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Inhibition of SCN2A ortholog upregulation in Xenopus laevis oocytes prevents cell death
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Transport of ions across the cell membrane is essential for the regulation of cell death and tissue homeostasis, and alterations in the function of voltage-gated ion channels and of the intracellular ionic compositions interfere with these processes. Opening of K, Na , or Cl channels have been linked to the apoptotic process and in many cases, opening of these channels precede caspase-3 activation and are thus early events in the apoptotic process. Consistent with the role of these channels in apoptosis, inhibition of these channels prevents or delays the apoptotic process. However, the role of ion channels during apoptosis has been difficult to explore, mainly due to unspecific/non-selective ion channe blockers. In the present investigation, the molecular identity of a  voltage-gated Na channel in oocytes from Xenopus laevis, which is crucial for the apoptotic response to mechanical stress, was identified. Specific down regulation of SCN2A Na channel expression by miRNA prevented apoptosis, suggesting that Na+ influx is essential for apoptosis in Xenopus oocytes.

Place, publisher, year, edition, pages
2014. Vol. 9
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:liu:diva-111044OAI: oai:DiVA.org:liu-111044DiVA: diva2:752779
Available from: 2014-10-06 Created: 2014-10-06 Last updated: 2014-10-06Bibliographically approved
In thesis
1. The role of ion channels and intracellular metal ions in apoptosis of Xenopus oocytes
Open this publication in new window or tab >>The role of ion channels and intracellular metal ions in apoptosis of Xenopus oocytes
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Apoptosis is one type of programmed cell death, important during tissue development and to maintain the tissue homeostasis. Apoptosis comprises a complex network of internal signaling pathways, and an important part of this signaling network is the action of voltage‐gated ion channels. The aim of this thesis was to explore the role of ion channels and the role of intracellular metal ions during apoptosis in Xenopus laevis oocytes. The reasons for using these oocytes are that they are large, robust, easy to handle, and easy to study electrophysiologically. Apoptosis was induced either chemically by incubation of the oocytes in staurosporine (STS) or mechanically by centrifugation of the oocytes. Ion currents were measured by a two‐electrode voltage clamp technique, intracellular ion concentrations were measured either directly by in‐house developed K+‐selective microelectrodes or indirectly by the electrophysiological technique, and apoptosis was measured by caspase‐3 activation. Paper I describes that the intracellular K+ concentration was reduced by about 30 % during STS‐induced apoptosis. However, this reduction was prevented by excessive expression of exogenous ion channels. Despite the magnitude of the intracellular K+ concentration, either normal or reduced level, the oocytes displayed normal signs of apoptosis, suggesting that the intracellular K+ reduction was not required for the apoptotic process. Because the intracellular K+ concentration was not critical for apoptosis we searched for other ion fluxes by exploring the electrophysiological properties of X. laevis oocytes. Paper II, describes a non‐inactivating Na+ current activated at positive membrane voltages that was upregulated by a factor of five during STS‐induced apoptosis. By preventing influx of Na+, the apoptotic signaling network involving capsase‐3 was prevented. To molecularly identify this voltage‐gated Na channel, the X. tropicalis genome and conserved regions of the human SCNA genes were used as a map. Paper III, shows that the voltage‐gated Na channel corresponds to the SCN2A gene ortholog and that supression of this SCN2A ortholog using miRNA prevented cell death. In conclusion, this thesis work demonstrated that a voltage‐gated Na channel is critical for the apoptotic process in X. laevis oocytes by increasing the intracellular Na+ concentration.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 47 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1424
National Category
Clinical Medicine Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-111045 (URN)10.3384/diss.diva-111045 (DOI)978‐91‐7519‐220‐8 (print) (ISBN)
Public defence
2014-11-07, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:15 (English)
Opponent
Supervisors
Available from: 2014-10-06 Created: 2014-10-06 Last updated: 2014-11-14Bibliographically approved

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Englund, UlrikaBrask, JohanElinder, Fredrik

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