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Role of Ion Transport in Control of Apoptotic Cell Death

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Abstract

Cell shrinkage is a hallmark and contributes to signaling of apoptosis. Apoptotic cell shrinkage requires ion transport across the cell membrane involving K+ channels, Cl or anion channels, Na+/H+ exchange, Na+,K+,Cl cotransport, and Na+/K+ATPase. Activation of K+ channels fosters K+ exit with decrease of cytosolic K+ concentration, activation of anion channels triggers exit of Cl, organic osmolytes, and HCO3. Cellular loss of K+ and organic osmolytes as well as cytosolic acidification favor apoptosis. Ca2+ entry through Ca2+‐permeable cation channels may result in apoptosis by affecting mitochondrial integrity, stimulating proteinases, inducing cell shrinkage due to activation of Ca2+‐sensitive K+ channels, and triggering cell‐membrane scrambling. Signaling involved in the modification of cell‐volume regulatory ion transport during apoptosis include mitogen‐activated kinases p38, JNK, ERK1/2, MEKK1, MKK4, the small G proteins Cdc42, and/or Rac and the transcription factor p53. Osmosensing involves integrin receptors, focal adhesion kinases, and tyrosine kinase receptors. Hyperosmotic shock leads to vesicular acidification followed by activation of acid sphingomyelinase, ceramide formation, release of reactive oxygen species, activation of the tyrosine kinase Yes with subsequent stimulation of CD95 trafficking to the cell membrane. Apoptosis is counteracted by mechanisms involved in regulatory volume increase (RVI), by organic osmolytes, by focal adhesion kinase, and by heat‐shock proteins. Clearly, our knowledge on the interplay between cell‐volume regulatory mechanisms and suicidal cell death is still far from complete and substantial additional experimental effort is needed to elucidate the role of cell‐volume regulatory mechanisms in suicidal cell death. © 2012 American Physiological Society. Compr Physiol 2:2037‐2061, 2012.

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Figure 1. Figure 1.

Ion transport during apoptotic cell death. During the execution phase of apoptosis, activation of K+ and anion channels typically lead to cellular loss of K+ and Cl with osmotically obliged water. The HCO3 permeability of the anion channels results in cellular loss of HCO3 and thus to cytosolic acidification. Inhibition of the Na+/H+ exchanger prevents restoration of cytosolic pH and cell volume, inhibition of the Na+/K+‐ATPase precludes K+ replenishment. (A,B) Original tracings demonstrating activation of anion channels (A) and decrease of the Na+/H+ exchanger (NHE) activity (B) in Jurkat T lymphocytes prior to and following exposure to apoptosis inducing activating anti‐CD95 antibody. (A) Cl current prior to (a) and 11 min following (b) activation of CD95. (B) NHE‐dependent realkalinization (arrows) following transient exposure to NH4Cl (ammonium pulse) prior to (left) and 1 h after (right) CD95 activation ().

Figure 2. Figure 2.

Cellular content of Cl, K+, Na+, and ninhydrin positive substances (NPS) after cisplatin exposure in Ehrlich ascites tumour cells (EATC). The cellular content of ions and NPS are given in μmol/g dry weight. (A) Cl content was measured using Ag+ titration. (B,C) K+ and Na+ content was measured using atomic flame absorption spectroscopy. (D) Amino acid (NPS) content was estimated by measuring the cellular content of NPS, using a calorimetric assay. (E) Net loss of Cl, K+, and Na+ in μmol/g dry weight from wt EATC after 8 h cisplatin exposure. Time frames of the stages of AVD1, AVDT, and AVD2 (see Figure ) are marked above the figures. Values are presented as means +/− SEM (standard error of the mean) of five experiments apart from Cl that is average of 8 experiments. * indicates significantly different from control, indicates significantly different from 6 h cisplatin exposure, p < 0.05 relative to control. Figure adapted from reference , used with permission from the American Physiological Society.

Figure 3. Figure 3.

Release of taurine during apoptosis of Jurkat T lymphocytes. (A) CD95 (Fas) triggerig leads to delayed, temperature‐sensitive taurine release. Taurine release into the supernatant of Jurkat T lymphocytes as a function of time after exposure to activating CD95 antibody. The cells were kept at either 37°C (closed squares) or initially at room temperature (open symbols) and then after 90 min (open squatres) or after 120 min (open triangles) to 37°C (see arrow). (B) The taurine release is inhibited by the pancase inhibitor z‐Val‐Ala‐Asp(OMe)‐fluoromethylketone (zVAD, 10 μmol/L). (C) The DNA fragmentation (and cell shrinkage, not shown) occurs only after taurine release. In the left panel, the cells have been kept at room temperature for the first 120 min of exposure to activating CD95 antibody, at the right panel the cells were exposed to activating CD95 antibody from the very beginning at 37°C ().

