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Silverå Ejneby, M., Wu, X., Ottosson, N., Münger, E. P., Lundström, I., Konradsson, P. & Elinder, F. (2018). Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid. The Journal of General Physiology, 150(5), 731-750
Open this publication in new window or tab >>Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid
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2018 (English)In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 150, no 5, p. 731-750Article in journal (Refereed) Published
Abstract [en]

Dehydroabietic acid (DHAA) is a naturally occurring component of pine resin that was recently shown to open voltage-gated potassium (KV) channels. The hydrophobic part of DHAA anchors the compound near the channel’s positively charged voltage sensor in a pocket between the channel and the lipid membrane. The negatively charged carboxyl group exerts an electrostatic effect on the channel’s voltage sensor, leading to the channel opening. In this study, we show that the channel-opening effect increases as the length of the carboxyl-group stalk is extended until a critical length of three atoms is reached. Longer stalks render the compounds noneffective. This critical distance is consistent with a simple electrostatic model in which the charge location depends on the stalk length. By combining an effective anchor with the optimal stalk length, we create a compound that opens the human KV7.2/7.3 (M type) potassium channel at a concentration of 1 µM. These results suggest that a stalk between the anchor and the effector group is a powerful way of increasing the potency of a channel-opening drug.

Place, publisher, year, edition, pages
New York, United States: Rockefeller Institute for Medical Research, 2018
National Category
Physiology
Identifiers
urn:nbn:se:liu:diva-147837 (URN)10.1085/jgp.201711965 (DOI)000434417800008 ()2-s2.0-85046705149 (Scopus ID)
Note

Funding agencies: Swedish Research Council [2016-02615]; Swedish Heart-Lung Foundation [20150672]; Swedish Brain Foundation [2016-0326]

Available from: 2018-05-15 Created: 2018-05-15 Last updated: 2018-06-28Bibliographically approved
Salari, S., Silverå Ejneby, M., Brask, J. & Elinder, F. (2018). Isopimaric acid - a multi-targeting ion channel modulator reducing excitability and arrhythmicity in a spontaneously beating mouse atrial cell line. Acta Physiologica, 222(1), Article ID e12895.
Open this publication in new window or tab >>Isopimaric acid - a multi-targeting ion channel modulator reducing excitability and arrhythmicity in a spontaneously beating mouse atrial cell line
2018 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 222, no 1, article id e12895Article in journal (Refereed) Published
Abstract [en]

AimAtrial fibrillation is the most common persistent cardiac arrhythmia, and it is not well controlled by present drugs. Because some resin acids open voltage-gated potassium channels and reduce neuronal excitability, we explored the effects of the resin acid isopimaric acid (IPA) on action potentials and ion currents in cardiomyocytes. MethodsSpontaneously beating mouse atrial HL-1 cells were investigated with the whole-cell patch-clamp technique. Results1-25 mol L-1 IPA reduced the action potential frequency by up to 50%. The effect of IPA on six different voltage-gated ion channels was investigated; most voltage-dependent parameters of ion channel gating were shifted in the negative direction along the voltage axis, consistent with a hypothesis that a lipophilic and negatively charged compound binds to the lipid membrane close to the positively charged voltage sensor of the ion channels. The major finding was that IPA inactivated sodium channels and L- and T-type calcium channels and activated the rapidly activating potassium channel and the transient outward potassium channel. Computer simulations of IPA effects on all of the ion currents were consistent with a reduced excitability, and they also showed that effects on the Na channel played the largest role to reduce the action potential frequency. Finally, induced arrhythmia in the HL-1 cells was reversed by IPA. ConclusionLow concentrations of IPA reduced the action potential frequency and restored regular firing by altering the voltage dependencies of several voltage-gated ion channels. These findings can form the basis for a new pharmacological strategy to treat atrial fibrillation.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2018
Keywords
arrhythmia; atrial fibrillation; ion channels; isopimaric acid; patch clamp; resin acid
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-144564 (URN)10.1111/apha.12895 (DOI)000419864000009 ()28514017 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Heart-Lung Foundation; Swedish Brain Foundation; ALF

Available from: 2018-01-29 Created: 2018-01-29 Last updated: 2018-05-15
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.
Open this publication in new window or tab >>Actions and Mechanisms of Polyunsaturated Fatty Acids on Voltage-Gated Ion Channels
2017 (English)In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, article id 43Article, review/survey (Refereed) 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.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2017
Keywords
voltage-gated ion channels; polyunsaturated fatty acids; voltage sensor domain; S4; Excitability disorders
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-134980 (URN)10.3389/fphys.2017.00043 (DOI)000393235000001 ()28220076 (PubMedID)
Note

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

Available from: 2017-03-06 Created: 2017-03-06 Last updated: 2018-05-02
Lundengård, K., Cedersund, G., Sten, S., Leong, F., Smedberg, A., Elinder, F. & Engström, M. (2016). Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI. PloS Computational Biology, 12(6), Article ID e1004971.
Open this publication in new window or tab >>Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI
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2016 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 12, no 6, article id e1004971Article in journal (Refereed) Published
Abstract [en]

