Effects of chloride and potassium channel blockers on apoptotic cell shrinkage and apoptosis in cortical neurons

Wei, Ling; Xiao, Ai; Jin, Chun‐Sil; Yang, Aimei; Lu, Zhongyang; Yu, Shan Ping

doi:10.1007/s00424-004-1277-2

Cited by 82 publications

(82 citation statements)

References 64 publications

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“…In regards to AVD and apoptosis, cultured cortical neurons treated with staurosporine or ceramide resulted in an inhibition of chloride currents preventing apoptotic cell shrinkage. However, these blockers did not significantly prevent caspase activation or DNA fragmentation [68]. In contrast, inhibition of potassium currents prevented cell shrinkage, caspase activation, and DNA fragmentation, suggesting distinct roles for individual ions in regulating different apoptotic events.…”

Section: Potassium As a Signal For Apoptosismentioning

confidence: 77%

“…Thus the loss or gain of a cation is usually countered by the loss or gain of an anion to maintain this homeostatic balance of ions and to remain electrochemically neutral. The loss of intracellular potassium during AVD as described above has also been shown in several studies to be paralleled by the activation of a chloride current [10,68,109] in a variety of cell types and apoptotic stimuli [reviewed in 110]. Similar to the protective effect of various K + channels inhibitors; pharmacological blockade of Cl -channels has also been shown to prevent AVD and apoptosis [110].…”

Section: Chloride As a Counter-ionmentioning

confidence: 88%

“…In cultured cortical neurons, CLC-2 and CLC-3 chloride channel activity was detected upon staurosporine, C2-ceramide, or serum deprivation resulting in AVD and apoptosis [68]. Addition of the Cl -channel blockers DIDS, SITS, or NPPB prevented AVD, however caspase activation and/or DNA fragmentation were still present.…”

Section: Chloride As a Counter-ionmentioning

confidence: 98%

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Cell shrinkage and monovalent cation fluxes: Role in apoptosis

Bortner

Cidlowski

2007

Archives of Biochemistry and Biophysics

230

193

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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.

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Section: Potassium As a Signal For Apoptosismentioning

confidence: 77%

Section: Chloride As a Counter-ionmentioning

confidence: 88%

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Cell shrinkage and monovalent cation fluxes: Role in apoptosis

Bortner

Cidlowski

2007

Archives of Biochemistry and Biophysics

230

193

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“…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).…”

mentioning

confidence: 99%

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

McCord

Aizenman

2013

Proc. Natl. Acad. Sci. U.S.A.

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A simultaneous increase in cytosolic Zn 2+ and Ca 2+ accompanies the initiation of neuronal cell death signaling cascades. However, the molecular convergence points of cellular processes activated by these cations are poorly understood. Here, we show that Ca 2+ -dependent activation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is required for a cell death-enabling process previously shown to also depend on Zn 2+ . We have reported that oxidant-induced intraneuronal Zn 2+ liberation triggers a syntaxin-dependent incorporation of Kv2.1 voltage-gated potassium channels into the plasma membrane. This channel insertion can be detected as a marked enhancement of delayed rectifier K + currents in voltage clamp measurements observed at least 3 h following a short exposure to an apoptogenic stimulus. This current increase is the process responsible for the cytoplasmic loss of K + that enables protease and nuclease activation during apoptosis. In the present study, we demonstrate that an oxidative stimulus also promotes intracellular Ca 2+ release and activation of CaMKII, which, in turn, modulates the ability of syntaxin to interact with Kv2.1. Pharmacological or molecular inhibition of CaMKII prevents the K + current enhancement observed following oxidative injury and, importantly, significantly increases neuronal viability. These findings reveal a previously unrecognized cooperative convergence of Ca 2+ -and Zn 2+ -mediated injurious signaling pathways, providing a potentially unique target for therapeutic intervention in neurodegenerative conditions associated with oxidative stress.

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“…One of the hallmarks of apoptosis is apoptotic volume decrease where increased efflux of K + and Cl -plays an important role during cell shrinkage (Barbiero et al, 1995;Beauvais et al, 1995;Cidlowski, 2007, 2002;Dezaki et al, 2012;Lang and Hoffmann, 2012;Maeno et al, 2000;Wei et al, 2004). Additionally, a dual role of Na + influx has been reported, where both absence and enhanced Na + influx causes the cell to swell Carini et al, 1995;Koike et al, 2000).…”

Section: Plasma Membrane-bound Voltage-gated Ion Channels Are Importamentioning

confidence: 99%

The role of ion channels and intracellular metal ions in apoptosis of Xenopus oocytes

Englund¹

2014

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Apoptosis is one type of programmed cell death, important during tissue development and to maintain the tissue homeostasis. Apoptosis comprises a complex network of internal signaling pathways, and an important part of this signaling network is the action of voltage‐gated ion channels. The aim of this thesis was to explore the role of ion channels and the role of intracellular metal ions during apoptosis in Xenopus laevis oocytes. The reasons for using these oocytes are that they are large, robust, easy to handle, and easy to study electrophysiologically. Apoptosis was induced either chemically by incubation of the oocytes in staurosporine (STS) or mechanically by centrifugation of the oocytes. Ion currents were measured by a two‐electrode voltage clamp technique, intracellular ion concentrations were measured either directly by in‐house developed K+‐selective microelectrodes or indirectly by the electrophysiological technique, and apoptosis was measured by caspase‐3 activation. Paper I describes that the intracellular K+ concentration was reduced by about 30 % during STS‐induced apoptosis. However, this reduction was prevented by excessive expression of exogenous ion channels. Despite the magnitude of the intracellular K+ concentration, either normal or reduced level, the oocytes displayed normal signs of apoptosis, suggesting that the intracellular K+ reduction was not required for the apoptotic process. Because the intracellular K+ concentration was not critical for apoptosis we searched for other ion fluxes by exploring the electrophysiological properties of X. laevis oocytes. Paper II, describes a non‐inactivating Na+ current activated at positive membrane voltages that was upregulated by a factor of five during STS‐induced apoptosis. By preventing influx of Na+, the apoptotic signaling network involving capsase‐3 was prevented. To molecularly identify this voltage‐gated Na channel, the X. tropicalis genome and conserved regions of the human SCNA genes were used as a map. Paper III, shows that the voltage‐gated Na channel corresponds to the SCN2A gene ortholog and that supression of this SCN2A ortholog using miRNA prevented cell death. In conclusion, this thesis work demonstrated that a voltage‐gated Na channel is critical for the apoptotic process in X. laevis oocytes by increasing the intracellular Na+ concentration

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Effects of chloride and potassium channel blockers on apoptotic cell shrinkage and apoptosis in cortical neurons

Cited by 82 publications

References 64 publications

Cell shrinkage and monovalent cation fluxes: Role in apoptosis

Cell shrinkage and monovalent cation fluxes: Role in apoptosis

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

The role of ion channels and intracellular metal ions in apoptosis of Xenopus oocytes

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Effects of chloride and potassium channel blockers on apoptotic cell shrinkage and apoptosis in cortical neurons

Cited by 82 publications

References 64 publications

Cell shrinkage and monovalent cation fluxes: Role in apoptosis

Cell shrinkage and monovalent cation fluxes: Role in apoptosis

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

The role of ion channels and intracellular metal ions in apoptosis of Xenopus oocytes

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