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  • 1.
    Asif, Muhammad H
    et al.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Fulati, Alimujiang
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Nor, Omer
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Willander, Magnus
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Johansson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Börjesson, Sara I.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Functionalized zinc oxide nanorod with ionophore-membrane coatingas an intracellular Ca2+ selective sensor2009In: Applied Physics Letters, ISSN 0003-6951, E-ISSN 1077-3118, Vol. 95, no 2, p. 23703-Article in journal (Refereed)
    Abstract [en]

    The tip of a borosilicate glass capillary with functionalized hexagonal ZnO nanorods was used to make a sensitive electrochemical intracellular Ca2+ sensor. To adjust the sensor for Ca2+ measurements with sufficient selectivity and stability, polyvinyl chloride (PVC) membrane containing Ca2+ ionophores were coated on the surface. The membrane covered ZnO nanorods exhibited a Ca2+-dependent electrochemical potential difference versus an Ag/AgCl reference electrode. The potential difference was linear over a large concentration range (100 nM to 10 mM). The measurements of Ca2+ concentrations using our ZnO nanorods sensor in human fat cells or in frog egg cells were consistent with values of Ca2+ concentrations reported in the literature. This nanoelectrode device paves the way to measurements of intracellular biochemical species in specific locations within single living cells.

  • 2.
    Barro-Soria, Rene
    et al.
    University of Miami, FL 33136 USA.
    Liin, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, H. Peter
    University of Miami, FL 33136 USA.
    Specificity of M-channel activators: binding or effect?2017In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 595, no 3, p. 605-606Article in journal (Other academic)
    Abstract [en]

    n/a

  • 3.
    Barro-Soria, Rene
    et al.
    Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, USA.
    Liin, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, H. Peter
    Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, USA.
    Using fluorescence to understand beta subunit-Na-V channel interactions2017In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 149, no 8, p. 757-762Article in journal (Other academic)
    Abstract [en]

    n/a

  • 4.
    Barro-Soria, Rene
    et al.
    University of Miami, FL 33136 USA.
    Ramentol, Rosamary
    University of Miami, FL 33136 USA.
    Liin, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. University of Miami, FL 33136 USA.
    Perez, Marta E.
    University of Miami, FL 33136 USA.
    Kass, Robert S.
    Columbia University, NY 10032 USA.
    Larsson, H. Peter
    University of Miami, FL 33136 USA.
    KCNE1 and KCNE3 modulate KCNQ1 channels by affecting different gating transitions2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 35, p. E7367-E7376Article in journal (Refereed)
    Abstract [en]

    KCNE beta-subunits assemble with and modulate the properties of voltage-gated K+ channels. In the heart, KCNE1 associates with the alpha-subunit KCNQ1 to generate the slowly activating, voltage-dependent potassium current (IKs) in the heart that controls the repolarization phase of cardiac action potentials. By contrast, in epithelial cells from the colon, stomach, and kidney, KCNE3 coassembles with KCNQ1 to form K+ channels that are voltage-independent K+ channels in the physiological voltage range and important for controlling water and salt secretion and absorption. How KCNE1 and KCNE3 subunits modify KCNQ1 channel gating so differently is largely unknown. Here, we use voltage clamp fluorometry to determine how KCNE1 and KCNE3 affect the voltage sensor and the gate of KCNQ1. By separating S4 movement and gate opening by mutations or phosphatidylinositol 4,5-bisphosphate depletion, we show that KCNE1 affects both the S4 movement and the gate, whereas KCNE3 affects the S4 movement and only affects the gate in KCNQ1 if an intact S4-to-gate coupling is present. Further, we show that a triple mutation in the middle of the transmembrane (TM) segment of KCNE3 introduces KCNE1-like effects on the second S4 movement and the gate. In addition, we show that differences in two residues at the external end of the KCNE TM segments underlie differences in the effects of the different KCNEs on the first S4 movement and the voltage sensor-to-gate coupling.