Functional magnetic resonance imaging (fMRI) measures brain activity by detecting the blood-oxygen-level dependent (BOLD) response to neural activity. The BOLD response depends on the neurovascular coupling, which connects cerebral blood flow, cerebral blood volume, and deoxyhemoglobin level to neuronal activity. The exact mechanisms behind this neurovascular coupling are not yet fully investigated. There are at least three different ways in which these mechanisms are being discussed. Firstly, mathematical models involving the so-called Balloon model describes the relation between oxygen metabolism, cerebral blood volume, and cerebral blood flow. However, the Balloon model does not describe cellular and biochemical mechanisms. Secondly, the metabolic feedback hypothesis, which is based on experimental findings on metabolism associated with brain activation, and thirdly, the neurotransmitter feed-forward hypothesis which describes intracellular pathways leading to vasoactive substance release. Both the metabolic feedback and the neurotransmitter feed-forward hypotheses have been extensively studied, but only experimentally. These two hypotheses have never been implemented as mathematical models. Here we investigate these two hypotheses by mechanistic mathematical modeling using a systems biology approach; these methods have been used in biological research for many years but never been applied to the BOLD response in fMRI. In the current work, model structures describing the metabolic feedback and the neurotransmitter feed-forward hypotheses were applied to measured BOLD responses in the visual cortex of 12 healthy volunteers. Evaluating each hypothesis separately shows that neither hypothesis alone can describe the data in a biologically plausible way. However, by adding metabolism to the neurotransmitter feed-forward model structure, we obtained a new model structure which is able to fit the estimation data and successfully predict new, independent validation data. These results open the door to a new type of fMRI analysis that more accurately reflects the true neuronal activity.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2016
National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:liu:diva-130437 (URN)10.1371/journal.pcbi.1004971 (DOI)000379349700045 ()27310017 (PubMedID)
Note

Funding Agencies|Swedish Research council [2014-6249]; Knut and Alice Wallenbergs foundation, KAW [2013.0076]; Research council of Southeast Sweden [FORSS-481691]; Linkoping University

Available from: 2016-08-06 Created: 2016-08-05 Last updated: 2018-03-19
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.
Open this publication in new window or tab >>Reciprocal voltage sensor-to-pore coupling leads to potassium channel C-type inactivation
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 27562Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Structural Biology
Identifiers
urn:nbn:se:liu:diva-130064 (URN)10.1038/srep27562 (DOI)000377343800001 ()27278891 (PubMedID)
Note

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

Available from: 2016-07-06 Created: 2016-07-06 Last updated: 2018-04-09
Yazdi, S., Stein, M., Elinder, F., Andersson, M. & Lindahl, E. (2016). The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel. PloS Computational Biology, 12(1), e1004704
Open this publication in new window or tab >>The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel
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2016 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 12, no 1, p. e1004704-Article in journal (Refereed) Published
Abstract [en]

Voltage-gated potassium (K-V) channels are membrane proteins that respond to changes in membrane potential by enabling K+ ion flux across the membrane. Polyunsaturated fatty acids (PUFAs) induce channel opening by modulating the voltage-sensitivity, which can provide effective treatment against refractory epilepsy by means of a ketogenic diet. While PUFAs have been reported to influence the gating mechanism by electrostatic interactions to the voltage-sensor domain (VSD), the exact PUFA-protein interactions are still elusive. In this study, we report on the interactions between the Shaker K-V channel in open and closed states and a PUFA-enriched lipid bilayer using microsecond molecular dynamics simulations. We determined a putative PUFA binding site in the open state of the channel located at the protein-lipid interface in the vicinity of the extracellular halves of the S3 and S4 helices of the VSD. In particular, the lipophilic PUFA tail covered a wide range of non-specific hydrophobic interactions in the hydrophobic central core of the protein-lipid interface, while the carboxylic head group displayed more specific interactions to polar/charged residues at the extracellular regions of the S3 and S4 helices, encompassing the S3-S4 linker. Moreover, by studying the interactions between saturated fatty acids (SFA) and the Shaker K-V channel, our study confirmed an increased conformational flexibility in the polyunsaturated carbon tails compared to saturated carbon chains, which may explain the specificity of PUFA action on channel proteins.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2016
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-125693 (URN)10.1371/journal.pcbi.1004704 (DOI)000369366100033 ()26751683 (PubMedID)
Note

Funding Agencies|Max Planck Society for Advancement of Science; Excellence Initiative "Research Center for Dynamic Systems: Biosystems Engineering"; Swedish Research Council [2013-5901]; Swedish Heart-Lung Foundation; Swedish Brain Foundation; Marie Curie Career Integration Grant [FP7-MC-CIG-618558]; Magnus Bergvalls Stiftelse [2014-00170]; Angstromke Wibergs Stiftelse [M14-0245]; Swedish e-Science Research Center (SeRC)

