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  • 1.
    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

  • 2.
    Bohannon, Briana M.
    et al.
    Univ Miami, FL 33136 USA.
    Wu, Xiaoan
    Univ Miami, FL 33136 USA.
    Wu, Xiongyu
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Perez, Marta E.
    Univ Miami, FL 33136 USA.
    Liin, Sara
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, H. Peter
    Univ Miami, FL 33136 USA.
    Polyunsaturated fatty acids produce a range of activators for heterogeneous I-Ks channel dysfunction2020In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 152, no 2, article id e201912396Article in journal (Refereed)
    Abstract [en]

    Repolarization and termination of the ventricular cardiac action potential is highly dependent on the activation of the slow delayed-rectifier potassium I-Ks channel. Disruption of the I-Ks current leads to the most common form of congenital long QT syndrome (LQTS), a disease that predisposes patients to ventricular arrhythmias and sudden cardiac death. We previously demonstrated that polyunsaturated fatty acid (PUFA) analogues increase outward K+ current in wild type and LQTS-causing mutant I-Ks channels. Our group has also demonstrated the necessity of a negatively charged PUFA head group for potent activation of the I-Ks channel through electrostatic interactions with the voltage-sensing and pore domains. Here, we test whether the efficacy of the PUFAs can be tuned by the presence of different functional groups in the PUFA head, thereby altering the electrostatic interactions of the PUFA head group with the voltage sensor or the pore. We show that PUFA analogues with taurine and cysteic head groups produced the most potent activation of I-Ks channels, largely by shifting the voltage dependence of activation. In comparison, the effect on voltage dependence of PUFA analogues with glycine and aspartate head groups was half that of the taurine and cysteic head groups, whereas the effect on maximal conductance was similar. Increasing the number of potentially negatively charged moieties did not enhance the effects of the PUFA on the I-Ks channel. Our results show that one can tune the efficacy of PUFAs on I-Ks channels by altering the pK(a) of the PUFA head group. Different PUFAs with different efficacy on I-Ks channels could be developed into more personalized treatments for LQTS patients with a varying degree of I-Ks channel dysfunction.

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  • 3. Bruening-Wright, Andrew
    et al.
    Elinder, Fredrik
    Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
    Larsson, H Peter
    Kinetic relationship between the voltage sensor and the activation gate in spHCN channels2007In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 130, no 1, p. 71-81Article in journal (Refereed)
    Abstract [en]

    Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are activated by membrane hyperpolarizations that cause an inward movement of the positive charges in the fourth transmembrane domain (S4), which triggers channel opening. The mechanism of how the motion of S4 charges triggers channel opening is unknown. Here, we used voltage clamp fluorometry (VCF) to detect S4 conformational changes and to correlate these to the different activation steps in spHCN channels. We show that S4 undergoes two distinct conformational changes during voltage activation. Analysis of the fluorescence signals suggests that the N-terminal region of S4 undergoes conformational changes during a previously characterized mode shift in HCN channel voltage dependence, while a more C-terminal region undergoes an additional conformational change during gating charge movements. We fit our fluorescence and ionic current data to a previously proposed 10-state allosteric model for HCN channels. Our results are not compatible with a fast S4 motion and rate-limiting channel opening. Instead, our data and modeling suggest that spHCN channels open after only two S4s have moved and that S4 motion is rate limiting during voltage activation of spHCN channels. © The Rockefeller University Press.

  • 4.
    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.

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  • 5.
    Jiang, Chong-He
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Lindström, Sivert
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Prolonged enhancement of the micturition reflex in the cat by repetitive stimulation of bladder afferents1999In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 517, no 2, p. 599-605Article in journal (Refereed)
    Abstract [en]
    1. Prolonged modulation of the parasympathetic micturition reflex was studied in cats anaesthetized by -chloralose. Reflex discharges were recorded from a thin pelvic nerve filament to the bladder and evoked by stimulation of the remaining ipsilateral bladder pelvic nerves or urethral branches of the pudendal nerve.

       

    2. Stimulation of bladder or urethral afferents at A intensity evoked micturition reflexes with a latency of 90-120 ms. Such reflexes were much enhanced following repetitive conditioning stimulation of the same afferents at 20 Hz for 5 min.

       

    3. The reflex enhancement lasted more than 1 h after the conditioning stimulation. The effect was not prevented by a preceding complete transection of the sympathetic supply to the bladder. A prolonged suppression of the reflex was obtained after conditioning stimulation of afferents in the dorsal clitoris nerves.

