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Electrostatic Tuning of Cellular Excitability
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0001-8493-0114
University of Kuopio, Finland.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
2010 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, no 3, 396-403 p.Article in journal (Refereed) Published
Abstract [en]

Voltage-gated ion channels regulate the electric activity of excitable tissues, such as the heart and brain. Therefore, treatment for conditions of disturbed excitability is often based on drugs that target ion channels. In this study of a voltage-gated K channel, we propose what we believe to be a novel pharmacological mechanism for how to regulate channel activity. Charged lipophilic substances can tune channel opening, and consequently excitability, by an electrostatic interaction with the channels voltage sensors. The direction of the effect depends on the charge of the substance. This was shown by three compounds sharing an arachiclonyl backbone but bearing different charge: arachidonic acid, methyl arachidonate, and arachidonyl amine. Computer simulations of membrane excitability showed that small changes in the voltage dependence of Na and K channels have prominent impact on excitability and the tendency for repetitive firing. For instance, a shift in the voltage dependence of a K channel with -5 or +5 mV corresponds to a threefold increase or decrease in K channel density, respectively. We suggest that electrostatic tuning of ion channel activity constitutes a novel and powerful pharmacological approach with which to affect cellular excitability.

Place, publisher, year, edition, pages
2010. Vol. 98, no 3, 396-403 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-54082DOI: 10.1016/j.bpj.2009.10.026ISI: 000274313200006OAI: oai:DiVA.org:liu-54082DiVA: diva2:298247
Note

Original Publication: Sara Börjesson, Teija Parkkari, Sven Hammarström and Fredrik Elinder, Electrostatic Tuning of Cellular Excitability, 2010, BIOPHYSICAL JOURNAL, (98), 3, 396-403. http://dx.doi.org/10.1016/j.bpj.2009.10.026 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/

Available from: 2010-02-22 Created: 2010-02-22 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Polyunsaturated Fatty Acids Modifying Ion Channel Voltage Gating
Open this publication in new window or tab >>Polyunsaturated Fatty Acids Modifying Ion Channel Voltage Gating
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Voltage-gated ion channels play fundamental roles in neuronal excitability and therefore dysfunctional channels can cause disease. Epilepsy is such a disease, affecting about 1% of the population and being characterized by synchronous electric activity of large groups of neurons leading to various types of seizures. In this thesis, polyunsaturated fatty acids (PUFAs) were used as key substances to study a new pharmacological mechanism for how to induce opening of voltage-gated potassium (Kv) channels, and how this possibly can protect against epileptic activity. All experiments were performed on cloned Shaker Kv channels expressed in Xenopus laevis oocytes. Channel activity was recorded with the electrophysiological two-electrode voltage clamp technique.

First we showed that both PUFAs and cerebrospinal fluid from children on the ketogenic diet open the Shaker Kv channel by shifting the channel voltage dependence towards more negative voltages, as we would expect for an antiepileptic effect. By testing fatty acids and related compounds with different properties and under different conditions we identified the critical structural components needed for the beneficial effect: a flexible cis-polyunsaturated lipid tail in combination with a negatively charged carboxyl head group. If substituting the negative charge for a positive amine group, channel opening was instead impeded. By mutating and modifying the channel at strategic positions the PUFA-action site was localized to a lipid-exposed surface close to the channel’s voltage sensor. We also showed that PUFAs induce channel opening by electrostatically facilitating a final voltage-sensor movement. The PUFA efficiency is dependent on the channel’s profile of charged residues in the outer end of the voltage sensor. This implies channel-specific effects. Finally, computer simulations demonstrated that small changes in channel voltage dependence can have dramatic effects on cellular excitability.

Both the identified PUFA-action site and the mechanism by which PUFAs induce channel opening are novel and could potentially be very useful in future drug design of compounds targeting neuronal and cardiac excitability. Our work also suggests that PUFA-induced Kv channel opening could be one important component in the ketogenic diet used as alternative epilepsy treatment.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 51 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1235
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68084 (URN)978-91-7393-204-2 (ISBN)
Public defence
2011-05-06, Linden, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2011-05-10 Created: 2011-05-10 Last updated: 2013-09-03Bibliographically approved

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Börjesson, SaraHammarström, SvenElinder, Fredrik

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