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Clofilium Inhibits Slick and Slack Potassium Channels

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Clofilium Inhibits Slick and Slack Potassium Channels Biologics: Targets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article OriginaL reSearCh Clofilium inhibits Slick and Slack potassium channels Maria de los Angeles Tejada1 Abstract: Slick and Slack high-conductance potassium channels have been recently discovered, Kathleen Stolpe1 and are found in the central nervous system and in the heart. Both channels are activated by Na+ Anne-Kristine Meinild2 and Cl-, and Slick channels are also inhibited by adenosine triphospate (ATP). An important Dan A Klaerke1 role of setting the resting membrane potential and controlling the basal excitability of neurons has been suggested for these channels. In addition, no specific blockers for these channels are 1Department of Physiology and Biochemistry, Faculty of Life Sciences, known up to the present. With the purpose of studying the pharmacological characteristics of 2Institute of Biology, Faculty of Slick and Slack channels, the effects of exposure to the antiarrhythmic compound clofilium were Science, University of Copenhagen, evaluated. Clofilium was able to modulate the activity of Slick and Slack channels effectively, Copenhagen, Denmark with a stronger effect on Slack than Slick channels. In order to evaluate the pharmacological For personal use only. behavior of Slick and Slack channels further, 38 commonly used potassium channel blockers were tested. Screening of these compounds did not reveal any modulators of Slick and Slack channels, except for clofilium. The present study provides a first approach towards elucidating the pharmacological characteristics of Slick and Slack channels and could be the basis for future studies aimed at developing potent and specific blockers and activators for these channels. Keywords: Slo2.1, Slo2.2, clofilium, potassium channel blockers Introduction Potassium channels are essential for numerous physiological processes, and are involved in a number of disorders, including cardiac arrhythmias, neuronal diseases (episodic ataxia, neurodegeneration), and renal disease (Bartter’s syndrome).1 A num- Biologics: Targets and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 17-Nov-2018 ber of small molecules with the ability either to block or to open specific types of potassium channels have been identified, and may be potential drugs for treatment of a number of diseases.2 In addition, a number of peptides derived from venom of the scorpion (see below), snakes (dendrotoxin), spiders (hanatoxin, SGTx), snails (conotoxins), and the honey bee (apamin, tertiapin) have been identified as being highly selective blockers of a number of ion channels. Scorpion toxins with the ability to block potassium channels include: charybdotoxin and iberiotoxin, affecting Slo1 channels; margatoxin and agitoxin, modulating Kv1.3 channels; and scyllatoxin and tamapin, affecting Slo1 channels.3 In general, peptide toxins (about 20–60 amino Correspondence: Dan A Klaerke Department of Physiology and acids in length) have high selectivity and bind to relatively large external motifs of Biochemistry, Faculty of Life potassium channels in contrast with small molecules (molecular weight 200–500), Sciences, University of Copenhagen, which normally occlude the inner pore.2 However, due to differential expression of Groennegaardsvej 7, 1870 Frederiksberg C, Denmark the numerous potassium channels in distinct cell types and even in specific regions Tel +45 3533 2511 inside cells, development of modulators constitutes a challenge for both academia Fax +45 3533 2525 Email [email protected] and pharmaceutical companies. submit your manuscript | www.dovepress.com Biologics: Targets and Therapy 2012:6 465–470 465 Dovepress © 2012 Tejada et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article http://dx.doi.org/10.2147/BTT.S33827 which permits unrestricted noncommercial use, provided the original work is properly cited. Powered by TCPDF (www.tcpdf.org) 1 / 1 Tejada et al Dovepress Slick (Slo2.1) and Slack (Slo2.2) are potassium channels Ipswich, MA). mRNA was obtained by in vitro transcription encoded by the Slo gene family of high-conductance using a mMessage mMachine kit (Ambion, Carlsbad, CA) potassium channels. In contrast with Slo1 channels, Slick according to the manufacturer’s instructions. RNA was and Slack channels are not activated by Ca2+, but by Na+ extracted using a MEGAclear kit (Ambion). Next, 50 nL and Cl-.4 Furthermore, Slick channels are also inhibited containing approximately 10 ng of Slick or Slack mRNA by adenosine triphosphate (ATP).5 Both channels have was injected into the oocytes, which were cultured in Kulori been found to be widely distributed in the central nervous