Ion channels in the regulation of apoptosis

Kondratskyi, Artem; Kondratska, Kateryna; Skryma, Roman; Prevarskaya, Natalia

doi:10.1016/j.bbamem.2014.10.030

Cited by 171 publications

(138 citation statements)

References 263 publications

Supporting

Mentioning

119

Contrasting

Unclassified

Order By: Relevance

“…These channels allow the cell to shrink (apoptotic volume decrease, AVD) by releasing anions and organic osmolytes to the extracellular space, which resembles the osmotic driving force for water exit ( Fig. 1) (Kondratskyi et al 2015;Lang et al 2007;Lang and Hoffmann 2012). Initial AVD in apoptosis is essential; its suppression strongly attenuates apoptosis and also reflects a mechanism for cancer cells to escape from apoptotic cell death (Maeno et al 2000).…”

Section: Introductionmentioning

confidence: 98%

Cl− channels in apoptosis

et al. 2016

View full text Add to dashboard Cite

A remarkable feature of apoptosis is the initial massive cell shrinkage, which requires opening of ion channels to allow release of K, Cl, and organic osmolytes to drive osmotic water movement and cell shrinkage. This article focuses on the role of the Cl channels LRRC8, TMEM16/anoctamin, and cystic fibrosis transmembrane conductance regulator (CFTR) in cellular apoptosis. LRRC8A-E has been identified as a volume-regulated anion channel expressed in many cell types. It was shown to be required for regulatory and apoptotic volume decrease (RVD, AVD) in cultured cell lines. Its presence also determines sensitivity towards cytostatic drugs such as cisplatin. Recent data point to a molecular and functional relationship of LRRC8A and anoctamins (ANOs). ANO6, 9, and 10 (TMEM16F, J, and K) augment apoptotic Cl currents and AVD, but it remains unclear whether these anoctamins operate as Cl channels or as regulators of other apoptotic Cl channels, such as LRRC8. CFTR has been known for its proapoptotic effects for some time, and this effect may be based on glutathione release from the cell and increase in cytosolic reactive oxygen species (ROS). Although we find that CFTR is activated by cell swelling, it is possible that CFTR serves RVD/AVD through accumulation of ROS and activation of independent membrane channels such as ANO6. Thus activation of ANO6 will support cell shrinkage and induce additional apoptotic events, such as membrane phospholipid scrambling.

show abstract

Section: Introductionmentioning

confidence: 98%

Cl− channels in apoptosis

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In terms of time-course, apoptotic volume decrease (AVD) occurs in two phases, an initial phase that starts 0.5-2 hours after exposure to the inductor and a late phase detected about 3 hours later. The two phases of AVD are accomplished by the same mechanism that includes outward fluxes of K 1 and Cl -moving across specific channels and a decrease in osmolyte intracellular concentration and water outflow resulting in AVD (Kondratskyi et al, 2015). It has yet to be determined whether this decrease in cell volume is a passive factor or an active signal in the induction of apoptosis, but evidence does exist that points to an explicit role for volume decrease in the apoptotic process; blockade of the main osmolyte pathways that reduce AVD impairs the progression of apoptosis (Yu and Choi, 2000;Grishin et al, 2005).…”

Section: Channels Involved In Volume Changes In Necrotic and Apoptotimentioning

confidence: 99%

Channels and Volume Changes in the Life and Death of the Cell

Pasantes‐Morales

2016

Mol Pharmacol

View full text Add to dashboard Cite

Volume changes deviating from original cell volume represent a major challenge for cellular homeostasis. Cell volume may be altered either by variations in the external osmolarity or by disturbances in the transmembrane ion gradients that generate an osmotic imbalance. Cells respond to anisotonicity-induced volume changes by active regulatory mechanisms that modify the intracellular/extracellular concentrations of K 1 , Cl -, Na 1 , and organic osmolytes in the direction necessary to reestablish the osmotic equilibrium. Corrective osmolyte fluxes permeate across channels that have a relevant role in cell volume regulation. Channels also participate as causal actors in necrotic swelling and apoptotic volume decrease. This is an overview of the types of channels involved in either corrective or pathologic changes in cell volume. The review also underlines the contribution of transient receptor potential (TRP) channels, notably TRPV4, in volume regulation after swelling and describes the role of other TRPs in volume changes linked to apoptosis and necrosis. Lastly we discuss findings showing that multimers derived from LRRC8A (leucine-rich repeat containing 8A) gene are structural components of the volume-regulated Cl -channel (VRAC), and we underline the intriguing possibility that different heteromer combinations comprise channels with different intrinsic properties that allow permeation of the heterogenous group of molecules acting as organic osmolytes.

show abstract

“…15 In vivo studies have suggested that diltiazem, an L-type calcium channel blocker (CCB), may reduce the concentration of calcium precipitates at the basolateral membrane of the OHCs. 16 There is also evidence demonstrating that L-type calcium channels can be localized to the inner ear and play a role in the pathogenesis of acoustic injury.…”

mentioning

confidence: 99%

Cisplatin‐Induced Ototoxicity and the Effects of Intratympanic Diltiazem in a Mouse Model

Naples

Parham

2015

Otolaryngol.--head neck surg.

View full text Add to dashboard Cite

Objective. To evaluate whether the calcium-channel blocker diltiazem has protective effects against cisplatin-induced ototoxicity in a mouse model. Study Design. Original basic science in vivo investigation.Setting. Academic setting: Otolaryngology-Head and Neck Surgery laboratory at University of Connecticut Health Center.Subjects. Thirty-nine female CBA/J mice.Methods. Pure tone-or click-evoked auditory brainstem responses (ABRs) were recorded in CBA/J mice to determine auditory thresholds. All mice had baseline ABRs recorded. They were then given a single cisplatin bolus (14 mg/kg), followed by 5 consecutive days of intratympanic diltiazem or saline control. Follow-up thresholds were recorded on days 7, 14, and 21 postcisplatin. Tone-evoked ABRs evaluated the otoprotective effect of 2-mg/kg diltiazem in 9 mice, and dose effect was examined in response to click-evoked ABR with 2-or 4-mg/kg diltiazem in 2 groups of 15 mice.Results. Saline-treated ears had significantly elevated toneevoked auditory thresholds when compared with diltiazemtreated ears (P = .038) on day 7 postcisplatin only. Clickevoked ABR thresholds were significantly elevated in salinetreated ears versus diltiazem-treated ears for the 2-mg/kg group (P = .001) and 4-mg/kg group (P = .011) on days 7, 14, and 21 postcisplatin. Conclusion.Intratympanic diltiazem has significant protective effects against cisplatin ototoxicity at 2 and 4 mg/kg. This is the first in vivo study to demonstrate that diltiazem offers a potentially novel therapy for cisplatininduced ototoxicity.

show abstract

Ion channels in the regulation of apoptosis

Cited by 171 publications

References 263 publications

Cl− channels in apoptosis

Cl− channels in apoptosis

Channels and Volume Changes in the Life and Death of the Cell

Cisplatin‐Induced Ototoxicity and the Effects of Intratympanic Diltiazem in a Mouse Model

Contact Info

Product

Resources

About