       

    4. It is proposed that the prolonged modulations of the micturition reflex represent physiological adaptive processes, which preserve a flawless function of the bladder during life. The observations provide a theoretical explanation for the beneficial effect of electric nerve stimulation in patients with voiding disorders.
  • 6.
    Larsson, Johan
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Urban
    Linköping University, Department of Biomedical and Clinical Sciences, Division 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.
    Liin, Sara
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology.
    Combining endocannabinoids with retigabine for enhanced M-channel effect and improved KV7 subtype selectivity2020In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 152, no 8Article in journal (Refereed)
    Abstract [en]

    Retigabine is unique among anticonvulsant drugs by targeting the neuronal M-channel, which is composed of KV7.2/KV7.3 and contributes to the negative neuronal resting membrane potential. Unfortunately, retigabine causes adverse effects, which limits its clinical use. Adverse effects may be reduced by developing M-channel activators with improved KV7 subtype selectivity. The aim of this study was to evaluate the prospect of endocannabinoids as M-channel activators, either in isolation or combined with retigabine. Human KV7 channels were expressed in Xenopus laevis oocytes. The effect of extracellular application of compounds with different properties was studied using two-electrode voltage clamp electrophysiology. Site-directed mutagenesis was used to construct channels with mutated residues to aid in the mechanistic understanding of these effects. We find that arachidonoyl-L-serine (ARA-S), a weak endocannabinoid, potently activates the human M-channel expressed in Xenopus oocytes. Importantly, we show that ARA-S activates the M-channel via a different mechanism and displays a different KV7 subtype selectivity compared with retigabine. We demonstrate that coapplication of ARA-S and retigabine at low concentrations retains the effect on the M-channel while limiting effects on other KV7 subtypes. Our findings suggest that improved KV7 subtype selectivity of M-channel activators can be achieved through strategically combining compounds with different subtype selectivity.

  • 7.
    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.

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  • 8.
    Madhvani, Roshni V.
    et al.
    Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, USA.
    Angelini, Marina
    Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, USA.
    Xie, Yuanfang
    Department of Pharmacology, University of California, David Geffen School of Medicine, University of California, Los Angeles, USA.
    Pantazis, Antonios
    Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, USA.
    Suriany, Silvie
    Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, USA.
    Borgstrom, Nils P.
    Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, USA.
    Garfinkel, Alan
    Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, USA.
    Qu, Qu
    Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, USA.
    Weiss, James N.
    Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, USA.
    Olcese, Riccardo
    Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, USA.
    Targeting the Late Component of the Cardiac L-type Ca2+ Current to Suppress Early Afterdepolarizations2015In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 145, no 5, p. 395-404Article in journal (Refereed)
    Abstract [en]

    Early afterdepolarizations (EADs) associated with prolongation of the cardiac action potential (AP) can create heterogeneity of repolarization and premature extrasystoles, triggering focal and reentrant arrhythmias. Because the L-type Ca2+ current (ICa,L) plays a key role in both AP prolongation and EAD formation, L-type Ca2+ channels (LTCCs) represent a promising therapeutic target to normalize AP duration (APD) and suppress EADs and their arrhythmogenic consequences. We used the dynamic-clamp technique to systematically explore how the biophysical properties of LTCCs could be modified to normalize APD and suppress EADs without impairing excitation–contraction coupling. Isolated rabbit ventricular myocytes were first exposed to H2O2 or moderate hypokalemia to induce EADs, after which their endogenous ICa,L was replaced by a virtual ICa,L with tunable parameters, in dynamic-clamp mode. We probed the sensitivity of EADs to changes in the (a) amplitude of the noninactivating pedestal current; (b) slope of voltage-dependent activation; (c) slope of voltage-dependent inactivation; (d) time constant of voltage-dependent activation; and (e) time constant of voltage-dependent inactivation. We found that reducing the amplitude of the noninactivating pedestal component of ICa,L effectively suppressed both H2O2- and hypokalemia-induced EADs and restored APD. These results, together with our previous work, demonstrate the potential of this hybrid experimental–computational approach to guide drug discovery or gene therapy strategies by identifying and targeting selective properties of LTCC.

