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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
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology.
Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden .
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden .
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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.

Place, publisher, year, edition, pages
2008. Vol. 7, no 20, 3225-3234 p.
Keyword [en]
patch clamp, single-channel recordings, apoptosis, VDAC, hippocampal neurons, neural stem cells, sodium channels
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-47952DOI: 10.4161/cc.7.20.6831OAI: oai:DiVA.org:liu-47952DiVA: diva2:268848
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2014-08-11
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)
Opponent
Supervisors
Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2010-01-14Bibliographically approved

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Akanda, NesarBrask, JohanElinder, Fredrik

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