  • 5.
    Bohannon, Briana M.
    et al.
    Univ Miami, FL 33136 USA.
    Perez, Marta E.
    Univ Miami, FL 33136 USA.
    Liin, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Hans Peter
    Univ Miami, FL 33136 USA.
    omega-6 and omega-9 polyunsaturated fatty acids with double bonds near the carboxyl head have the highest affinity and largest effects on the cardiac I-Ks potassium channel2019In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 225, no 2, article id UNSP e13186Article in journal (Refereed)
    Abstract [en]

    Aim The I-Ks channel is important for termination of the cardiac action potential. Hundreds of loss-of-function mutations in the I-Ks channel reduce the K+ current and, thereby, delay the repolarization of the action potential, causing Long QT Syndrome. Long QT predisposes individuals to Torsades de Pointes which can lead to ventricular fibrillation and sudden death. Polyunsaturated fatty acids (PUFAs) are potential therapeutics for Long QT Syndrome, as they affect I-Ks channels. However, it is unclear which properties of PUFAs are essential for their effects on I-Ks channels. Methods To understand how PUFAs influence I-Ks channel activity, we measured effects on I-Ks current by two-electrode voltage clamp while changing different properties of the hydrocarbon tail. Results There was no, or weak, correlation between the tail length or number of double bonds in the tail and the effects on or apparent binding affinity for I-Ks channels. However, we found a strong correlation between the positions of the double bonds relative to the head group and effects on I-Ks channels. Conclusion Polyunsaturated fatty acids with double bonds closer to the head group had higher apparent affinity for I-Ks channels and increased I-Ks current more; shifting the bonds further away from the head group reduced apparent binding affinity for and effects on the I-Ks current. Interestingly, we found that omega-6 and omega-9 PUFAs, with the first double bond closer to the head group, left-shifted the voltage dependence of activation the most. These results allow for informed design of new therapeutics targeting I-Ks channels in Long QT Syndrome.

  • 6.
    Börjesson, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Polyunsaturated Fatty Acids Modifying Ion Channel Voltage Gating2011Doctoral 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.

    List of papers
    1. Polyunsaturated fatty acids and cerebrospinal fluid from children on the ketogenic diet open a voltage-gated K channel: A putative mechanism of antiseizure action
    Open this publication in new window or tab >>Polyunsaturated fatty acids and cerebrospinal fluid from children on the ketogenic diet open a voltage-gated K channel: A putative mechanism of antiseizure action
    Show others...
    2008 (English)In: Epilepsy Research, ISSN 0920-1211, E-ISSN 1872-6844, Vol. 80, no 1, p. 57-66Article in journal (Refereed) Published
    Abstract [en]

    Purpose: Many children with epilepsy do not satisfactorily respond to conventional pharmacological therapy, but to the ketogenic diet, a high-fat, low-carbohydrate diet. This diet increases the concentrations of ketone bodies and polyunsaturated fatty acids (PUFAs) in cerebrospinal fluid (CSF) and plasma. However, its anticonvulsant mechanism is not known. Methods: To investigate the mechanism by which the diet protects against seizures, we studied the effects of several PUFAs (docosahexaenoic acid, eicosapentaenoic acid, and linoleic acid), ketone bodies (β-hydroxybuturic acid and acetoacetic acid), and CSF from patients on the ketogenic diet on the voltage-gated Shaker K channel expressed in Xenopus oocytes. Results: We found that PUFAs at concentrations down to 21 μM clearly increased the K current by shifting the conductance versus voltage curve in negative direction along the voltage axis. CSF from patients on the ketogenic diet has similar but smaller effects. In contrast, high concentrations (1-5 mM) of ketone bodies did not affect the K current. Computer simulations showed that the observed shifts for clinically relevant concentrations of PUFAs, and CSF from patients could effectively impair repetitive firing. Conclusions: These data suggest that the ketogenic diet could prevent epileptic seizures by PUFA-induced openings of voltage-gated K channels. © 2008 Elsevier B.V. All rights reserved.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-43176 (URN)10.1016/j.eplepsyres.2008.03.013 (DOI)72319 (Local ID)72319 (Archive number)72319 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2018-01-25Bibliographically approved
    2. Lipoelectric modification of ion channel voltage gating by polyunsaturated fatty acids
    Open this publication in new window or tab >>Lipoelectric modification of ion channel voltage gating by polyunsaturated fatty acids
    2008 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 95, no 5, p. 2242-2253Article 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.

