannitol and sucrose or NaCl. These hypertonic conditions led to a rapid killing of S49 Neo cells. Evaluation of the mode of cell death revealed that these hypertonic conditions resulted in apoptosis. Unlike glucocorticoid-induced cell death, hypertonically induced apoptosis did not require protein synthesis. When S49 Neo cells were cultured under hypotonic conditions, the cells swelled but apoptosis did not occur. Analysis of several cell types revealed that all lymphoid cells examined (S49 Neo, CEM-C7, primary thymocytes) undergo apoptosis in response to hypertonic conditions, whereas several other cell types (L cells, COS, HeLa, GH3) did not. Although these nonlymphoid cells showed a similar initial reduction in cell volume in response to hypertonic conditions, they subsequently maintained volume or regulated back to a near normal cell volume. These data indicate that thymic lymphoid cells have the machinery in place for rapid induction of apoptosis in response to physical shrinkage, whereas other cell types resist shrinkage-induced apoptosis by the activation of cell volume regulatory mechanisms.

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Proapoptotic BH3-only protein Bim is essential for developmentally programmed death of germinal center-derived memory B cells and antibody-forming cells

Blood ◽

10.1182/blood-2007-05-091306 ◽

2007 ◽

Vol 110 (12) ◽

pp. 3978-3984 ◽

Cited By ~ 77

Author(s):

Silke F. Fischer ◽

Philippe Bouillet ◽

Kristy O'Donnell ◽

Amanda Light ◽

David M. Tarlinton ◽

...

Keyword(s):

Immune Response ◽

Cell Death ◽

B Cells ◽

Cell Types ◽

Memory B Cells ◽

Death Process ◽

Programmed Death ◽

Cell Death Process ◽

A Cell ◽

First Time

Abstract T cell–dependent B-cell immune responses induce germinal centers that are sites for expansion, diversification, and selection of antigen-specific B cells. During the immune response, antigen-specific B cells are removed in a process that favors the retention of cells with improved affinity for antigen, a cell death process inhibited by excess Bcl-2. In this study, we examined the role of the BH3-only protein Bim, an initiator of apoptosis in the Bcl-2–regulated pathway, in the programmed cell death accompanying an immune response. After immunization, Bim-deficient mice showed persistence of both memory B cells lacking affinity-enhancing mutations in their immunoglobulin genes and antibody-forming cells secreting low-affinity antibodies. This was accompanied by enhanced survival of both cell types in culture. We have identified for the first time the physiologic mechanisms for killing low-affinity antibody-expressing B cells in an immune response and have shown this to be dependent on the BH3-only protein Bim.

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Cell death and cell protection genes determine the fate of pistils in maize

Development ◽

10.1242/dev.126.3.435 ◽

1999 ◽

Vol 126 (3) ◽

pp. 435-441

Author(s):

A. Calderon-Urrea ◽

S.L. Dellaporta

Keyword(s):

Cell Death ◽

Sex Determination ◽

Sexual Maturation ◽

Temporal Pattern ◽

Death Process ◽

Cell Protection ◽

Selective Elimination ◽

Cell Death Process ◽

A Cell ◽

Unisexual Flowers

The formation of unisexual flowers in maize requires the selective elimination and sexual maturation of floral organs in an initially bisexual floral meristem. Elimination of pistil primordia occurs in the primary and secondary florets of the tassel spikelets, and in the secondary florets of ear spikelets. Ill-fated pistil cells undergo a cell death process associated with nuclear degeneration in a specific spatial-temporal pattern that begins in the subepidermis, eventually aborting the entire organ. The sex determination genes tasselseed1 and tasselseed2 are required for death of pistil cells. tasselseed1 is required for the accumulation of TASSELSEED2 mRNA in pistil cells. All pistil primordia express TASSELSEED2 RNA but functional pistils found in ear spikelets are protected from cell death by the action of the silkless1 gene. silkless1 blocks tasselseed-induced cell death in the pistil primordia of primary ear florets. A model is proposed for the control of pistil fate by the action of the ts1-ts2-sk1 pathway.

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Homotypic cell cannibalism, a cell‐death process regulated by the nuclear protein 1, opposes to metastasis in pancreatic cancer

EMBO Molecular Medicine ◽

10.1002/emmm.201201255 ◽

2012 ◽

Vol 4 (9) ◽

pp. 964-979 ◽

Cited By ~ 45

Author(s):

Carla E. Cano ◽

María José Sandí ◽

Tewfik Hamidi ◽

Ezequiel L. Calvo ◽

Olivier Turrini ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Death ◽

Nuclear Protein ◽

Death Process ◽

Cell Death Process ◽

A Cell

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MORPHOLOGICAL AND BIOCHEMICAL CHARACTERIZATION OF A CELL DEATH PROCESS INDUCED BY E3, A NEW SYNTHETIC DIARYLSULFONILUREA ANALOGUE

The Scientific World JOURNAL ◽

10.1100/tsw.2001.23.179 ◽

2001 ◽

Vol 1 (S3) ◽

pp. 50-50

Author(s):

M. Alonso ◽

M. Miglaccio ◽

I. Encio ◽

A. Asumendi ◽

V. Martinez-Merino ◽

...

Keyword(s):

Cell Death ◽

Biochemical Characterization ◽

Death Process ◽

Cell Death Process ◽

A Cell

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Cytochrome c activates K+ channels before inducing apoptosis

AJP Cell Physiology ◽

10.1152/ajpcell.00592.2001 ◽

2002 ◽

Vol 283 (4) ◽

pp. C1298-C1305 ◽

Cited By ~ 59

Author(s):

Oleksandr Platoshyn ◽

Shen Zhang ◽

Sharon S. McDaniel ◽

Jason X.-J. Yuan

Keyword(s):

Cytochrome C ◽

Early Stage ◽

Specific Inhibitor ◽

Cell Types ◽

Caspase 9 ◽

Cell Shrinkage ◽

Nuclear Condensation ◽

Apoptotic Volume Decrease ◽

Cyt C ◽

Volume Decrease

Cell shrinkage is an early prerequisite for apoptosis. The apoptotic volume decrease is due primarily to loss of cytoplasmic ions. Increased outward K+ currents have indeed been implicated in the early stage of apoptosis in many cell types. We found that cytoplasmic dialysis of cytochrome c(cyt- c), a mitochondria-dependent apoptotic inducer, increases K+ currents before inducing nuclear condensation and breakage in pulmonary vascular smooth muscle cells. The cyt- c-mediated increase in K+ currents took place rapidly and was not affected by treatment with a specific inhibitor of caspase-9. Cytoplasmic dialysis of recombinant (active) caspase-9 negligibly affected the K+ currents. Furthermore, treatment of the cells with staurosporine (ST), an apoptosis inducer that mediates translocation of cyt- c from mitochondria to the cytosol, also increased K+ currents, caused cell shrinkage, and induced apoptosis (determined by apoptotic nuclear morphology and TdT-UTP nick end labeling assay). The staurosporine-induced increase in K+ currents concurred to the volume decrease but preceded the activation of apoptosis (nuclear condensation and breakage). These results suggest that the cyt- c-induced activation of K+ channels and the resultant K+ loss play an important role in initiating the apoptotic volume decrease when cells undergo apoptosis.

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