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  • 9.
    Männikkö, Roope
    et al.
    Karolinska Institutet.
    Pandey, Shilpi
    Oregon Health and Science University.
    Larsson, H Peter
    Oregon Health and Science University.
    Elinder, Fredrik
    Karolinska Institutet.
    Hysteresis in the voltage dependence of HCN channels: Conversion between two modes affects pacemaker properties2005In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 125, p. 305-326Article in journal (Refereed)
    Abstract [en]

    Hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels are important for rhythmic activity in the brain and in the heart. In this study, using ionic and gating current measurements, we show that cloned spHCN channels undergo a hysteresis in their voltage dependence during normal gating. For example, both the gating charge versus voltage curve, Q(V), and the conductance versus voltage curve, G(V), are shifted by about +60 mV when measured from a hyperpolarized holding potential compared with a depolarized holding potential. In addition, the kinetics of the tail current and the activation current change in parallel to the voltage shifts of the Q(V) and G(V) curves. Mammalian HCN1 channels display similar effects in their ionic currents, suggesting that the mammalian HCN channels also undergo voltage hysteresis. We propose a model in which HCN channels transit between two modes. The voltage dependence in the two modes is shifted relative to each other, and the occupancy of the two modes depends on the previous activation of the channel. The shifts in the voltage dependence are fast (τ ≈ 100 ms) and are not accompanied by any apparent inactivation. In HCN1 channels, the shift in voltage dependence is slower in a 100 mM K extracellular solution compared with a 1 mM K solution. Based on these findings, we suggest that molecular conformations similar to slow (C-type) inactivation of K channels underlie voltage hysteresis in HCN channels. The voltage hysteresis results in HCN channels displaying different voltage dependences during different phases in the pacemaker cycle. Computer simulations suggest that voltage hysteresis in HCN channels decreases the risk of arrhythmia in pacemaker cells.

  • 10.
    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.

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  • 11.
    Pantazis, Antonios
    et al.
    Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, USA.
    Kohanteb, Azadeh P.
    Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, USA.
    Olcese, Riccardo
    Department of Anesthesiology, Division of Molecular Medicine, Brain Research Institute, and Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, USA.
    Relative Motion of Transmembrane Segments S0 and S4 during Voltage Sensor Activation in the Human BKCa Channel2010In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 136, no 6, p. 645-657Article in journal (Refereed)
    Abstract [en]

    Large-conductance voltage- and Ca2+-activated K+ (BKCa) channel α subunits possess a unique transmembrane helix referred to as S0 at their N terminus, which is absent in other members of the voltage-gated channel superfamily. Recently, S0 was found to pack close to transmembrane segments S3 and S4, which are important components of the BKCa voltage-sensing apparatus. To assess the role of S0 in voltage sensitivity, we optically tracked protein conformational rearrangements from its extracellular flank by site-specific labeling with an environment-sensitive fluorophore, tetramethylrhodamine maleimide (TMRM). The structural transitions resolved from the S0 region exhibited voltage dependence similar to that of charge-bearing transmembrane domains S2 and S4. The molecular determinant of the fluorescence changes was identified in W203 at the extracellular tip of S4: at hyperpolarized potential, W203 quenches the fluorescence of TMRM labeling positions at the N-terminal flank of S0. We provide evidence that upon depolarization, W203 (in S4) moves away from the extracellular region of S0, lifting its quenching effect on TMRM fluorescence. We suggest that S0 acts as a pivot component against which the voltage-sensitive S4 moves upon depolarization to facilitate channel activation.

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  • 12.
    Pantazis, Antonios
    et al.
    Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90075, USA.
    Olcese, Riccardo
    Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90075 // Brain Research Institute and Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90075, USA.
    Relative transmembrane segment rearrangements during BK channel activation resolved by structurally assigned fluorophore-quencher pairing2012In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 140, no 2, p. 207-218Article in journal (Refereed)
    Abstract [en]

