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Kv1.5 Open Channel Block by the Antiarrhythmic Drug Disopyramide: Molecular Determinants of Block

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Kv1.5 Open Channel Block by the Antiarrhythmic Drug Disopyramide: Molecular Determinants of Block J Pharmacol Sci 108, 49 – 55 (2008)1 Journal of Pharmacological Sciences ©2008 The Japanese Pharmacological Society Full Paper Kv1.5 Open Channel Block by the Antiarrhythmic Drug Disopyramide: Molecular Determinants of Block Iván A. Aréchiga1, Gabriel F. Barrio-Echavarria1, Aldo A. Rodríguez-Menchaca1, Eloy G. Moreno-Galindo1, Niels Decher2, Martin Tristani-Firouzi3, José A. Sánchez-Chapula1, and Ricardo A. Navarro-Polanco1,* 1Unidad de Investigación “Carlos Méndez” del Centro de Investigaciones Biomédicas de la Universidad de Colima, Colima, México 2Institute of Physiology, Philipps-University, Marburg, Germany 3Department of Pediatric of Cardiology, University of Utah, Salt Lake City, UT 84132, USA Received March 26, 2008; Accepted July 9, 2008 Abstract. Kv1.5 is considered to be a potential molecular target for treatment of atrial fibrilla- tion or flutter. Disopyramide is widely used in the treatment of atrial flutter and/or atrial fibril- lation. The present study was undertaken to characterize the effects of disopyramide on currents mediated by Kv1.5 channels and to determine the putative binding site involved in the inhibitory effects of disopyramide. Experiments were carried out on wild-type and site directed mutated hKv1.5 channels expressed on HEK 293 cells using the patch-clamp technique. Disopyramide acting from the cytoplasmic side of the membrane produced blocking effects on Kv1.5 that exhibited several features typical of an open channel blocker. Ala-scanning mutagenesis of the Kv1.5 pore domain combined with macroscopic current analysis suggested that disopyramide interacted only with the Val512 residue that faces to the central cavity of the channel. Mutation of this key residue to Ala caused marked change in the IC50 of disopyramide (22-fold). The single interaction between disopyramide and Val512 in the PVP region is able to change the mechanism of channel closure, reproducing the “foot-in-the-door” phenomenon. Keywords: potassium channel, ultra rapid delayed rectifier, Kv1.5, antiarrhythmic, disopyramide Introduction selective block of IKur produced a stronger prolongation of action potential in patients with AF compared to The most common sustained cardiac arrhythmias in patients with sinus rhythm (SR) (7). Class 1A (sodium clinical practice are atrial flutter and/or atrial fibrillation channel blocker) and Class III (potassium channel (AF). The goals of antiarrhythmic therapy are to restore blocker) antiarrhythmic agents reduce the rate of sinus rhythm, to facilitate electrical cardioversion, to recurrence of AF, but are of limited use because of a prevent AF recurrence, and to control ventricular rate variety of potentially adverse effects including ventri- (1). Kv1.5 channels are highly expressed in human atria cular proarrhythmia (1, 8). Disopyramide is a widely (but not ventricle) and conduct the ultrarapid delayed used Class Ia antiarrhythmic agent that is employed in rectifier current (IKur) that contributes to action potential the treatment of AF (9). Disopyramide is a nonspecific repolarization of human atrial myocytes (2 – 4). Thus, channel blocker (9), which blocks cardiac Na+ channels Kv1.5 is a potential target for treatment of atrial to slow conduction (10 – 12). In addition, disopyramide fibrillation or atrial flutter. In different animal models, it blocks repolarizing cardiac K+ channels to prolong was shown that AF could be terminated effectively by action potential duration (13 – 16). selective blockers of IKur (5, 6). Also in human atria, Ongoing studies of potassium channel inhibition by synthetic compounds and toxins provide important *Corresponding author. [email protected] contributions to our understanding of these membrane Published online in J-STAGE proteins. Classical ion channel blockers, such as local doi: 10.1254/jphs.08084FP anesthetics and antiarrhythmics are used both clinically 49 50 IA Aréchiga et al and as molecular probes for studying ion channel external solution contained 130 mM NaCl, 4 mM KCl, function. Drug-binding from the internal side takes place 1 mM MgCl2, 10 mM Hepes, 1.8 mM CaCl2, and 10 mM inside a large water-filled inner cavity and requires a glucose (pH was adjusted to 7.35 with NaOH). Patch change in protein conformation to allow entrance of pipettes were filled with 5 mM K4BAPTA, 100 mM the blocker. Disopyramide blocks various potassium KCl, 10 mM Hepes, 5 mM MgCl2, 5 mM ATP-K2 (pH currents like the transient outward current Ito (15) and adjusted to 7.2 with KOH). The holding potential was the delayed rectifying outward current IKr (13, 14, 16). −80 mV. The interpulse interval for all the protocols Disopyramide is suggested to bind only to open channels was 15 s to allow channels to fully recover from and either has extremely low affinity or is unable to bind inactivation