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Elinder, F. & Börjesson, S. I. (2017). Actions and Mechanisms of Polyunsaturated Fatty Acids on Voltage-Gated Ion Channels. Frontiers in Physiology, 8, Article ID 43.
Åpne denne publikasjonen i ny fane eller vindu >>Actions and Mechanisms of Polyunsaturated Fatty Acids on Voltage-Gated Ion Channels
2017 (engelsk)Inngår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, artikkel-id 43Artikkel, forskningsoversikt (Fagfellevurdert) Published
Abstract [en]

Polyunsaturated fatty acids (PUFAs) act on most ion channels, thereby having significant physiological and pharmacological effects. In this review we summarize data from numerous PUFAs on voltage-gated ion channels containing one or several voltage-sensor domains, such as voltage-gated sodium (NaV), potassium (KV), calcium (CaV), and proton (HV) channels, as well as calcium-activated potassium (KCa), and transient receptor potential (TRP) channels. Some effects of fatty acids appear to be channel specific, whereas others seem to be more general. Common features for the fatty acids to act on the ion channels are at least two double bonds in cis geometry and a charged carboxyl group. In total we identify and label five different sites for the PUFAs. PUFA site 1: The intracellular cavity. Binding of PUFA reduces the current, sometimes as a time-dependent block, inducing an apparent inactivation. PUFA site 2: The extracellular entrance to the pore. Binding leads to a block of the channel. PUFA site 3: The intracellular gate. Binding to this site can bend the gate open and increase the current. PUFA site 4: The interface between the extracellular leaflet of the lipid bilayer and the voltage-sensor domain. Binding to this site leads to an opening of the channel via an electrostatic attraction between the negatively charged PUFA and the positively charged voltage sensor. PUFA site 5: The interface between the extracellular leaflet of the lipid bilayer and the pore domain. Binding to this site affects slow inactivation. This mapping of functional PUFA sites can form the basis for physiological and pharmacological modifications of voltage-gated ion channels.

sted, utgiver, år, opplag, sider
FRONTIERS MEDIA SA, 2017
Emneord
voltage-gated ion channels; polyunsaturated fatty acids; voltage sensor domain; S4; Excitability disorders
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-134980 (URN)10.3389/fphys.2017.00043 (DOI)000393235000001 ()28220076 (PubMedID)
Merknad

Funding Agencies|Swedish Research Council; Swedish Brain Foundation; Swedish Society for Medical Research; Swedish Heart-Lung Foundation

Tilgjengelig fra: 2017-03-06 Laget: 2017-03-06 Sist oppdatert: 2018-05-02
Conti, L., Renhorn, J., Gabrielsson, A., Turesson, F., Liin, S., Lindahl, E. & Elinder, F. (2016). Reciprocal voltage sensor-to-pore coupling leads to potassium channel C-type inactivation. Scientific Reports, 6, Article ID 27562.
Åpne denne publikasjonen i ny fane eller vindu >>Reciprocal voltage sensor-to-pore coupling leads to potassium channel C-type inactivation
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2016 (engelsk)Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 27562Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Voltage-gated potassium channels open at depolarized membrane voltages. A prolonged depolarization causes a rearrangement of the selectivity filter which terminates the conduction of ions - a process called slow or C-type inactivation. How structural rearrangements in the voltage-sensor domain (VSD) cause alteration in the selectivity filter, and vice versa, are not fully understood. We show that pulling the pore domain of the Shaker potassium channel towards the VSD by a Cd2+ bridge accelerates C-type inactivation. Molecular dynamics simulations show that such pulling widens the selectivity filter and disrupts the K+ coordination, a hallmark for C-type inactivation. An engineered Cd2+ bridge within the VSD also affect C-type inactivation. Conversely, a pore domain mutation affects VSD gating-charge movement. Finally, C-type inactivation is caused by the concerted action of distant amino acid residues in the pore domain. All together, these data suggest a reciprocal communication between the pore domain and the VSD in the extracellular portion of the channel.

