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Lipoelectric modification of ion channel voltage gating by polyunsaturated fatty acids
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.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
2008 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 95, no 5, 2242-2253 p.Article in journal (Refereed) Published
Abstract [en]

Polyunsaturated fatty acids (PUFAs) have beneficial effects on epileptic seizures and cardiac arrhythmia. We report that ω-3 and ω-6 all-cis-PUFAs affected the voltage dependence of the Shaker K channel by shifting the conductance versus voltage and the gating charge versus voltage curves in negative direction along the voltage axis. Uncharged methyl esters of the PUFAs did not affect the voltage dependence, whereas changes of pH and charge mutations on the channel surface affected the size of the shifts. This suggests an electrostatic effect on the channel's voltage sensors. Monounsaturated and saturated fatty acids, as well as trans-PUFAs did not affect the voltage dependence. This suggests that fatty acid tails with two or more cis double bonds are required to place the negative carboxylate charge of the PUFA in a position to affect the channel's voltage dependence. We propose that charged lipophilic compounds could play a role in regulating neuronal excitability by electrostatically affecting the channel's voltage sensor. We believe this provides a new approach for pharmacological treatment that is voltage sensor pharmacology. © 2008 by the Biophysical Society.

Place, publisher, year, edition, pages
2008. Vol. 95, no 5, 2242-2253 p.
Keyword [en]
Animals Docosahexaenoic Acids/metabolism Electrophysiology Fatty Acids, Unsaturated/analysis/*physiology Hydrogen-Ion Concentration Ion Channel Gating/*physiology Magnesium/physiology Membrane Potentials Oocytes/*physiology Patch-Clamp Techniques Shaker S
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-43208DOI: 10.1529/biophysj.108.130757Local ID: 72950OAI: oai:DiVA.org:liu-43208DiVA: diva2:264067
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically 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)
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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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