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Flecainide Increases Kir2.1 Currents by Interacting with Cysteine 311, Decreasing the Polyamine- Induced Rectification

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Flecainide Increases Kir2.1 Currents by Interacting with Cysteine 311, Decreasing the Polyamine- Induced Rectification Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine- induced rectification Ricardo Caballeroa,1, Pablo Dolz-Gaitóna,1, Ricardo Gómeza,2, Irene Amorósa, Adriana Baranaa, Marta González de la Fuentea, Lourdes Osunaa, Juan Duarteb, Angelica López–Izquierdoc, Ignacio Moraledad, Enrique Gálvezd, José Antonio Sánchez–Chapulac, Juan Tamargoa, and Eva Delpóna aDepartment of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain; bDepartment of Pharmacology, School of Pharmacy, Universidad de Granada, 18071 Granada, Spain; cUnidad de Investigación Carlos Méndez, Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, 28045 Colima, Mexico; and dDepartment of Organic Chemistry, School of Pharmacy, Universidad de Alcalá, 28871 Alcalá de Henares, Spain Edited by Lily Yeh Jan, University of California, San Francisco, CA, and approved July 23, 2010 (received for review March 25, 2010) Both increase and decrease of cardiac inward rectifier current (IK1)are in patients with coronary artery disease and/or heart failure. Con- associated with severe cardiac arrhythmias. Flecainide, a widely used versely, in a limited number of patients, it has been reported that antiarrhythmic drug, exhibits ventricular proarrhythmic effects while flecainide is effective in controlling ventricular tachycardia associ- effectively controlling ventricular arrhythmias associated with muta- ated with the autosomal dominant trait Andersen syndrome (AS), tions in the gene encoding Kir2.1 channels that decrease IK1 (Andersen which is produced by loss-of-function mutations in KCNJ2 (9, 10). syndrome). Here we characterize the electrophysiological and molec- We hypothesized that a putative differential flecainide effect on ular basis of the flecainide-induced increase of the current generated atrial and ventricular IK1 (blockade of atrial and increase of ven- by Kir2.1 channels (IKir2.1)andIK1 recorded in ventricular myocytes. tricular IK1) can account for the selective prolongation of the atrial Flecainide increases outward IKir2.1 generated by homotetrameric APD, the ventricular proarrhythmic effects, and the antiarrhyth- Kir2.1 channels by decreasing their affinity for intracellular poly- mic effects in the AS patients. Therefore, we have analyzed the amines, which reduces the inward rectification of the current. Flecai- flecainide effects on the currents generated by human WT and nide interacts with the HI loop of the cytoplasmic domain of the mutated Kir2.1, Kir2.2, and Kir2.3 channels (IKir2.x) and compared PHARMACOLOGY fl channel, Cys311 being critical for the effect. This explains why flecai- its effects on atrial and ventricular IK1. Acutely applied ecainide selectively increased ventricular I and I , an effect deter- nide does not increase IKir2.2 and IKir2.3, because Kir2.2 and Kir2.3 chan- K1 Kir2.1 nels do not exhibit a Cys residue at the equivalent position. We mined by the presence of Cys311 at the cytoplasmic domain of fl further show that incubation with flecainide increases expression of Kir2.1 channels. Binding of ecainide reduced the Kir2.1 poly- fi functional Kir2.1 channels in the membrane, an effect also determined amine blockade, thus reducing the inward recti cation. Addition- fl by Cys311. Indeed, flecainide pharmacologically rescues R67W, but ally, incubation with ecainide increased functional ion channel fi not R218W, channel mutations found in Andersen syndrome patients. density, an effect also determined by Cys311. Overall, the ndings Moreover, our findings provide noteworthy clues about the structural show that Kir2.1 channels can be affected through the pharma- determinants of the C terminus cytoplasmic domain of Kir2.1 channels cological modulation of their polyamine blockade by a therapeu- involved in the control of gating and rectification. tically used drug. Results cardiac I | Kir2.2 channel | Kir2.3 channel | Andersen mutations | inward K1 A rectifying channel Flecainide Increases Kir2.1 Currents. Figure 1 shows IKir2.1 traces recorded in transiently transfected Chinese hamster ovary (CHO) − + cells by applying 250-ms pulses from 60 mV to potentials ranging he cardiac inwardly rectifying K current (IK1) stabilizes resting − μ fl + 120 and +20 mV in the absence and presence of 1 M ecainide. Tmembrane potential (RMP) close to the reversal potential of K ± Flecainide increased IKir2.1 at voltages negative (16.5 2.4% at (EK) and