sted, utgiver, år, opplag, sider
NATURE PUBLISHING GROUP, 2016
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-130064 (URN)10.1038/srep27562 (DOI)000377343800001 ()27278891 (PubMedID)
Merknad

Funding Agencies|Swedish Research Council; Swedish Brain Foundation; Swedish Heart-Lung Foundation; Swedish e-Science Research Center; Foundation Blanceflor Boncompagni Ludovisi, nee Bildt

Tilgjengelig fra: 2016-07-06 Laget: 2016-07-06 Sist oppdatert: 2018-04-09
Johansson, P., Jullesson, D., Elfwing, A., Liin, S., Musumeci, C., Zeglio, E., . . . Inganäs, O. (2015). Electronic polymers in lipid membranes. Scientific Reports, 5(11242)
Åpne denne publikasjonen i ny fane eller vindu >>Electronic polymers in lipid membranes
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2015 (engelsk)Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, nr 11242Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Electrical interfaces between biological cells and man-made electrical devices exist in many forms, but it remains a challenge to bridge the different mechanical and chemical environments of electronic conductors (metals, semiconductors) and biosystems. Here we demonstrate soft electrical interfaces, by integrating the metallic polymer PEDOT-S into lipid membranes. By preparing complexes between alkyl-ammonium salts and PEDOT-S we were able to integrate PEDOT-S into both liposomes and in lipid bilayers on solid surfaces. This is a step towards efficient electronic conduction within lipid membranes. We also demonstrate that the PEDOT-S@alkyl-ammonium: lipid hybrid structures created in this work affect ion channels in the membrane of Xenopus oocytes, which shows the possibility to access and control cell membrane structures with conductive polyelectrolytes.

sted, utgiver, år, opplag, sider
Nature Publishing Group, 2015
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-120045 (URN)10.1038/srep11242 (DOI)000356090400002 ()26059023 (PubMedID)
Merknad

Funding Agencies|Knut and Alice Wallenberg Foundation; Swedish Research Council

Tilgjengelig fra: 2015-07-06 Laget: 2015-07-06 Sist oppdatert: 2018-01-25
Liin, S., Silverå Ejneby, M., Barro-Soria, R., Alexander Skarsfeldt, M., Larsson, J., Starck Härlin, F., . . . Elinder, F. (2015). Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac I-Ks channel. Proceedings of the National Academy of Sciences of the United States of America, 112(18), 5714-5719
Åpne denne publikasjonen i ny fane eller vindu >>Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac I-Ks channel
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2015 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 18, s. 5714-5719Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Polyunsaturated fatty acids (PUFAs) affect cardiac excitability. Kv7.1 and the beta-subunit KCNE1 form the cardiac I-Ks channel that is central for cardiac repolarization. In this study, we explore the prospects of PUFAs as I-Ks channel modulators. We report that PUFAs open Kv7.1 via an electrostatic mechanism. Both the polyunsaturated acyl tail and the negatively charged carboxyl head group are required for PUFAs to open Kv7.1. We further show that KCNE1 coexpression abolishes the PUFA effect on Kv7.1 by promoting PUFA protonation. PUFA analogs with a decreased pK(a) value, to preserve their negative charge at neutral pH, restore the sensitivity to open I-Ks channels. PUFA analogs with a positively charged head group inhibit I-Ks channels. These different PUFA analogs could be developed into drugs to treat cardiac arrhythmias. In support of this possibility, we show that PUFA analogs act antiarrhythmically in embryonic rat cardiomyocytes and in isolated perfused hearts from guinea pig.

sted, utgiver, år, opplag, sider
National Academy of Sciences, 2015
Emneord
Kv7.1; KCNQ1; KCNE1; I-Ks; antiarrhythmic
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-118981 (URN)10.1073/pnas.1503488112 (DOI)000353953800056 ()25901329 (PubMedID)
Merknad

