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An electrostatic potassium channel opener targeting the final voltage-sensor transition
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0001-8493-0114
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
2011 (English)In: The Journal of General Physiology, ISSN 0022-1295, Vol. 137, no 6, 563-577 p.Article in journal (Refereed) Published
Abstract [en]

Free polyunsaturated fatty acids (PUFAs) modulate the voltage dependence of voltage-gated ion channels. As an important consequence thereof, PUFAs can suppress epileptic seizures and cardiac arrhythmia. However, molecular details for the interaction between PUFA and ion channels are not well understood. In this study we have localized the site of action for PUFAs on the voltage-gated Shaker K channel, by introducing positive charges on the channel surface which potentiated the PUFA effect. We furthermore found that PUFA mainly affects the final voltage-sensor movement, which is closely linked to channel opening, and that specific charges at the extracellular end of the voltage sensor are critical for the PUFA effect. Because different voltage-gated K channels have different charge profiles, this implies channel-specific PUFA effects. The identified site and the pharmacological mechanism will potentially be very useful in future drug design of small-molecule compounds specifically targeting neuronal and cardiac excitability.

Place, publisher, year, edition, pages
The Rockefeller University Press , 2011. Vol. 137, no 6, 563-577 p.
Keyword [en]
Docosahexaenoic acid, ketogenic diet, voltage clamp, Xenopus oocytes
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-68083DOI: 10.1085/jgp.201110599ISI: 000291047100008OAI: oai:DiVA.org:liu-68083DiVA: diva2:416140
Note
Original Publication: Sara I Börjesson and Fredrik Elinder, An electrostatic potassium channel opener targeting the final voltage-sensor transition, 2011, The Journal of General Physiology, (137), 6, 563-577. http://dx.doi.org/10.1085/jgp.201110599 Licensee: The Rockefellow University Press http://www.rupress.org/ Available from: 2011-05-10 Created: 2011-05-10 Last updated: 2013-09-03Bibliographically 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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