    Keywords
    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:nbn:se:liu:diva-43208 (URN)10.1529/biophysj.108.130757 (DOI)72950 (Local ID)72950 (Archive number)72950 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2018-01-25Bibliographically approved
    3. Electrostatic Tuning of Cellular Excitability
    Open this publication in new window or tab >>Electrostatic Tuning of Cellular Excitability
    2010 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, no 3, p. 396-403Article 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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-54082 (URN)10.1016/j.bpj.2009.10.026 (DOI)000274313200006 ()
    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: 2018-01-25Bibliographically approved
    4. An electrostatic potassium channel opener targeting the final voltage-sensor transition
    Open this publication in new window or tab >>An electrostatic potassium channel opener targeting the final voltage-sensor transition
    2011 (English)In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 137, no 6, p. 563-577Article 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
    Keywords
    Docosahexaenoic acid, ketogenic diet, voltage clamp, Xenopus oocytes
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-68083 (URN)10.1085/jgp.201110599 (DOI)000291047100008 ()
    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: 2018-01-25Bibliographically approved
  • 7.
    Börjesson, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Hammarström, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lipoelectric modification of ion channel voltage gating by polyunsaturated fatty acids2008In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 95, no 5, p. 2242-2253Article in journal (Refereed)
    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.

  • 8.
    Börjesson, Sara I
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    An electrostatic potassium channel opener targeting the final voltage-sensor transition2011In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 137, no 6, p. 563-577Article in journal (Refereed)
    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.

  • 9.
    Börjesson, Sara I.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Structure, function, and modification of the voltage sensor in voltage-gated ion channels2008In: Cell Biochemistry and Biophysics, ISSN 1085-9195, E-ISSN 1559-0283, Vol. 52, no 3, p. 149-174Article in journal (Refereed)
    Abstract [en]

    Voltage-gated ion channels are crucial for both neuronal and cardiac excitability. Decades of research have begun to unravel the intriguing machinery behind voltage sensitivity. Although the details regarding the arrangement and movement in the voltage-sensing domain are still debated, consensus is slowly emerging. There are three competing conceptual models: the helical-screw, the transporter, and the paddle model. In this review we explore the structure of the activated voltage-sensing domain based on the recent X-ray structure of a chimera between Kv1.2 and Kv2.1. We also present a model for the closed state. From this we conclude that upon depolarization the voltage sensor S4 moves ~13 Å outwards and rotates ~180º, thus consistent with the helical-screw model. S4 also moves relative to S3b which is not consistent with the paddle model. One interesting feature of the voltage sensor is that it partially faces the lipid bilayer and therefore can interact both with the membrane itself and with physiological and pharmacological molecules reaching the channel from the membrane. This type of channel modulation is discussed together with other mechanisms for how voltage-sensitivity is modified. Small effects on voltage-sensitivity can have profound effects on excitability. Therefore, medical drugs designed to alter the voltage dependence offer an interesting way to regulate excitability.