medium (90 nM NaCl, 1 mM KCl, 1 mM MgCl2, 1 mM 6,7 system and apparently in cardiac myocytes. Given these CaCl2, 5 mM HEPES, pH 7.4) at 19°C for 4–5 days prior to characteristics, together with their low voltage sensitivity, our experiments. Slick and Slack channels most likely play an important role in tuning of the resting potential and basal excitability Electrophysiological measurements and in neurons. The importance of channels setting the resting screening for Slick and Slack blockers membrane potential seems to increase during episodes of Expression of Slick and Slack channels was verified by hypoxia, when the intracellular Na+ concentration rises due measuring current flow through the channels using a two- + + to failure of Na /K -ATPase. The protective role these channels electrode voltage clamp amplifier (Warner Instruments, may have during hypoxia is supported by the fact that Novarto, CA). Oocytes were impaled with electrodes mutations of the Slack ortholog in Caenorhabditis elegans pulled from a micropipette puller (P-97, Sutter Instruments, result in animals that are hypersensitive to hypoxia.4 In Novato, CA) and filled with 1 M KCl (resistance about addition, it has been shown that Slack channels are activated 0.5–1.5 mΩ). Currents were measured either by a stepwise by estradiol, a fact that could account for estradiol-dependent protocol, ie, 500 msec depolarizations from -100 to +80 mV neuroprotection in ischemia.8 Together, these observations (holding potential -80 mV for 4 seconds) or by a pulse raise the possibility that Slick and Slack channels could protocol, ie, 500 msec depolarizations from -80 to +80 mV be used therapeutically as drug targets. Additionally, (holding potential -80 mV for 3 seconds). For personal use only. identification of pharmacological agents targeting these In order to screen for compounds able to modulate the channels will result in important tools for the study of the activity of Slick and Slack channels, 38 potassium channel physiological significance of Slick and Slack channels in blockers (Alomone, Jerusalem, Israel) were dissolved in bath different tissues and organs. However, at present, knowledge solution (Kulori) immediately before the experiments were concerning the pharmacology of Slick and Slack channels conducted. Currents were measured before and after treatment. is limited, and no specific pharmacological agents targeting The compounds tested were E-4031 (10 µM), recombinant Slick and Slack potassium channels have been identified. margatoxin (300 nM), mast cell degranulating peptide For Slack channels, antiarrhythmic drugs like quinidine and (10 µM), δ-dendrotoxin (1 µM), dendrotoxin K (1 µM), bepridil have been found to act as inhibitors, and bithionol, an dendrotoxin-I (1 µM), recombinant BeKm-1 (500 nM), antiparasitic compound, is an activator of Slack channels as recombinant Aa1 (1.3 µM), BDS-I (1.06 µM), BDS-II Biologics: Targets and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 17-Nov-2018 well as Slo1 channels.9 In addition, it was recently found that (1.05 µM), recombinant argitoxin-1 (500 nM), recombinant niflumic acid and loxapine, an antipsychotic drug, activate argitoxin-2 (500 nM), recombinant argitoxin-3 (500 nM), Slick and Slack channels, respectively.10,11 The present work sApamin (10 µM), γ-dendrotoxin (1 µM), α-dendrotoxin constitutes a first approach towards analyzing the effect of (2 µM), recombinant charybdotoxin (500 nM), recombinant clofilium, a potent antiarrhythmic compound, on Slick and tityustoxin Kα (300 nM), β-dendrotoxin (2 µM), recombinant Slack channels. A number of other well known ion channel ergotoxin (500 nM), recombinant hongotoxin-1 (955 nM), modulators were also screened for a potential effect. recombinant OsK (500 nM), recombinant kaliotoxin-1 (500 nM), Lq2 (300 nM), recombinant maurotoxin Materials and methods (600 nM), recombinant noxiustoxin (1 µM), phrixotoxin-2 heterologous expression of Slick and (1 µM), recombinant scyllatoxin (500 nM), recombinant Slack channels in Xenopus laevis oocytes stichodactyla toxin (500 nM), recombinant stromatoxin Preparation of Xenopus laevis oocytes was performed as (1.32 µM), recombinant tertiapin Q (1 µM), recombinant previously described by Grunnet et al.12 hSlick and rSlack tapamin (1 µM), recombinant tertiapin (1 µM), recombinant cDNA cloned into a pOX vector (kindly provided by Heteropodatoxin-2 (1 µM), recombinant iberiotoxin (500 nM), L Salkoff) was linearized with NotI (New England Biolabs, paxiline (5 µM), penitrem A (5 µM), and verruculogen (5 µM). 466 submit your manuscript | www.dovepress.com Biologics: Targets and Therapy 2012:6 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress Clofilium inhibits Slick and Slack +K channels Paxiline, penitrem A, and verruculogen were dissolved in A
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