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  • 1.
    Akanda, Nesar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Voltage-dependent anion channels (VDAC) in the plasma membrane induce apoptosis2006Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

    Delarbeten
    1. Opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli
    Öppna denna publikation i ny flik eller fönster >>Opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli
    Visa övriga...
    2005 (Engelska)Ingår i: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 12, nr 8, s. 1134-1140Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    VDAC, voltage-dependent anion channel; STS, staurosporine; PS, phosphatidylserine
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14278 (URN)10.1038/sj.cdd.4401646 (DOI)
    Tillgänglig från: 2007-02-01 Skapad: 2007-02-01 Senast uppdaterad: 2018-01-25
    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
    Öppna denna publikation i ny flik eller fönster >>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
    Visa övriga...
    2008 (Engelska)Ingår i: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 7, nr 20, s. 3225-3234Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    patch clamp, single-channel recordings, apoptosis, VDAC, hippocampal neurons, neural stem cells, sodium channels
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-47952 (URN)10.4161/cc.7.20.6831 (DOI)
    Tillgänglig från: 2009-10-11 Skapad: 2009-10-11 Senast uppdaterad: 2018-01-25
    3. Biophysical properties of the apoptosis-inducing plasma membrane voltage-dependent anion channel
    Öppna denna publikation i ny flik eller fönster >>Biophysical properties of the apoptosis-inducing plasma membrane voltage-dependent anion channel
    2006 (Engelska)Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 90, nr 12, s. 4405-4417Artikel i tidskrift (Refereegranskat) 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.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14280 (URN)10.1529/biophysj.105.080028 (DOI)
    Tillgänglig från: 2007-02-01 Skapad: 2007-02-01 Senast uppdaterad: 2018-01-25
    4. Sucrose reduces the current through plasma membrane voltage-dependent anion channels (VDACpl) mainly by reducing the open probability
    Öppna denna publikation i ny flik eller fönster >>Sucrose reduces the current through plasma membrane voltage-dependent anion channels (VDACpl) mainly by reducing the open probability
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:liu:diva-14281 (URN)
    Tillgänglig från: 2007-02-01 Skapad: 2007-02-01 Senast uppdaterad: 2010-01-13
  • 2.
    Akanda, Nesar
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Biophysical properties of the apoptosis-inducing plasma membrane voltage-dependent anion channel2006Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 90, nr 12, s. 4405-4417Artikel i tidskrift (Refereegranskat)
    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.

  • 3.
    Akanda, Nesar
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi.
    Tofighi, Roshan
    Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden .
    Brask, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Tamm, Christoffer
    Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden .
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Ceccatelli, Sandra
    Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden .
    Voltage-dependent anion channels (VDAC) in the plasma membrane play a critical role in apoptosis in differentiated hippocampal neurons but not in neural stem cells2008Ingår i: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 7, nr 20, s. 3225-3234Artikel i tidskrift (Refereegranskat)
    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.

  • 4.
    Elinder, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Akanda, Nesar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Tofighi, R.
    Institute of Environmental Medicine, Division of Toxicology and Neurotoxicology, Karolinska Institutet, Stockholm, Sweden.
    Shimizu, S.
    Laboratory of Molecular Genetics, Osaka University Medical School and Graduate School of Medicine, Osaka, Japan.
    Tsujimoto, Y.
    Laboratory of Molecular Genetics, Osaka University Medical School and Graduate School of Medicine, Osaka, Japan.
    Orrenius, S.
    Institute of Environmental Medicine, Division of Toxicology and Neurotoxicology, Karolinska Institutet, Stockholm, Sweden.
    Ceccatelli, C.
    Institute of Environmental Medicine, Division of Toxicology and Neurotoxicology, Karolinska Institutet, Stockholm, Sweden.
    Opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli2005Ingår i: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 12, nr 8, s. 1134-1140Artikel i tidskrift (Refereegranskat)
    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.

1 - 4 av 4
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  • en-US
  • fi-FI
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