  • 10.
    Börjesson, Sara I.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Englund, Ulrika H.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Asif, Muhammad H.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Willander, Magnus
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Intracellular potassium (K+) concentration decrease is not obligatory for apoptosis2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 46, p. 39823-39828Article in journal (Refereed)
    Abstract [en]

    K+ efflux is observed as an early event in the apoptotic process in various cell types. Loss of intracellular K+ and subsequent reduction in ionic strength is suggested to release the inhibition of proapoptotic caspases. In this work, a new K+-specific microelectrode was used to study possible alterations in intracellular K+ in Xenopus laevis oocytes during chemically induced apoptosis. The accuracy of the microelectrode to detect changes in intracellular K+ was verified with parallel electrophysiological measurements within the same cells. In concordance with previous studies on other cell types, apoptotic stimuli reduced the intracellular K+ concentration in Xenopus oocytes and increased caspase-3 activity. The reduction in intracellular K+ was prevented by dense expression of voltage-gated K (Kv) channels. Despite this, the caspase-3 activity was increased similarly in Kv channel expressing oocytes as in oocytes not expressing Kv channels. Thus, in Xenopus oocytes caspase-3 activity is not dependent on the intracellular concentration of K+.

  • 11.
    Börjesson, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Parkkari, Teija
    University of Kuopio, Finland.
    Hammarström, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Electrostatic Tuning of Cellular Excitability2010In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, no 3, p. 396-403Article in journal (Refereed)
    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.

  • 12.
    Conti, Luca
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Renhorn, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Gabrielsson, Anders
    KTH Royal Institute Technology, Sweden.
    Turesson, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Liin, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lindahl, Erik
    KTH Royal Institute Technology, Sweden; Stockholm University, Sweden.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Reciprocal voltage sensor-to-pore coupling leads to potassium channel C-type inactivation2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 27562Article in journal (Refereed)
    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.

  • 13.
    Elinder, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Börjesson, Sara I.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Actions and Mechanisms of Polyunsaturated Fatty Acids on Voltage-Gated Ion Channels2017In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, article id 43Article, review/survey (Refereed)
    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.

  • 14.
    Fulati, Alimujiang
    et al.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Usman Ali, Syed M.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Asif, Muhammad H.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology. Pakistan.
    Hassan Alvi, Naveed Ul
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Willander, Magnus
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Brännmark, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Börjesson, Sara I.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Danielsson, Bengt
    Lund University, Sweden.
    An intracellular glucose biosensor based on nanoflake ZnO2010In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 150, no 2, p. 673-680Article in journal (Other academic)
    Abstract [en]

    In this study, an improved potentiometric intracellular glucose biosensor was fabricated with immobilization of glucose oxidase on a ZnO nanoporous material. The ZnO nanoporous material with a wall thickness around 200 nm was grown on the tip of a borosilicate glass capillary and used as a selective intracellular glucose sensor for the measurement of glucose concentrations in human adipocytes and frog oocytes. The results showed a fast response within 4 s and a linear glucosedependent electrochemical response over a wide range of glucose concentration (500 nM-10 mM). The measurements of intracellular glucose concentrations with our biosensor were consistent with the values of intracellular glucose concentrations reported in the literature. The sensor also demonstrated its capability by detecting an increase in the intracellular glucose concentration induced by insulin. We found that the ZnO nanoporous material provides sensitivity as high as 1.8 times higher than that obtained using ZnO nanorods under the same conditions. Moreover, the fabrication method in our experiment is simple and the excellent performance of the developed nanosensor in sensitivity, stability, selectivity, reproducibility and anti-interference was achieved. All these advantageous features of this intracellular glucose biosensor based on functionalised ZnO nanoporous material compared to ZnO nanorods demonstrate a promising way of enhancing glucose biosensor performance to measure reliable intracellular glucose concentrations within single living cells.

  • 15.
    Henrion, Ulrike
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology.
    Renhorn, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Börjesson, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nelson, Erin M
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Schwaiger, Christine S
    Royal Institute of Technology, Sweden .
    Bjelkmar, Par
    Royal Institute of Technology, Sweden Stockholm University, Sweden .
    Wallner, Björn
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Lindahl, Erik
    Royal Institute of Technology, Sweden Stockholm University, Sweden .
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Tracking a complete voltage-sensor cycle with metal-ion bridges2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 22, p. 8552-8557Article in journal (Refereed)
    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.

