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Opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Institute of Environmental Medicine, Division of Toxicology and Neurotoxicology, Karolinska Institutet, Stockholm, Sweden.
Laboratory of Molecular Genetics, Osaka University Medical School and Graduate School of Medicine, Osaka, Japan.
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2005 (English)In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 12, no 8, 1134-1140 p.Article in journal (Refereed) Published
Abstract [en]

Apoptotic cell death is an essential process in the development of the central nervous system and in the pathogenesis of its degenerative diseases. Efflux of K+ and Cl- ions leads to the shrinkage of the apoptotic cell and facilitates the activation of caspases. Here, we present electrophysiological and immunocytochemical evidences for the activation of a voltage-dependent anion channel (VDAC) in the plasma membrane of neurons undergoing apoptosis. Anti-VDAC antibodies blocked the channel and inhibited the apoptotic process. In nonapoptotic cells, plasma membrane VDAC1 protein can function as a NADH (-ferricyanide) reductase. Opening of VDAC channels in apoptotic cells was associated with an increase in this activity, which was partly blocked by VDAC antibodies. Hence, it appears that there might be a dual role for this protein in the plasma membrane: (1) maintenance of redox homeostasis in normal cells and (2) promotion of anion efflux in apoptotic cells.

Place, publisher, year, edition, pages
2005. Vol. 12, no 8, 1134-1140 p.
Keyword [en]
VDAC, voltage-dependent anion channel; STS, staurosporine; PS, phosphatidylserine
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-14278DOI: 10.1038/sj.cdd.4401646OAI: oai:DiVA.org:liu-14278DiVA: diva2:23082
Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2017-12-13
In thesis
1. Voltage-dependent anion channels (VDAC) in the plasma membrane induce apoptosis
Open this publication in new window or tab >>Voltage-dependent anion channels (VDAC) in the plasma membrane induce apoptosis
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Apoptosis, or programmed cell death, is essential for proper development and functioning of the body systems. During development, apoptosis plays a central role to sculpt the embryo, and in adults, to maintain tissue homeostasis by eliminating redundant, damaged or effete cells. Therefore, a tight regulation of this process is essential. Cell shrinkage associated efflux of K+ and Cl through plasma membrane ion channels is an early event of apoptosis. However, little is known about these fluxes. The aim of this thesis was to investigate ion channels in the plasma membrane of neurons undergoing apoptosis. We studied differentiated (the mouse hippocampal cell line HT22, the human neuroblastoma cell line SK-N-MC, and rat primary hippocampal neurons) and undifferentiated (rat primary cortical neural stem cells cNSCs) cells with the patch-clamp technique. All cell types displayed a low electrical activity under control conditions. However, during apoptosis in differentiated neurons, we found an activation of a voltage-dependent anion channel. The conductance of the channel is 400 pS, the voltage dependence of the opening is bell shaped with respect to membrane voltage with a maximum open probability at 0 mV, and the Cl to cation selectivity is >5:1. These biophysical properties remind about the voltage-dependent anion channel normally found in the outer mitochondrial membrane (VDACmt). Hence, we call our apoptosis-inducing plasma membrane channel VDACpl. The molecular identity of the channel was corroborated with the specific labelling of different anti-VDAC antibodies. Block of this channel either with antibodies or with sucrose prevented apoptosis, suggesting a critical role for VDACpl in the apoptotic process. VDACpl is a NADH (-ferricyanide) reductase in control cells. We found that the enzymatic activity is altered while the VDACpl channel is activated during apoptosis. Surprisingly, in cNSCs we did not find any activation of VDACpl, no VDACpl-specific labelling, no enzymatic activity, and no prevention of apoptosis with VDACpl-blocking strategies. Instead, we found an activation of a voltage-independent 37 pS ion channel, and that the Cl channel blocker DIDS prevented apoptosis in cNSCs. Our finding that activation of VDACpl is critical for apoptosis in differentiated neurons hopefully can lead to new strategies in the treatment of several diseases related to apoptosis.

Place, publisher, year, edition, pages
Institutionen för biomedicin och kirurgi, 2006. 55 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 975
Keyword
Physiology, Apoptosis, Cell membrane, Hippocampus, Membrane potentials, Neurons, Voltage-dependent anion channels
National Category
Clinical Science
Identifiers
urn:nbn:se:liu:diva-8240 (URN)91-85643-23-8 (ISBN)
Public defence
2006-12-22, Eken, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
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Supervisors
Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2010-01-14Bibliographically approved

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Elinder, FredrikAkanda, Nesar

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