Figure 4. Figure 4.

Typical apoptotic volume decrease (AVD) after addition of the chemotherapeutic drug cisplatin. Cell water content and cell volume changes during cisplatin‐induced apoptosis are divided into three obvious stages identified by changes in the cell water and volume and designated AVD1, AVDT (as transition), and AVD2. (A) Ehrlich ascites tumour (EAT) cells were incubated with 5 μmol/L cisplatin and samples taken as a function of time for estimation of cell water content, which is given as mL/g dry weight, normalized to values at time 0. The values are mean values ± SEM of eight sets of experiments. *Significantly different from the initial value at time 0, tested using anova with Tukey‐Kramer multiple comparison test. (B) Cell volume (in fL) measured by electronic cell sizing (Coulter Counter) under the same conditions, normalized to values at time 0. Values are given as mean value ± SEM of 11 experiments. *Significantly different from the initial value obtained at time 0 and ‡significantly different from AVD1 tested using repeated measures anova with Tukey‐Kramer multiple comparison test.

Figure adapted from reference , reproduced with permission from the American Physiological Society.
Figure 5. Figure 5.

Mechanisms and regulation of eryptosis induced by cell shrinkage. Excessive osmotic cell shrinkage stimulates phospholipases A (PLA), which generate platelet‐activating factor (PAF) on the one side and arachidonic acid (AA) on the other. PAF stimulates an enzyme sphingomyelinase‐generating ceramide, which in turn fosters cell‐membrane scrambling with phoshpatidylserine (red) exposure at the cell surface. Cell shrinkage further activates a cycloxygenase (COX) converting AA into prostaglandin E2 (PGE2), which in turn activates a nonselective, Ca2+‐permeable cation channel (NSC). Ca2+ entering through this channel activates K+ channels leading to K+ exit, hyperpolarization, Cl exit, and thus (further) cell shrinkage. Ca2+, in addition, leads to cell‐membrane scrambling (SCR). The NSC is modified by erythropoietin, oxidative stress, energy depletion, cGMP‐dependent protein kinase type I (cGK) and AMP activated protein kinase (AMPK) ().

Figure 6. Figure 6.

Changes in the activity of mitogen‐activated protein kinases (MAPKs) by cell shrinkage.

(A) Inhibition of ERK1, and activation of JNK1, and p38 MAPK in in Ehrlich Letrée ascites (ELA) cells after osmotic shrinkage induced by doubling of extracellular osmolarity with NaCl. Kinase activity was evaluated by western blotting against the phosphorylated, active forms of the proteins, normalized to total protein. Values adapted from reference , the figure is reproduced, with permission, from reference . (B) Immunofluorescence images signifying the translocation of p38 MAPK and ERK1/2 to the nucleus in NIH3T3 cells confronted with hyper‐ and hypo‐osmotic challenge, respectively. [Values adapted from reference , the figure is reproduced, with permission, from reference .]
Figure 7. Figure 7.

Some signaling events involved in cell‐shrinkage‐induced apoptosis.

(A) Cell shrinkage detected by a volume sensor activates the monomeric GTP (Guanosine triphosphate)‐binding protein Rac, and the MAPKinase p38, followed by phosphorylation and nuclear translocation of the transcription factor p53. This is proposed to result in the transcription of proapoptotic proteins and experimentally found to result in caspase‐3 activation. Green indicates stimulatory pathways supported by experimental evidence. Model based on reference , as reprinted in reference , used with permission. (B) Cell shrinkage inhibits PDGFββ‐receptor‐mediated signalling. Red indicates the inhibited pathways supported by experimental evidence. Reduced Akt/PKB activity results in reduced Bad phosphorylation and hence an increase in Bad‐mediated programmed cell death. Reduced MEK1/2 and ERK 1/2 activity leads to reduced cell survival. Model based on reference , as reprinted in reference , used with permission. (C) The death receptor CD95 normally shows a predominant intracellular localization. Hyperosmotic exposure induces CD95 trafficking to the plasma membrane, followed by activation of caspase‐3 and ‐8 and sensitization of the cells towards CD95. Model based on reference , as reprinted in reference , used with permission.
Figure 8. Figure 8.