  • 16.
    Johansson, Patrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Jullesson, David
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Elfwing, Anders
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Liin, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Musumeci, Chiara
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Zeglio, Erica
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Solin, Niclas
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Inganäs, Olle
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Electronic polymers in lipid membranes2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 11242Article in journal (Refereed)
    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.

  • 17.
    Larsson, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, H. Peter
    Univ Miami, FL USA.
    Liin, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    KCNE1 tunes the sensitivity a: K(v)7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e37257Article in journal (Refereed)
    Abstract [en]

    The voltage-gated potassium channel K(v)7.1 and the auxiliary subunit KCNE1 together form the cardiac I-Ks channel, which is a proposed target for future anti-arrhythmic drugs. We previously showed that polyunsaturated fatty acids (PUFAs) activate K(v)7.1 via an electrostatic mechanism. The activating effect was abolished when K(v)7.1 was co-expressed with KCNE1, as KCNE1 renders PUFAs ineffective by promoting PUFA protonation. PUFA protonation reduces the potential of PUFAs as anti-arrhythmic compounds. It is unknown how KCNE1 promotes PUFA protonation. Here, we found that neutralization of negatively charged residues in the S5-P-helix loop of K(v)7.1 restored PUFA effects on K(v)7.1 co-expressed with KCNE1 in Xenopus oocytes. We propose that KCNE1 moves the S5-P-helix loop of K(v)7.1 towards the PUFA-binding site, which indirectly causes PUFA protonation, thereby reducing the effect of PUFAs on K(v)7.1. This mechanistic understanding of how KCNE1 alters K(v)7.1 pharmacology is essential for development of drugs targeting the I-Ks channel.

  • 18.
    Liin, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Urban
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bentzen, B. H.
    University of Copenhagen, Denmark.
    Schmitt, N.
    University of Copenhagen, Denmark.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Polyunsaturated fatty acids are potent openers of human M-channels expressed in Xenopus laevis oocytes2016In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 218, no 1, p. 28-37Article in journal (Refereed)
    Abstract [en]

    Aim: Polyunsaturated fatty acids have been reported to reduce neuronal excitability, in part by promoting inactivation of voltage-gated sodium and calcium channels. Effects on neuronal potassium channels are less explored and experimental data ambiguous. The aim of this study was to investigate anti-excitable effects of polyunsaturated fatty acids on the neuronal M-channel, important for setting the resting membrane potential in hippocampal and dorsal root ganglion neurones. Methods: Effects of fatty acids and fatty acid analogues on mouse dorsal root ganglion neurones and on the human KV7.2/3 channel expressed in Xenopus laevis oocytes were studied using electrophysiology. Results: Extracellular application of physiologically relevant concentrations of the polyunsaturated fatty acid docosahexaenoic acid hyperpolarized the resting membrane potential (-2.4 mV by 30 mu M) and increased the threshold current to evoke action potentials in dorsal root ganglion neurones. The polyunsaturated fatty acids docosahexaenoic acid, alpha-linolenic acid and eicosapentaenoic acid facilitated opening of the human M-channel, comprised of the heteromeric human KV7.2/3 channel expressed in Xenopus oocytes, by shifting the conductance-vs.-voltage curve towards more negative voltages (by -7.4 to -11.3 mV by 70 mu M). Uncharged docosahexaenoic acid methyl ester and monounsaturated oleic acid did not facilitate opening of the human KV7.2/3 channel. Conclusions: These findings suggest that circulating polyunsaturated fatty acids, with a minimum requirement of multiple double bonds and a charged carboxyl group, dampen excitability by opening neuronal M-channels. Collectively, our data bring light to the molecular targets of polyunsaturated fatty acids and thus a possible mechanism by which polyunsaturated fatty acids reduce neuronal excitability.

