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Oxaliplatin neurotoxicity - No general ion channel surface-charge effect
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Karolinska Institutet.
University Hospital Uppsala.
Karolinska Institutet.
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2009 (English)In: Journal of Negative Results in BioMedicine, ISSN 1477-5751, Vol. 8, no 1, 2- p.Article in journal (Refereed) Published
Abstract [en]

Background. Oxaliplatin is a platinum-based chemotherapeutic drug. Neurotoxicity is the dose-limiting side effect. Previous investigations have reported that acute neurotoxicity could be mediated via voltage-gated ion channels. A possible mechanism for some of the effects is a modification of surface charges around the ion channel, either because of chelation of extracellular Ca2+, or because of binding of a charged biotransformation product of oxaliplatin to the channel. To elucidate the molecular mechanism, we investigated the effects of oxaliplatin and its chloride complex [Pt(dach)oxCl]- on the voltage-gated Shaker K channel expressed in Xenopus oocytes. The recordings were made with the two-electrode and the cut-open oocyte voltage clamp techniques. Conclusion. To our surprise, we did not see any effects on the current amplitudes, on the current time courses, or on the voltage dependence of the Shaker wild-type channel. Oxaliplatin is expected to bind to cysteines. Therefore, we explored if there could be a specific effect on single (E418C) and double-cysteine (R362C/F416C) mutated Shaker channels previously shown to be sensitive to cysteine-specific reagents. Neither of these channels were affected by oxaliplatin. The clear lack of effect on the Shaker K channel suggests that oxaliplatin or its monochloro complex has no general surface-charge effect on the channels, as has been suggested before, but rather a specific effect to the channels previously shown to be affected.

Place, publisher, year, edition, pages
2009. Vol. 8, no 1, 2- p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-18758DOI: 10.1186/1477-5751-8-2OAI: diva2:221322
Original Publication: Amir Broomand, E. Jerremalm, J. Yachnin, H. Ehrsson and Fredrik Elinder , Oxaliplatin neurotoxicity - No general ion channel surface-charge effect, 2009, Journal of Negative Results in BioMedicine, (8), 1, 2. Licensee: BioMed Central Available from: 2009-06-04 Created: 2009-06-03 Last updated: 2010-04-23
In thesis
1. Molecular aspects on voltage-sensor movement
Open this publication in new window or tab >>Molecular aspects on voltage-sensor movement
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Voltage-gated ion channels are fundamental for electrical signaling in living cells. They are composed of four subunits, each holding six transmembrane helices, S1-S6. Each subunit contains a voltage-sensor domain, S1-S4, and a pore domain, S5-S6. S4 contains several positively charged amino-acid residues and moves in response to changes in membrane voltage. This movement controls the opening and closing of the channel. The structure of the pore domain is solved and demonstrates principles of channel selectivity. The molecular mechanism of how the voltage sensor regulates the opening of the channel is still under discussion. Several models have been discussed. One of the models is the paddle model where S3b and S4 move together. The second one is the helical-twist where S4 makes a small rotation in order for the channel to open. The third one is the helical-screw model where S4 twists around its axis and moves diagonally towards the extracellular side of the channel.

The aim of this PhD project was to study the molecular movement of the voltage sensor in the depolarization-activated Shaker K channel. Cloned channels were expressed in Xenopus laevis oocytes, and investigated with several electrophysiological techniques.

1. We show that S4 moves in relation to both S3b and S5. The formation of some disulfide bonds between S4 and neighboring positions, in only the open state, shows that the paddle model cannot be correct. Furthermore, electrostatic and steric effects of residues in S3b suggest that S3b is tilted, with the intracellular part close to S4.

2. We show that the relatively Mg-sensitive Shaker K channel is changed into the less Mg-sensitive Kv2.1 K channel with respect to its sensitivity to extracellularly applied Mg2+ by changing the charge of three extracellularly positioned amino acid residues. One of the residues, F425C, mediates its effect through the neighboring residue K427.

3. We show that oxaliplatin, an anti-cancer drug, has no effect on the Shaker K channel. It has been suggested that a negatively charged monochloro complex of oxaliplatin is the active substance, and also causes the neurotoxic side effects. Neither this complex shows any effect on the channel.

Our experiments point towards the helical-screw model. The other models for voltage-sensor movements are incompatible with the results in this study.

Place, publisher, year, edition, pages
Institutionen för klinisk och experimentell medicin, 2007
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1028
Potassium channels, voltage-gated, chemistry, metabolism, physiology, patch-clamp techniques, oocytes
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-11229 (URN)978-91-85895-53-3 (ISBN)
Public defence
2007-11-30, Linden, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Available from: 2008-03-10 Created: 2008-03-10 Last updated: 2009-06-10

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