Available from: 2016-03-01 Created: 2016-02-29 Last updated: 2018-01-25
Johansson, P., Jullesson, D., Elfwing, A., Liin, S., Musumeci, C., Zeglio, E., . . . Inganäs, O. (2015). Electronic polymers in lipid membranes. Scientific Reports, 5(11242)
Open this publication in new window or tab >>Electronic polymers in lipid membranes
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 11242Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2015
National Category
Biophysics
Identifiers
urn:nbn:se:liu:diva-120045 (URN)10.1038/srep11242 (DOI)000356090400002 ()26059023 (PubMedID)
Note

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

Available from: 2015-07-06 Created: 2015-07-06 Last updated: 2018-01-25
Lundengård, K., Cedersund, G., Elinder, F. & Engström, M. (2015). Mechanistic Modelling Investigates the Neural Basis behind the Hemodynamic Response in fMRI. In: 16TH NORDIC-BALTIC CONFERENCE ON BIOMEDICAL ENGINEERING: . Paper presented at 16th Nordic-Baltic Conference on Biomedical Engineering (NBC) / 10th MTD Joint Conference (pp. 86-87). Springer Science Business Media, 48
Open this publication in new window or tab >>Mechanistic Modelling Investigates the Neural Basis behind the Hemodynamic Response in fMRI
2015 (English)In: 16TH NORDIC-BALTIC CONFERENCE ON BIOMEDICAL ENGINEERING, Springer Science Business Media , 2015, Vol. 48, p. 86-87Conference paper, Published paper (Refereed)
Abstract [en]

This work serves as a basis for a new type of fMRI analysis, which is based on a mechanistic interpretation of the hemodynamic response to synaptic activity. Activation was measured in the visual cortex of 12 healthy controls and ordinary differential equation models were fitted to the time series of the hemodynamic response. This allowed us to reject or refine previously proposed mechanistic hypotheses. This is the first attempt to describe the hemodynamic response quantitatively based on recent neurobiological findings. This mechanistic approach stands in contrast to the standard phenomenological description using the gamma variate function.

Place, publisher, year, edition, pages
Springer Science Business Media, 2015
Series
IFMBE Proceedings, ISSN 1680-0737 ; 48
Keywords
functional magnetic resonance imaging (fMRI); blood oxygen level dependent (BOLD) response; mechanistic modeling; ordinary differential equations (ODE); neurovascular coupling
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-114431 (URN)10.1007/978-3-319-12967-9_23 (DOI)000347893000023 ()978-3-319-12966-2 (ISBN)
Conference
16th Nordic-Baltic Conference on Biomedical Engineering (NBC) / 10th MTD Joint Conference
Available from: 2015-03-02 Created: 2015-02-20 Last updated: 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
Open this publication in new window or tab >>Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac I-Ks channel
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2015 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 18, p. 5714-5719Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
National Academy of Sciences, 2015
Keywords
Kv7.1; KCNQ1; KCNE1; I-Ks; antiarrhythmic
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-118981 (URN)10.1073/pnas.1503488112 (DOI)000353953800056 ()25901329 (PubMedID)
Note

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

Available from: 2015-06-08 Created: 2015-06-05 Last updated: 2018-01-25
Ottosson, N., Wu, X., Nolting, A., Karlsson, U., Lund, P.-E., Ruda, K., . . . Elinder, F. (2015). Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability. Scientific Reports, 5(13278)
Open this publication in new window or tab >>Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 13278Article in journal (Refereed) Published
Abstract [en]

Voltage-gated ion channels generate cellular excitability, cause diseases when mutated, and act as drug targets in hyperexcitability diseases, such as epilepsy, cardiac arrhythmia and pain. Unfortunately, many patients do not satisfactorily respond to the present-day drugs. We found that the naturally occurring resin acid dehydroabietic acid (DHAA) is a potent opener of a voltage-gated K channel and thereby a potential suppressor of cellular excitability. DHAA acts via a non-traditional mechanism, by electrostatically activating the voltage-sensor domain, rather than directly targeting the ion-conducting pore domain. By systematic iterative modifications of DHAA we synthesized 71 derivatives and found 32 compounds more potent than DHAA. The most potent compound, Compound 77, is 240 times more efficient than DHAA in opening a K channel. This and other potent compounds reduced excitability in dorsal root ganglion neurons, suggesting that resin-acid derivatives can become the first members of a new family of drugs with the potential for treatment of hyperexcitability diseases.

Place, publisher, year, edition, pages
Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group, 2015
National Category
Clinical Medicine Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-121307 (URN)10.1038/srep13278 (DOI)000359905300001 ()26299574 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Brain Foundation; Swedish Heart-Lung Foundation; ALF; County Council of Ostergotland

Available from: 2015-09-16 Created: 2015-09-14 Last updated: 2018-01-25Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-9125-5583

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