between pulses. To obtain current–voltage to closed channels (15 – 17). To our knowledge, the relationships and activation curves, 200-ms voltage effect of disopyramide on IKur or Kv1.5 has not been steps were applied in 10-mV increments to potentials studied. that varied from −60 to +60 mV, followed by repolariza- Identification of the drug binding site and understand- tion to −40 mV. The ratio of current in the presence of ing of the channel blocker binding mode may help to drug divided by current before drug (Idrug/Icontrol) was promote the development of in silico prediction methods determined to calculate the fraction of unblocked current for identifying potential Kv1.5 channel blockers. as a function of time. The time constant of current block Quinidine has been reported to block Kv1.5 by interact- ( b) was determined by fitting Idrug/Icontrol to a mono- ing primarily with residues in the S6 domain (18). exponential function. The voltage dependence of Kv1.5 Recently, Decher et al. (19, 20) used an alanine- channel activation (with or without disopyramide) was scanning mutagenesis approach to define residues in the determined from tail current analyses at −40 mV. The pore of Kv1.5 that interact with S0100176 and resulting relationship between test voltage (Vt) and AVE0118, two novel antiarrhythmic agents. Mutation of normalized tail current (In) was fit to a Boltzmann residues located at the base of the pore helix and the S6 equation to obtain the halfpoint (V1/2) and slope factor domain had the greatest effect on reducing the potency (k): In = 1 / {1 + exp[(V1/2 − Vt) /k]}. Other voltage pulse of these Kv1.5 channel blockers. In the present study, protocols are described under Results and Figure we investigated the effects of disopyramide on currents legends. mediated by Kv1.5 channels expressed in a mammalian cell line, with the following aims: i) to characterize Data analyses the nature of the inhibitory action on Kv1.5 by dis- pCLAMP 8 (Molecular Devices, Sunnyvale, CA, opyramide; and ii) to define the molecular basis of USA) and Origin 7 (OriginLab Corp, Northampton, disopyramide block of Kv1.5 channels. MA, USA) software were used for data acquisition and analysis on a personal computer. All the fitting Materials and Methods procedures were based on the simplex algorithm. The concentration required for 50% block of current (IC50) Molecular biology was determined from Hill plots using 3 – 5 concentra- Wild-type (WT) and mutant Kv1.5 (KCNA5) cDNA tions of drug for each mutant (5 – 12 cells/point). were generously donated by Dr. Michael Sanguinetti Results are each reported as the mean ± S.E.M. from the University of Utah and Dr. Niels Decher (n = number of cells). Statistical differences between (Aventis Pharma GmbH, Frankfurt, Germany). WT and mutant channels were evaluated by ANOVA and Bonferroni’s test. Significance was assumed for Transfection of HEK 293 cells P<0.05. HEK 293 cells were maintained in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with Drugs 10% horse serum at 37°C in an air 5% CO2 incubator. Disopyramide (Sigma-Aldrich, Mexico City, Mexico) Cells were transiently transfected using Lipofectamine was prepared daily, dissolved at the desired concentra- 2000 (Invitrogen, Mexico City, Mexico) according to tions in the external or internal solution. the supplier’s directions. Soluble GFP was coexpressed with the channel subunits to identify cells for voltage Results clamp experiments. Voltage-dependent block of Kv1.5 channels by dis- Voltage clamp protocols opyramide Currents were recorded at room temperature (23°C The effect of disopyramide on Kv1.5 was character- –25°C) with standard patch clamp techniques. The ized by recording currents in a voltage range from −60 to Disopyramide Blocking of hKv1.5 51 Fig. 1. Disopyramide effect on WT Kv1.5 channel. Whole cell currents recorded from HEK-293 cells before (A) and after (B) extracellular applica- tion of disopyramide (100 µM). Cur- rents were elicited by 200-ms depolar- izations from a holding potential of −80 mV to test potentials between −60 to +60 mV in 10-mV steps. Test potential was followed by a repolar- izing step to −40 mV to record deactivation currents. C: I-V relation- ships for currents measured at the end of the 200-ms test pulse before and after application of 100 and 300 µM disopyramide (n = 5). D: Fractional block of WT Kv1.5 currents, measured at the end of 200-ms pulses and plotted as a function of test potential. E: Acti- vation curves generated with tail currents in the absence or presence of drug. Tail currents were normalized to the peak value under control conditions for each cell. The smooth curves were obtained by fitting average data to a Boltzmann function. F: Tail currents recorded in control conditions and in the presence of disopyramide. +60 mV, applied in 10-mV increments from a holding disopyramide, Fig. 1E). Figure 1F shows the super- potential of −80 mV. In the absence of drug, Kv1.5 position of the tail currents obtained at −40 mV after a slowly inactivates during the test pulse (Fig.
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