    Voltage-activated proteins can sense, and respond to, changes in the electric field pervading the cell membrane by virtue of a transmembrane helix bundle, the voltage-sensing domain (VSD). Canonical VSDs consist of four transmembrane helices (S1-S4) of which S4 is considered a principal component because it possesses charged residues immersed in the electric field. Membrane depolarization compels the charges, and by extension S4, to rearrange with respect to the field. The VSD of large-conductance voltage- and Ca-activated K(+) (BK) channels exhibits two salient inconsistencies from the canonical VSD model: (1) the BK channel VSD possesses an additional nonconserved transmembrane helix (S0); and (2) it exhibits a "decentralized" distribution of voltage-sensing charges, in helices S2 and S3, in addition to S4. Considering these unique features, the voltage-dependent rearrangements of the BK VSD could differ significantly from the standard model of VSD operation. To understand the mode of operation of this unique VSD, we have optically tracked the relative motions of the BK VSD transmembrane helices during activation, by manipulating the quenching environment of site-directed fluorescent labels with native and introduced Trp residues. Having previously reported that S0 and S4 diverge during activation, in this work we demonstrate that S4 also diverges from S1 and S2, whereas S2, compelled by its voltage-sensing charged residues, moves closer to S1. This information contributes spatial constraints for understanding the BK channel voltage-sensing process, revealing the structural rearrangements in a non-canonical VSD.

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  • 13.
    Savalli, Nicoletta
    et al.
    Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA.
    Pantazis, Antonios
    Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA.
    Sigg, Daniel
    dPET, Spokane, USA.
    Weiss, James N.
    Department of Medicine (Cardiology), and Department of Physiology, and Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, USA.
    Neely, Alan
    Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA and Centro Interdisciplinario de Neurociencias de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile.
    Olcese, Riccardo
    Department of Anesthesiology, Division of Molecular Medicine, and Department of Physiology, and Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, USA.
    The α2δ-1 Subunit Remodels CaV1.2 Voltage Sensors, Allowing for Ca2+ Influx at Physiological Membrane Potentials2016In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 148, no 2, p. 147-159Article in journal (Refereed)
    Abstract [en]

    Excitation-evoked calcium influx across cellular membranes is strictly controlled by voltage-gated calcium channels (CaV), which possess four distinct voltage-sensing domains (VSDs) that direct the opening of a central pore. The energetic interactions between the VSDs and the pore are critical for tuning the channel’s voltage dependence. The accessory α2δ-1 subunit is known to facilitate CaV1.2 voltage-dependent activation, but the underlying mechanism is unknown. In this study, using voltage clamp fluorometry, we track the activation of the four individual VSDs in a human L-type CaV1.2 channel consisting of α1C and β3 subunits. We find that, without α2δ-1, the channel complex displays a right-shifted voltage dependence such that currents mainly develop at nonphysiological membrane potentials because of very weak VSD–pore interactions. The presence of α2δ-1 facilitates channel activation by increasing the voltage sensitivity (i.e., the effective charge) of VSDs I–III. Moreover, the α2δ-1 subunit also makes VSDs I–III more efficient at opening the channel by increasing the coupling energy between VSDs II and III and the pore, thus allowing Ca influx within the range of physiological membrane potentials.

  • 14.
    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.

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  • 15.
    Yusifov, Taleh
    et al.
    Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California, Los Angeles, USA.
    Javaherian, Anoosh D.
    Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California, Los Angeles, USA.
    Pantazis, Antonios
    Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California, Los Angeles, USA.
    Gandhi, Chris S.
    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, USA.
    Olcese, Olcese
    Division of Molecular Medicine, Department of Anesthesiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, USA.
    The RCK1 Domain of the Human BKCa Channel Transduces Ca2+ Binding into Structural Rearrangements2010In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 136, no 2, p. 189-202Article in journal (Refereed)
    Abstract [en]

    Large-conductance voltage- and Ca2+-activated K+ (BKCa) channels play a fundamental role in cellular function by integrating information from their voltage and Ca2+ sensors to control membrane potential and Ca2+ homeostasis. The molecular mechanism of Ca2+-dependent regulation of BKCa channels is unknown, but likely relies on the operation of two cytosolic domains, regulator of K+ conductance (RCK)1 and RCK2. Using solution-based investigations, we demonstrate that the purified BKCa RCK1 domain adopts an α/β fold, binds Ca2+, and assembles into an octameric superstructure similar to prokaryotic RCK domains. Results from steady-state and time-resolved spectroscopy reveal Ca2+-induced conformational changes in physiologically relevant [Ca2+]. The neutralization of residues known to be involved in high-affinity Ca2+ sensing (D362 and D367) prevented Ca2+-induced structural transitions in RCK1 but did not abolish Ca2+ binding. We provide evidence that the RCK1 domain is a high-affinity Ca2+ sensor that transduces Ca2+ binding into structural rearrangements, likely representing elementary steps in the Ca2+-dependent activation of human BKCa channels.

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