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  • 51.
    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.

  • 52.
    Ottosson, Nina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Silverå Ejneby, Malin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Wu, Xiongyu
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Yazdi, Samira
    Stockholm University, Sweden.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lindahl, Erik
    Stockholm University, Sweden; KTH Royal Institute Technology, Sweden.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    A drug pocket at the lipid bilayer-potassium channel interface2017In: Science Advances, ISSN 0036-8156, E-ISSN 2375-2548, Vol. 3, no 10, article id e1701099Article in journal (Refereed)
    Abstract [en]

    Many pharmaceutical drugs against neurological and cardiovascular disorders exert their therapeutic effects by binding to specific sites on voltage-gated ion channels of neurons or cardiomyocytes. To date, all molecules targeting known ion channel sites bind to protein pockets that are mainly surrounded by water. We describe a lipid-protein drug-binding pocket of a potassium channel. We synthesized and electrophysiologically tested 125 derivatives, analogs, and related compounds to dehydroabietic acid. Functional data in combination with docking and molecular dynamics simulations mapped a binding site for small-molecule compounds at the interface between the lipid bilayer and the transmembrane segments S3 and S4 of the voltage-sensor domain. This fundamentally new binding site for small-molecule compounds paves the way for the design of new types of drugs against diseases caused by altered excitability.

  • 53.
    Ottosson, Nina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Wu, Xiongyu
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nolting, Andreas
    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.
    Lund, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ruda, Katinka
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Svensson, Stefan
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. 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.
    Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 13278Article in journal (Refereed)
    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.

  • 54.
    Salari, Sajjad
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology.
    Silverå Ejneby, Malin
    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.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Isopimaric acid - a multi-targeting ion channel modulator reducing excitability and arrhythmicity in a spontaneously beating mouse atrial cell line2018In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 222, no 1, article id e12895Article in journal (Refereed)
    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.

  • 55.
    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.

  • 56.
    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.

  • 57.
    Silverå Ejneby, Malin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Wu, Xiongyu
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Ottosson, Nina
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Münger, E Peter
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics. Linköping University, Faculty of Science & Engineering.
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Sensor and Actuator Systems. Linköping University, Faculty of Science & Engineering.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. 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.
    Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid2018In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 150, no 5, p. 731-750Article in journal (Refereed)
    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.

  • 58.
    Skold, A C
    et al.
    AstraZeneca RandD Sodertalje.
    Danielsson, C
    Karolinska Institute.
    Brask, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Salari, Sajjad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Stockling, K
    AstraZeneca RandD Sodertalje.
    Andersson, A
    AstraZeneca RandD Sodertalje.
    Jalkesten, E
    AstraZeneca RandD Sodertalje.
    Grebius, M
    AstraZeneca RandD Sodertalje.
    Larsson, M
    AstraZeneca RandD Sodertalje.
    Lindstrom, A
    AstraZeneca RandD Sodertalje.
    Blomgren, B
    AstraZeneca RandD Sodertalje.
    Pehrson, R
    AstraZeneca RandD Sodertalje.
    Danielsson, B
    Pharmanet Dev Group.
    Hellmold, H
    AstraZeneca RandD Sodertalje.
    Sylven, C
    Karolinska Institute.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Translational Research: Electrophysiological Development in the Embryonic Heart of Rats, Rabbits, and Humans in BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY, vol 91, issue 5, pp 357-3572011In: BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY, WILEY-BLACKWELL, COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA , 2011, Vol. 91, no 5, p. 357-357Conference paper (Refereed)
    Abstract [en]

    n/a

  • 59.
    Sten, Sebastian
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Lundengård, Karin
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Witt, Suzanne Tyson
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Cedersund, Gunnar
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Engström, Maria
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Neural inhibition can explain negative BOLD responses: A mechanistic modelling and fMRI study2017In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 158, p. 219-231Article in journal (Refereed)
    Abstract [en]