Funding Agencies|National Institutes of Health [R01GM109762]; American Heart Association [14GRNT20380041]; Swedish Research Council; Swedish Heart-Lung Foundation; County Council of Ostergotland; Queen Silvias Anniversary Foundation; Academy of Finland

Tilgjengelig fra: 2015-06-08 Laget: 2015-06-05 Sist oppdatert: 2018-01-25
Ottosson, N., Liin, S. I. & Elinder, F. (2014). Drug-induced ion channel opening tuned by the voltage sensor charge profile. The Journal of General Physiology, 143(2), 173-182
Åpne denne publikasjonen i ny fane eller vindu >>Drug-induced ion channel opening tuned by the voltage sensor charge profile
2014 (engelsk)Inngår i: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 143, nr 2, s. 173-182Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Polyunsaturated fatty acids modulate the voltage dependence of several voltage-gated ion channels, thereby being potent modifiers of cellular excitability. Detailed knowledge of this molecular mechanism can be used in designing a new class of small-molecule compounds against hyperexcitability diseases. Here, we show that arginines on one side of the helical K-channel voltage sensor S4 increased the sensitivity to docosahexaenoic acid (DHA), whereas arginines on the opposing side decreased this sensitivity. Glutamates had opposite effects. In addition, a positively charged DHA-like molecule, arachidonyl amine, had opposite effects to the negatively charged DHA. This suggests that S4 rotates to open the channel and that DHA electrostatically affects this rotation. A channel with arginines in positions 356, 359, and 362 was extremely sensitive to DHA: 70 mu M DHA at pH 9.0 increased the current greater than500 times at negative voltages compared with wild type (WT). The small-molecule compound pimaric acid, a novel Shaker channel opener, opened the WT channel. The 356R/359R/362R channel drastically increased this effect, suggesting it to be instrumental in future drug screening.

sted, utgiver, år, opplag, sider
Rockefeller University Press, 2014
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-105035 (URN)10.1085/jgp.201311087 (DOI)000330628500006 ()
Tilgjengelig fra: 2014-03-06 Laget: 2014-03-06 Sist oppdatert: 2018-01-25
Schwaiger, C. S., Liin, S. I., Elinder, F. & Lindahl, E. (2013). The Conserved Phenylalanine in the K+ Channel Voltage-Sensor Domain Creates a Barrier with Unidirectional Effects. Biophysical Journal, 104(1), 75-84
Åpne denne publikasjonen i ny fane eller vindu >>The Conserved Phenylalanine in the K+ Channel Voltage-Sensor Domain Creates a Barrier with Unidirectional Effects
2013 (engelsk)Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 104, nr 1, s. 75-84Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Voltage-gated ion channels are crucial for regulation of electric activity of excitable tissues such as nerve cells, and play important roles in many diseases. During activation, the charged S4 segment in the voltage sensor domain translates across a hydrophobic core forming a barrier for the gating charges. This barrier is critical for channel function, and a conserved phenylalanine in segment S2 has previously been identified to be highly sensitive to substitutions. Here, we have studied the kinetics of K(v)1-type potassium channels (Shaker and K(v)1.2/2.1 chimera) through site-directed mutagenesis, electrophysiology, and molecular simulations. The F290L mutation in Shaker (F233L in K(v)1.2/2.1) accelerates channel closure by at least a factor 50, although opening is unaffected. Free energy profiles with the hydrophobic neighbors of F233 mutated to alanine indicate that the open state with the fourth arginine in S4 above the hydrophobic core is destabilized by similar to 17 kJ/mol compared to the first closed intermediate. This significantly lowers the barrier of the first deactivation step, although the last step of activation,is unaffected. Simulations of wild-type F233 show that the phenyl ring always rotates toward the extracellular side both for activation and deactivation, which appears to help stabilize a well-defined open state.

sted, utgiver, år, opplag, sider
Elsevier (Cell Press) / Biophysical Society, 2013
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-88664 (URN)10.1016/j.bpj.2012.11.3827 (DOI)000313541200010 ()
Merknad