  • 19.
    Liin, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Miami, FL, USA.
    Larsson, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Berro-Soria, Rene
    University of Miami, FL, USA.
    Hjorth Bentzen, Bo
    The Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Larson, H. Peter
    University of Miami, FL, USA.
    Fatty acid analogue N-arachidonoyl taurine restores function of I-Ks channels with diverse long QT mutations2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e20272Article in journal (Refereed)
    Abstract [en]

    About 300 loss-of-function mutations in the I-Ks channel have been identified in patients with Long QT syndrome and cardiac arrhythmia. How specific mutations cause arrhythmia is largely unknown and there are no approved I-Ks channel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated IKs channel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in IKs channel currents may be caused by different molecular mechanisms. Finally, we find that the fatty acid analogue N-arachidonoyl taurine restores channel gating of many different mutant channels, even though the mutations are in different domains of the IKs channel and affect the channel by different molecular mechanisms. N-arachidonoyl taurine is therefore an interesting prototype compound that may inspire development of future IKs channel activators to treat Long QT syndrome caused by diverse IKs channel mutations.

  • 20.
    Liin, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Lund, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Brask, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Wallner, Björn
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors2018In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 150, no 8, p. 1215-1230Article in journal (Refereed)
    Abstract [en]

    Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more beneficial. Here, to search for new channel-opening compounds, we screen 18,000 compounds with high-throughput patch-clamp technology and find several potassium-channel openers that share a distinct biaryl-sulfonamide motif. Our data suggest that the negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel. Although we show here that biaryl-sulfonamide compounds open a potassium channel, they have also been reported to block sodium and calcium channels. However, because they inactivate voltage-gated sodium channels by promoting activation of one voltage sensor, we suggest that, despite different effects on the channel gates, the biaryl-sulfonamide motif is a general ion-channel activator motif. Because these compounds block action potential-generating sodium and calcium channels and open an action potential-dampening potassium channel, they should have a high propensity to reduce excitability. This opens up the possibility to build new excitability-reducing pharmaceutical drugs from the biaryl-sulfonamide scaffold.

  • 21.
    Liin, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Miami, FL 33136 USA.
    Silverå Ejneby, Malin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Barro-Soria, Rene
    University of Miami, FL 33136 USA.
    Alexander Skarsfeldt, Mark
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Larsson, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Miami, FL 33136 USA.
    Starck Härlin, Frida
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Miami, FL 33136 USA.
    Parkkari, Teija
    University of Eastern Finland, Finland.
    Hjorth Bentzen, Bo
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Schmitt, Nicole
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Peter Larsson, H.
    University of Miami, FL 33136 USA.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac I-Ks channel2015In: 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)
    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.

  • 22.
    Liin, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Yazdi, Samira
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Ramentol, Rosamary
    Univ Miami, FL 33136 USA.
    Barro-Soria, Rene
    Univ Miami, FL 33136 USA.
    Larsson, H. Peter
    Univ Miami, FL 33136 USA.
    Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.12018In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 24, no 11, p. 2908-2918Article in journal (Refereed)
    Abstract [en]

    Polyunsaturated fatty acid (PUFA) analogs represent a new class of potential anti-arrhythmic K(V)7.1 and K(V)7.1+KCNE1 channel activators. In this study, we describe dual independent activating effects of negatively charged PUFA analogs on K(V)7.1 and K(V)7.1+KCNE1 that are dependent on discrete channel motifs. PUFA analogs are critically dependent on K326 in S6 of K(V)7.1 to increase the maximum conductance and critically dependent on specific S4 arginines in K(V)7.1 to shift the voltage dependence of channel opening toward negative voltages. Our findings provide insights into how K(V)7.1+KCNE1 activators may interact electrostatically both with the pore domain and the voltage-sensing domain to augment channel activity. We believe that the molecular understanding of how PUFA analogs induce dual independent activating effects is an important step toward the development of effective anti-arrhythmic drugs that target K(V)7.1 channels.

