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Updated: May 12, 2026
Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
Cell volume and monovalent ion transporters: their role in cell death machinery triggering and progression
Sergei N Orlov1, Alexandra A Platonova, Pavel Hamet
1Centre de recherche, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada. sergei.n.orlov@umontreal.ca
Abstract:
Cell death is accompanied by the dissipation of electrochemical gradients of monovalent ions across the plasma membrane that, in turn, affects cell volume via modulation of intracellular osmolyte content. In numerous cell types, apoptotic and necrotic stimuli caused cell shrinkage and swelling, respectively. Thermodynamics predicts a cell type-specific rather than an ubiquitous impact of monovalent ion transporters on volume perturbations in dying cells, suggesting their diverse roles in the cell death machinery. Indeed, recent data showed that apoptotic collapse may occur in the absence of cell volume changes and even follow cell swelling rather than shrinkage. Moreover, side-by-side with cell volume adjustment, monovalent ion transporters contribute to cell death machinery engagement independently of volume regulation via cell type-specific signaling pathways. Thus, inhibition of Na(+)-K(+)-ATPase by cardiotonic steroids (CTS) rescues rat vascular smooth muscle cells from apoptosis via a novel Na(+)i-K(+)i-mediated, Ca(2+)i-independent mechanism of excitation-transcription coupling. In contrast, CTS kill renal epithelial cells independently of Na(+)-K(+)-ATPase inhibition and increased [Na(+)]i/[K(+)]i ratio. The molecular origin of [Na(+)]i/[K(+)]i sensors involved in the inhibition of apoptosis as well as upstream intermediates of Na(+)i/K(+)i-independent death signaling triggered by CTS remain unknown.
Insights
Monovalent ion transporters influence cell death and volume changes differently across cell types. Cardiotonic steroids show cell-specific effects, rescuing some cells from apoptosis while killing others through distinct mechanisms.
Area of Science:
- Cellular Biology
- Physiology
- Biochemistry
Background:
- Cell death involves changes in ion gradients and cell volume.
- Monovalent ion transporters play a role in regulating cell volume during cell death.
- Existing data suggest cell type-specific roles for these transporters.
Purpose of the Study:
- To investigate the cell type-specific roles of monovalent ion transporters in cell death.
- To explore the mechanisms by which cardiotonic steroids (CTS) affect cell death in different cell types.
- To elucidate the signaling pathways involved in CTS-induced cell death and apoptosis inhibition.
Main Methods:
- Studied ion gradients and cell volume changes during apoptosis and necrosis.
- Investigated the effects of cardiotonic steroids (CTS) on rat vascular smooth muscle cells and renal epithelial cells.
- Analyzed Na(+)-K(+)-ATPase activity and intracellular ion concentrations ([Na+]i/[K+]i ratio).
Main Results:
- Apoptotic stimuli can cause cell shrinkage or swelling, and cell death can occur without volume changes.
- Inhibition of Na(+)-K(+)-ATPase by CTS rescues rat vascular smooth muscle cells from apoptosis via a novel mechanism.
- CTS induce death in renal epithelial cells independently of Na(+)-K(+)-ATPase inhibition.
Conclusions:
- Monovalent ion transporters have diverse, cell type-specific roles in cell death.
- Cardiotonic steroids exhibit differential effects on cell death pathways depending on the cell type.
- The precise molecular sensors and signaling pathways for CTS-induced cell death remain to be identified.
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