Funding Agencies|European Research Council|209825|Swedish Foundation for Strategic Research||Swedish Research Council||Swedish Heart-Lung Foundation||Swedish Brain Foundation||County Council of Ostergotland||Queen Silvias Anniversary Foundation||King Gustaf V and Queen Victorias Freemasons Foundation||Swedish Society for Medical Research||

Tilgjengelig fra: 2013-02-14 Laget: 2013-02-14 Sist oppdatert: 2018-01-25bibliografisk kontrollert
Tigerholm, J., Börjesson, S., Lundberg, L., Elinder, F. & Fransen, E. (2012). Dampening of Hyperexcitability in CA1 Pyramidal Neurons by Polyunsaturated Fatty Acids Acting on Voltage-Gated Ion Channels. PLoS ONE, 7(9), E44388
Åpne denne publikasjonen i ny fane eller vindu >>Dampening of Hyperexcitability in CA1 Pyramidal Neurons by Polyunsaturated Fatty Acids Acting on Voltage-Gated Ion Channels
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2012 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 9, s. E44388-Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

A ketogenic diet is an alternative treatment of epilepsy in infants. The diet, rich in fat and low in carbohydrates, elevates the level of polyunsaturated fatty acids (PUFAs) in plasma. These substances have therefore been suggested to contribute to the anticonvulsive effect of the diet. PUFAs modulate the properties of a range of ion channels, including K and Na channels, and it has been hypothesized that these changes may be part of a mechanistic explanation of the ketogenic diet. Using computational modelling, we here study how experimentally observed PUFA-induced changes of ion channel activity affect neuronal excitability in CA1, in particular responses to synaptic input of high synchronicity. The PUFA effects were studied in two pathological models of cellular hyperexcitability associated with epileptogenesis. We found that experimentally derived PUFA modulation of the A-type K (K-A) channel, but not the delayed-rectifier K channel, restored healthy excitability by selectively reducing the response to inputs of high synchronicity. We also found that PUFA modulation of the transient Na channel was effective in this respect if the channels steady-state inactivation was selectively affected. Furthermore, PUFA-induced hyperpolarization of the resting membrane potential was an effective approach to prevent hyperexcitability. When the combined effect of PUFA on the K-A channel, the Na channel, and the resting membrane potential, was simulated, a lower concentration of PUFA was needed to restore healthy excitability. We therefore propose that one explanation of the beneficial effect of PUFAs lies in its simultaneous action on a range of ion-channel targets. Furthermore, this work suggests that a pharmacological cocktail acting on the voltage dependence of the Na-channel inactivation, the voltage dependences of K-A channels, and the resting potential can be an effective treatment of epilepsy.

sted, utgiver, år, opplag, sider
Public Library of Science, 2012
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-85610 (URN)10.1371/journal.pone.0044388 (DOI)000309556100013 ()
Merknad

Funding Agencies|Swedish Research Council|621-2007-422313043|USA NIH|MH061492-06A2|Swedish Heart-Lung Foundation||Swedish Brain Foundation||County Council of Ostergotland||King Gustaf V and Queen Victorias Freemasons Foundation||