  • 23.
    Ottosson, Nina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Liin, Sara I.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Drug-induced ion channel opening tuned by the voltage sensor charge profile2014In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 143, no 2, p. 173-182Article in journal (Refereed)
    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.

  • 24.
    Schwaiger, Christine S
    et al.
    Science Life Lab, Sweden Royal Institute Technology, Sweden .
    Börjesson, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Hess, Berk
    Science Life Lab, Sweden Royal Institute Technology, Sweden .
    Wallner, Björn
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lindahl, Erik
    Science Life Lab, Sweden Royal Institute Technology, Sweden Stockholm University, Sweden .
    The Free Energy Barrier for Arginine Gating Charge Translation Is Altered by Mutations in the Voltage Sensor Domain2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. E45880-Article in journal (Refereed)
    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.

  • 25.
    Schwaiger, Christine S.
    et al.
    Royal Institute of Technology, KTH, Sweden .
    Liin, Sara I.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lindahl, Erik
    Royal Institute of Technology, KTH, Sweden .
    The Conserved Phenylalanine in the K+ Channel Voltage-Sensor Domain Creates a Barrier with Unidirectional Effects2013In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 104, no 1, p. 75-84Article in journal (Refereed)
    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.

  • 26.
    Tigerholm, Jenny
    et al.
    KTH Royal Institute Technology, Sweden.
    Börjesson, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lundberg, Linnea
    KTH Royal Institute Technology, Sweden .
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Fransen, Erik
    KTH Royal Institute Technology, Sweden.
    Dampening of Hyperexcitability in CA1 Pyramidal Neurons by Polyunsaturated Fatty Acids Acting on Voltage-Gated Ion Channels2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, p. E44388-Article in journal (Refereed)
    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.

  • 27.
    Xu, Xianping
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Erichsen, Daniel
    Department of Neuroscience, The Nobel Institute for Neurophysiology, Karolinska Institutet Karolinska Institutet, Stockholm.
    Börjesson, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Dahlin, Maria
    Department of Child Neurology, Astrid Lindgren Children¿s Hospital Karolinska Hospital, Stockholm.
    Åmark, Per
    Department of Child Neurology, Astrid Lindgren Children¿s Hospital Karolinska Karolinska Hospital, Stockholm.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Polyunsaturated fatty acids and cerebrospinal fluid from children on the ketogenic diet open a voltage-gated K channel: A putative mechanism of antiseizure action2008In: Epilepsy Research, ISSN 0920-1211, E-ISSN 1872-6844, Vol. 80, no 1, p. 57-66Article in journal (Refereed)
    Abstract [en]

    Purpose: Many children with epilepsy do not satisfactorily respond to conventional pharmacological therapy, but to the ketogenic diet, a high-fat, low-carbohydrate diet. This diet increases the concentrations of ketone bodies and polyunsaturated fatty acids (PUFAs) in cerebrospinal fluid (CSF) and plasma. However, its anticonvulsant mechanism is not known. Methods: To investigate the mechanism by which the diet protects against seizures, we studied the effects of several PUFAs (docosahexaenoic acid, eicosapentaenoic acid, and linoleic acid), ketone bodies (β-hydroxybuturic acid and acetoacetic acid), and CSF from patients on the ketogenic diet on the voltage-gated Shaker K channel expressed in Xenopus oocytes. Results: We found that PUFAs at concentrations down to 21 μM clearly increased the K current by shifting the conductance versus voltage curve in negative direction along the voltage axis. CSF from patients on the ketogenic diet has similar but smaller effects. In contrast, high concentrations (1-5 mM) of ketone bodies did not affect the K current. Computer simulations showed that the observed shifts for clinically relevant concentrations of PUFAs, and CSF from patients could effectively impair repetitive firing. Conclusions: These data suggest that the ketogenic diet could prevent epileptic seizures by PUFA-induced openings of voltage-gated K channels. © 2008 Elsevier B.V. All rights reserved.

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