Effect of cell volume on vesicular pH. The pH within intracellular vesicles is sensitive to cell volume. The intravesicular pH increases upon cell shrinkage and decreases upon cell swelling. The acidification depends on the H+ pump paralleled by Cl channels, the alkalinization is accomplished by an illdefined H+ exit mechanism either coupled to or paralleled by Cl exit. The mechanism involves and requires an intact microtubule network. The original tracings show the change of lysosomal pH following transient cell swelling (HYPO = transient exposure to hypotonic solution) in the presence of the H+‐ATPase inhibitor bafilomycin (100 nmol/L) (left panel), as well as in the presence of Cl channel blocker 5 nitro‐2‐(3‐phenylpropylamino) benzoic acid (NPPB, 100 μmol/L) (right panel). The acidification requires the H+‐ATPase, the alkalinization requires neither H+‐ATPase nor NPPB sensitive Cl channels, ().



Figure 1.

Ion transport during apoptotic cell death. During the execution phase of apoptosis, activation of K+ and anion channels typically lead to cellular loss of K+ and Cl with osmotically obliged water. The HCO3 permeability of the anion channels results in cellular loss of HCO3 and thus to cytosolic acidification. Inhibition of the Na+/H+ exchanger prevents restoration of cytosolic pH and cell volume, inhibition of the Na+/K+‐ATPase precludes K+ replenishment. (A,B) Original tracings demonstrating activation of anion channels (A) and decrease of the Na+/H+ exchanger (NHE) activity (B) in Jurkat T lymphocytes prior to and following exposure to apoptosis inducing activating anti‐CD95 antibody. (A) Cl current prior to (a) and 11 min following (b) activation of CD95. (B) NHE‐dependent realkalinization (arrows) following transient exposure to NH4Cl (ammonium pulse) prior to (left) and 1 h after (right) CD95 activation ().



Figure 2.

Cellular content of Cl, K+, Na+, and ninhydrin positive substances (NPS) after cisplatin exposure in Ehrlich ascites tumour cells (EATC). The cellular content of ions and NPS are given in μmol/g dry weight. (A) Cl content was measured using Ag+ titration. (B,C) K+ and Na+ content was measured using atomic flame absorption spectroscopy. (D) Amino acid (NPS) content was estimated by measuring the cellular content of NPS, using a calorimetric assay. (E) Net loss of Cl, K+, and Na+ in μmol/g dry weight from wt EATC after 8 h cisplatin exposure. Time frames of the stages of AVD1, AVDT, and AVD2 (see Figure ) are marked above the figures. Values are presented as means +/− SEM (standard error of the mean) of five experiments apart from Cl that is average of 8 experiments. * indicates significantly different from control, indicates significantly different from 6 h cisplatin exposure, p < 0.05 relative to control. Figure adapted from reference , used with permission from the American Physiological Society.



Figure 3.

Release of taurine during apoptosis of Jurkat T lymphocytes. (A) CD95 (Fas) triggerig leads to delayed, temperature‐sensitive taurine release. Taurine release into the supernatant of Jurkat T lymphocytes as a function of time after exposure to activating CD95 antibody. The cells were kept at either 37°C (closed squares) or initially at room temperature (open symbols) and then after 90 min (open squatres) or after 120 min (open triangles) to 37°C (see arrow). (B) The taurine release is inhibited by the pancase inhibitor z‐Val‐Ala‐Asp(OMe)‐fluoromethylketone (zVAD, 10 μmol/L). (C) The DNA fragmentation (and cell shrinkage, not shown) occurs only after taurine release. In the left panel, the cells have been kept at room temperature for the first 120 min of exposure to activating CD95 antibody, at the right panel the cells were exposed to activating CD95 antibody from the very beginning at 37°C ().



Figure 4.

Typical apoptotic volume decrease (AVD) after addition of the chemotherapeutic drug cisplatin. Cell water content and cell volume changes during cisplatin‐induced apoptosis are divided into three obvious stages identified by changes in the cell water and volume and designated AVD1, AVDT (as transition), and AVD2. (A) Ehrlich ascites tumour (EAT) cells were incubated with 5 μmol/L cisplatin and samples taken as a function of time for estimation of cell water content, which is given as mL/g dry weight, normalized to values at time 0. The values are mean values ± SEM of eight sets of experiments. *Significantly different from the initial value at time 0, tested using anova with Tukey‐Kramer multiple comparison test. (B) Cell volume (in fL) measured by electronic cell sizing (Coulter Counter) under the same conditions, normalized to values at time 0. Values are given as mean value ± SEM of 11 experiments. *Significantly different from the initial value obtained at time 0 and ‡significantly different from AVD1 tested using repeated measures anova with Tukey‐Kramer multiple comparison test.

