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Voltage-dependent anion channels (VDAC) in the plasma membrane induce apoptosis
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
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 [en]
Physiology, Apoptosis, Cell membrane, Hippocampus, Membrane potentials, Neurons, Voltage-dependent anion channels
National Category
Clinical Science
Identifiers
URN: urn:nbn:se:liu:diva-8240ISBN: 91-85643-23-8 (print)OAI: oai:DiVA.org:liu-8240DiVA: diva2:23086
Public defence
2006-12-22, Eken, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2010-01-14Bibliographically approved
List of papers
1. Opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli
Open this publication in new window or tab >>Opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli
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2005 (English)In: Cell Death and Differentiation, ISSN 1350-9047, 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.

Keyword
VDAC, voltage-dependent anion channel; STS, staurosporine; PS, phosphatidylserine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14278 (URN)10.1038/sj.cdd.4401646 (DOI)
Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2009-05-11
2. Voltage-dependent anion channels (VDAC) in the plasma membrane play a critical role in apoptosis in differentiated hippocampal neurons but not in neural stem cells
Open this publication in new window or tab >>Voltage-dependent anion channels (VDAC) in the plasma membrane play a critical role in apoptosis in differentiated hippocampal neurons but not in neural stem cells
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2008 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 7, no 20, 3225-3234 p.Article in journal (Refereed) Published
Abstract [en]

microRNAs (miRNAs) are small non-coding RNAs that regulate a large variety of cellular processes including differentiation, apoptosis and proliferation. Several miRNAs display defective expression patterns in human tumors with the consequent alteration of target oncogene or tumor suppressor genes. Many of these miRNAs modulate the major proliferation pathways through direct interaction with critical regulators such as RAS, PI3K/PTEN or ABL, as well as members of the retinoblastoma pathway, Cyclin-CDK complexes or cell cycle inhibitors of the INK4 or Cip/Kip families. A complex interplay between miRNAs and MYC or E2F family members also exists to modulate cell cycle-dependent transcription during normal or tumoral proliferation. The ability of miRNAs to modulate these proliferation pathways may have relevant implications not only in physiological or developmental processes but also in tumor progression or cancer therapy.

Keyword
patch clamp, single-channel recordings, apoptosis, VDAC, hippocampal neurons, neural stem cells, sodium channels
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-47952 (URN)10.4161/cc.7.20.6831 (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2014-08-11
3. Biophysical properties of the apoptosis-inducing plasma membrane voltage-dependent anion channel
Open this publication in new window or tab >>Biophysical properties of the apoptosis-inducing plasma membrane voltage-dependent anion channel
2006 (English)In: Biophysical Journal, ISSN 0006-3495, Vol. 90, no 12, 4405-4417 p.Article in journal (Refereed) Published
Abstract [en]

Ion channels in the plasma membrane play critical roles in apoptosis. In a recent study we found that a voltage-dependent anion channel in the plasma membrane (VDACpl) of neuronal hippocampal cell line (HT22) cells was activated during apoptosis and that channel block prevented apoptosis. Whether or not VDACpl is identical to the mitochondrial VDACmt has been debated. Here, we biophysically characterize the apoptosis-inducing VDACpl and compare it with other reports of VDACpls and VDACmt. Excised membrane patches of apoptotic HT22 cells were studied with the patch-clamp technique. VDACpl has a large main-conductance state (400 pS) and occasionally subconductance states of µ28 pS and 220 pS. The small subconductance state is associated with long-lived inactivated states, and the large subconductance state is associated with excision of the membrane patch and subsequent activation of the channel. The open-probability curve is bell shaped with its peak around 0mV and is blocked by 30µM Gd3+. The gating can be described by a symmetrical seven-state model with one open state and six closed or inactivated states. These channel properties are similar to those of VDACmt and other VDACpls and are discussed in relation to apoptosis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14280 (URN)10.1529/biophysj.105.080028 (DOI)
Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2009-02-09
4. Sucrose reduces the current through plasma membrane voltage-dependent anion channels (VDACpl) mainly by reducing the open probability
Open this publication in new window or tab >>Sucrose reduces the current through plasma membrane voltage-dependent anion channels (VDACpl) mainly by reducing the open probability
Manuscript (Other academic)
Identifiers
urn:nbn:se:liu:diva-14281 (URN)
Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2010-01-13

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