Tilgjengelig fra: 2012-11-26 Laget: 2012-11-26 Sist oppdatert: 2018-01-25
Schwaiger, C. S., Börjesson, S., Hess, B., Wallner, B., Elinder, F. & Lindahl, E. (2012). The Free Energy Barrier for Arginine Gating Charge Translation Is Altered by Mutations in the Voltage Sensor Domain. PLoS ONE, 7(10), E45880
Åpne denne publikasjonen i ny fane eller vindu >>The Free Energy Barrier for Arginine Gating Charge Translation Is Altered by Mutations in the Voltage Sensor Domain
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2012 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 10, s. E45880-Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The gating of voltage-gated ion channels is controlled by the arginine-rich S4 helix of the voltage-sensor domain moving in response to an external potential. Recent studies have suggested that S4 moves in three to four steps to open the conducting pore, thus visiting several intermediate conformations during gating. However, the exact conformational changes are not known in detail. For instance, it has been suggested that there is a local rotation in the helix corresponding to short segments of a 3(10)-helix moving along S4 during opening and closing. Here, we have explored the energetics of the transition between the fully open state (based on the X-ray structure) and the first intermediate state towards channel closing (C-1), modeled from experimental constraints. We show that conformations within 3 angstrom of the X-ray structure are obtained in simulations starting from the C-1 model, and directly observe the previously suggested sliding 3(10)-helix region in S4. Through systematic free energy calculations, we show that the C-1 state is a stable intermediate conformation and determine free energy profiles for moving between the states without constraints. Mutations indicate several residues in a narrow hydrophobic band in the voltage sensor contribute to the barrier between the open and C-1 states, with F233 in the S2 helix having the largest influence. Substitution for smaller amino acids reduces the transition cost, while introduction of a larger ring increases it, largely confirming experimental activation shift results. There is a systematic correlation between the local aromatic ring rotation, the arginine barrier crossing, and the corresponding relative free energy. In particular, it appears to be more advantageous for the F233 side chain to rotate towards the extracellular side when arginines cross the hydrophobic region.

sted, utgiver, år, opplag, sider
Public Library of Science, 2012
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-85629 (URN)10.1371/journal.pone.0045880 (DOI)000310050200005 ()
Merknad

Funding Agencies|European Research Council|209825|Vetenskapsradet|2010-5107|Swedish Foundation for Strategic Research||Swedish e-Science Research Center||

Tilgjengelig fra: 2012-11-26 Laget: 2012-11-26 Sist oppdatert: 2018-01-25
Henrion, U., Renhorn, J., Börjesson, S., Nelson, E. M., Schwaiger, C. S., Bjelkmar, P., . . . Elinder, F. (2012). Tracking a complete voltage-sensor cycle with metal-ion bridges. Proceedings of the National Academy of Sciences of the United States of America, 109(22), 8552-8557
Åpne denne publikasjonen i ny fane eller vindu >>Tracking a complete voltage-sensor cycle with metal-ion bridges
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2012 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 22, s. 8552-8557Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 angstrom along its axis to open the channel with a 3(10) helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states.

sted, utgiver, år, opplag, sider
National Academy of Sciences, 2012
Emneord
electrophysiology, inactivation, Xenopus oocytes, voltage clamp, conformational transition
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-78812 (URN)10.1073/pnas.1116938109 (DOI)000304881700044 ()
Merknad

Funding Agencies|Swedish Research Council||Swedish Heart-Lung Foundation||Swedish Brain Foundation||County Council of Ostergotland||Queen Silvias Anniversary Foundation||King Gustaf V and Queen Victorias Freemasons Foundation||Stina and Birger Johanssons Foundation||Swedish Society for Medical Research||Swedish Foundation for Strategic Research||European Research Council||

Tilgjengelig fra: 2012-06-21 Laget: 2012-06-21 Sist oppdatert: 2018-04-09
Börjesson, S. I. & Elinder, F. (2011). An electrostatic potassium channel opener targeting the final voltage-sensor transition. The Journal of General Physiology, 137(6), 563-577
Åpne denne publikasjonen i ny fane eller vindu >>An electrostatic potassium channel opener targeting the final voltage-sensor transition
2011 (engelsk)Inngår i: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 137, nr 6, s. 563-577Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
The Rockefeller University Press, 2011
Emneord
Docosahexaenoic acid, ketogenic diet, voltage clamp, Xenopus oocytes
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-68083 (URN)10.1085/jgp.201110599 (DOI)000291047100008 ()
Merknad
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/ Tilgjengelig fra: 2011-05-10 Laget: 2011-05-10 Sist oppdatert: 2018-01-25bibliografisk kontrollert
Organisasjoner
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0001-8493-0114