Figure adapted from reference , reproduced with permission from the American Physiological Society.


Figure 5.

Mechanisms and regulation of eryptosis induced by cell shrinkage. Excessive osmotic cell shrinkage stimulates phospholipases A (PLA), which generate platelet‐activating factor (PAF) on the one side and arachidonic acid (AA) on the other. PAF stimulates an enzyme sphingomyelinase‐generating ceramide, which in turn fosters cell‐membrane scrambling with phoshpatidylserine (red) exposure at the cell surface. Cell shrinkage further activates a cycloxygenase (COX) converting AA into prostaglandin E2 (PGE2), which in turn activates a nonselective, Ca2+‐permeable cation channel (NSC). Ca2+ entering through this channel activates K+ channels leading to K+ exit, hyperpolarization, Cl exit, and thus (further) cell shrinkage. Ca2+, in addition, leads to cell‐membrane scrambling (SCR). The NSC is modified by erythropoietin, oxidative stress, energy depletion, cGMP‐dependent protein kinase type I (cGK) and AMP activated protein kinase (AMPK) ().



Figure 6.

Changes in the activity of mitogen‐activated protein kinases (MAPKs) by cell shrinkage.

(A) Inhibition of ERK1, and activation of JNK1, and p38 MAPK in in Ehrlich Letrée ascites (ELA) cells after osmotic shrinkage induced by doubling of extracellular osmolarity with NaCl. Kinase activity was evaluated by western blotting against the phosphorylated, active forms of the proteins, normalized to total protein. Values adapted from reference , the figure is reproduced, with permission, from reference . (B) Immunofluorescence images signifying the translocation of p38 MAPK and ERK1/2 to the nucleus in NIH3T3 cells confronted with hyper‐ and hypo‐osmotic challenge, respectively. [Values adapted from reference , the figure is reproduced, with permission, from reference .]


Figure 7.

Some signaling events involved in cell‐shrinkage‐induced apoptosis.

(A) Cell shrinkage detected by a volume sensor activates the monomeric GTP (Guanosine triphosphate)‐binding protein Rac, and the MAPKinase p38, followed by phosphorylation and nuclear translocation of the transcription factor p53. This is proposed to result in the transcription of proapoptotic proteins and experimentally found to result in caspase‐3 activation. Green indicates stimulatory pathways supported by experimental evidence. Model based on reference , as reprinted in reference , used with permission. (B) Cell shrinkage inhibits PDGFββ‐receptor‐mediated signalling. Red indicates the inhibited pathways supported by experimental evidence. Reduced Akt/PKB activity results in reduced Bad phosphorylation and hence an increase in Bad‐mediated programmed cell death. Reduced MEK1/2 and ERK 1/2 activity leads to reduced cell survival. Model based on reference , as reprinted in reference , used with permission. (C) The death receptor CD95 normally shows a predominant intracellular localization. Hyperosmotic exposure induces CD95 trafficking to the plasma membrane, followed by activation of caspase‐3 and ‐8 and sensitization of the cells towards CD95. Model based on reference , as reprinted in reference , used with permission.


Figure 8.

Effect of cell volume on vesicular pH. The pH within intracellular vesicles is sensitive to cell volume. The intravesicular pH increases upon cell shrinkage and decreases upon cell swelling. The acidification depends on the H+ pump paralleled by Cl channels, the alkalinization is accomplished by an illdefined H+ exit mechanism either coupled to or paralleled by Cl exit. The mechanism involves and requires an intact microtubule network. The original tracings show the change of lysosomal pH following transient cell swelling (HYPO = transient exposure to hypotonic solution) in the presence of the H+‐ATPase inhibitor bafilomycin (100 nmol/L) (left panel), as well as in the presence of Cl channel blocker 5 nitro‐2‐(3‐phenylpropylamino) benzoic acid (NPPB, 100 μmol/L) (right panel). The acidification requires the H+‐ATPase, the alkalinization requires neither H+‐ATPase nor NPPB sensitive Cl channels, ().

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Florian Lang, Else K. Hoffmann. Role of Ion Transport in Control of Apoptotic Cell Death. Compr Physiol 2012, 2: 2037-2061. doi: 10.1002/cphy.c110046