    Functional magnetic resonance imaging (fMRI) of hemodynamic changes captured in the blood oxygen level-dependent (BOLD) response contains information of brain activity. The BOLD response is the result of a complex neurovascular coupling and comes in at least two fundamentally different forms: a positive and a negative deflection. Because of the complexity of the signaling, mathematical modelling can provide vital help in the data analysis. For the positive BOLD response, there are plenty of mathematical models, both physiological and phenomenological. However, for the negative BOLD response, no physiologically based model exists. Here, we expand our previously developed physiological model with the most prominent mechanistic hypothesis for the negative BOLD response: the neural inhibition hypothesis. The model was trained and tested on experimental data containing both negative and positive BOLD responses from two studies: 1) a visual-motor task and 2) a workin-gmemory task in conjunction with administration of the tranquilizer diazepam. Our model was able to predict independent validation data not used for training and provides a mechanistic underpinning for previously observed effects of diazepam. The new model moves our understanding of the negative BOLD response from qualitative reasoning to a quantitative systems-biology level, which can be useful both in basic research and in clinical use.

  • 60.
    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.

  • 61.
    Usman Ali, Syed
    et al.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Asif, Muhammad
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology. Pakistan.
    Fulati, Alimujiang
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Nur, 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.
    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.
    Englund, Ulrika
    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.
    Intracellular K(+) Determination With a Potentiometric Microelectrode Based on ZnO Nanowires2011In: IEEE transactions on nanotechnology, ISSN 1536-125X, E-ISSN 1941-0085, Vol. 10, no 4, p. 913-919Article in journal (Refereed)
    Abstract [en]

    The fabrication and application of an intracellular K(+)-selective microelectrode is demonstrated. ZnO nanowires with a diameter of 100-180 nm and a length of approximately 1.5. m are grown on a borosilicate glass microcapillary. The ZnO nanowires were coated by a K(+)-ionophore-containing membrane. The K(+)-selective microelectrode exhibited a K(+)-dependent potentiometric response versus an Ag/AgCl reference microelectrode that was linear over a large concentration range (25 . M-125 mM) with a minimum detection limit of 1 . M. The measured K(+) concentrations in human adipocytes and in frog oocytes were consistent with values of K(+) concentrations reported in the literature. The sensor has several advantages including ease of fabrication, ease of insertion into the cells, low cost, and high selectivity features that make this type of sensor suitable to characterize physiologically relevant ions within single living cells.

  • 62.
    Wu, Xiongyu
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Silverå Ejneby, Malin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Ottosson, Nina
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    A Suzuki-Miyaura Coupling of ortho-Hydroxyaryl Bromide with Isopropenylboronic Pinacol Ester: Synthesis of the Potassium-Channel Opener (+)-Callitrisic Acid2018In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 14, p. 1730-1734Article in journal (Refereed)
    Abstract [en]

    A Suzuki-Miyaura coupling reaction of ortho-hydroxy-aromatic bromide 8 with isopropenylboronic acid pinacol ester has been investigated. It was found that the catalyst of Pd-2(dba)(3)/PCy3 in dioxan-water gave good yield by suppressing the formation of isomeric side product 14. (+)-Callitrisic acid was synthesized from (+)-podocarpic acid using this condition with an overall yield of 54 % in about five steps. (+)-Callitrisic acid was found to be almost three times more potent than dehydroabietic acid to open a voltage-gated potassium channel.

  • 63.
    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.

  • 64.
    Yazdi, Samira
    et al.
    Max Planck Institute Dynam Complex Technical Syst, Germany.
    Stein, Matthias
    Max Planck Institute Dynam Complex Technical Syst, Germany.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Magnus
    Science Life Lab, Sweden; KTH, Sweden.
    Lindahl, Erik
    Science Life Lab, Sweden; KTH, Sweden; Stockholm University, Sweden.
    The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel2016In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 12, no 1, p. e1004704-Article in journal (Refereed)
    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.

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