shapes the final repolarization phase of the action po- −120 mV) and, more importantly, at voltages positive to EK (45.8 ± tential (AP) (1). Three inwardly rectifying channels (Kir2.1, Kir2.2, 9.8% at −50 mV, n =8,P < 0.05; Fig. 1 A and B). These effects and Kir2.3) contribute to IK1 in the human heart assembled as were completely reversible upon washout (Fig. S1). The concen- homo- and/or heterotetramers (2). Experimental data suggest that tration that produces the half-maximum effect (EC50) and the in humans, Kir2.1 is the major isoform underlying ventricular IK1, maximum effect (E ) were calculated by fitting the Hill equation whereas its relative contribution to atrial I seems to be lower (3). max K1 to the increase produced by different flecainide concentrations and The strong inward rectification of Kir2.x channels, i.e., the prefer- averaged 0.8 ± 0.01 μM(n =1.6± 0.4) and 22 ± 1.9% at −120 mV, ential conduction of inward compared with outward current, de- H respectively (Fig. S1). At −50 mV, the EC and the E averaged pends on the binding of intracellular Mg2+ and polyamines to the 50 max 0.4 ± 0.01 μM(nH =2.2± 0.2) and 53.9 ± 3.6%, respectively (Fig. cytoplasmic pore and to the inner vestibule of the channel (4). fl Gain- and loss-of-function mutations in the gene that encodes S1). Therefore, ecainide preferentially increased the outward IKir2.1 generated at physiological potentials. Kir2.1 (KCNJ2) have been reported, and both the IK1 increase and decrease produced by these mutations are associated with severe ventricular arrhythmias (1). Furthermore, experimental data showed Author contributions: R.C., J.T., and E.D. designed research; R.C., P.D.-G., R.G., I.A., A.B., that as the amplitude of the outward component of the IK1 increases, M.G.d.l.F., L.O., J.D., A.L.-I., I.M., E.G., and J.A.S.-C. performed research; R.C., P.D.-G., R.G., the frequency of the fast and stable reentry of spiral waves (rotors) I.A., A.B., M.G.d.l.F., and J.A.S.-C. analyzed data; and J.T. and E.D. wrote the paper. increases. Indeed, the importance of IK1 in the establishment of fl rotors and ventricular fibrillation dynamics has been shown (5). The authors declare no con ict of interest. Flecainide is a class I antiarrhythmic drug that, besides its Na+ This article is a PNAS Direct Submission. channel-blocking properties, exhibits class III antiarrhythmic effects Freely available online through the PNAS open access option. [i.e., prolongs AP duration (APD) and refractoriness] at the atrial 1R.C. and P.D.-G. contributed equally to this work. but not at the ventricular level (6, 7). Flecainide is widely used to 2To whom correspondence should be addressed. E-mail: [email protected]. fi suppress recent onset atrial brillation (AF) (8), though it is asso- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. ciated with an increased risk of ventricular proarrhythmia, especially 1073/pnas.1004021107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1004021107 PNAS Early Edition | 1of6 Downloaded by guest on September 28, 2021 +20 mV Membrane potential (mV) A -60 mV A B 0 mV 2 50 ms -120 mV uH m Fp/Ap2 Control -110 -90 -70 -50 -30 na a An1 Fleca 1 μM 20 mV -2 irt a Il K -4 1 ( p -40 mV A Control / -6 Fp Control -40 mV Flecainide 1 μM -120 mV Fleca 1 μM ) -8 Membrane potential (mV) B 5050 msms Control C Fp D Membrane potential (mV) * * * / A p G I 10 01 K -140 -60 20 u i r -0.5 2 -1 1. * -aeni * 0.3 ( * p * i An ** 0.2 -1.5 -130 -110 -90 -70 -50 -30 g ) 0.1 50 ms a μ t -2 Flecainide 1 M r ** i -80 -60 -40 -20 -10 -0.1 -2.5 la I -0.2 K ** 1 ( Control Fleca 1 μM Control -20 Ap μ Fp/ 70 Fleca 1 M ) d e -30 C cu 60 )%(egnahc dn 50 Vm= -50 mV i -ed 40 5050 ms ms Control Fp/ i 30 E F Membrane potential (mV) G n ia A u 20 p celF i 0 10 * n 10 * 2 * * e 0 * a - -10 p i .1 .2 .3 .2 .3 -130 -110 -90 -70 -50 -30 g r2 r2 r2 2 2 v i i i 1+ 1+ K K K . 50 ms -10 ir2 ir2 Flecainide 1 μM ne K K t r i -20 c u * l Fig. 1. Flecainide increases IKir2.1.(A)IKir2.1 traces recorded by applying the ra fl – * -30 I protocol shown in the absence and presence of ecainide. (B)IVcurvesfor Control 1K ( currents measured at the end of the pulses. (Inset) Data at potentials positive * -40 p A μ / to EK in an expanded scale. *P < 0.05 and **P < 0.01 vs. control. (C)Flecainide- Fleca 1 M * Fp -50 induced change on the current recorded at −50 mV in cells expressing homo- ) tetramers of Kir2.1, Kir2.2, or Kir2.3 channels or heterotetramers of Kir2.1 + Membrane potential (mV) Kir2.2 and Kir2.1 + Kir2.3. *P < 0.05 vs. Kir2.1. Each point/bar represents the G G H u ± fi 10 i Atria Ventricles mean SEM of ve or more experiments. * n e -130 -110 -90 -70 -30 a r e 1 2 1 2 - .
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