Original article About half of the late sodium current in cardiac myocytes from dog ventricle is due to non-cardiac-type Na + channels Michael Biet 1 , Hector Barajas-Martínez 1, 2 , Anh-Tuan Ton, Jean-Francois Delabre, Nathalie Morin, Robert Dumaine ⁎ Département de Physiologie et Biophysique, Faculté of Medicine, Université of Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4 abstract article info Article history: Received 20 April 2012 Received in revised form 31 May 2012 Accepted 20 June 2012 Available online 30 June 2012 Keywords: Ion channels Na-channel Myocytes Arrhythmias Voltage gated sodium channels (Na V s) are essential to propagate neuronal and cardiac electrical impulses. While the cardiac Na + current (I Na ) is often all attributed to the cardiac isoform, Na V 1.5, some evidence suggests that other Na + channel isoforms are also expressed in the heart ventricle. One way to distinguish Na + channels is by their sensitivity to tetrodotoxin (TTX); various “non-cardiac-type” Na + channels are relatively sensitive to TTX (denoted tNa V channels) compared to Na V 1.5 channels. tNa V channels have been detected in hearts with various pathological conditions such as hypertrophy, infarction and ischemia, where they might enhance the late Na + current (I NaL ) thereby prolonging the action potential under such conditions (resulting in a prolonged QT interval on the EKG). The principal aim of this article is to evaluate the extent to which non-cardiac isotypes contribute to I NaL under normal physiological conditions. I NaL was measured in acutely dissociated dog cardiomyocytes using the patch-clamp technique. Our results indicate that 44% on average of the late I Na current is due to non-cardiac Na V s. Previous studies indicated that the overexpression of non-cardiac Na V channels is responsible for the prolonged duration of the cardiac action potential (and, thereby, a prolonged QT interval) under pathophysiological conditions associated with vari- ous heart diseases. Our finding indicates that non-cardiac Na V channels are strong contributors to I NaL under physiological conditions thereby suggesting that these channels are also major determinants of the duration of the cardiac action potential even in healthy hearts. Interestingly, these results may explain the observations of cardiac arrhythmias associated with prolonged QT intervals in people with inherited neuro- nal and musculoskeletal diseases involving mutations that enhance the current from non-cardiac-type Na V s, a connection which apparently was never made before. © 2012 Elsevier Ltd. All rights reserved. 1. Introduction The main determinant of the rapid upstroke of the cardiac action potential is due to sodium current (I Na ) through the α subunit of the voltage-dependent channel denoted Na V 1.5, also referred to as the “cardiac Na channel”. Normal Na V 1.5 channels rapidly inactivate following the peak of the action potential, remaining almost completely inactivated for the remainder of the action potential. There is significant evidence that human [1], dog [2], mouse [3–5] and rat [6,7] cardiac tissue includes Na channels other than the “car- diac Na channel” that may contribute to propagation of the action po- tential [8]. In 1983, Renaud et al. [7] found at least two types of channels in ventricular muscle from adult rat hearts, distinguished by their sensitivity to tetrodotoxin (TTX). Most of the TTX binding (>97%) occurred to channels with relative low affinity for TTX (K D = 170 nM) and the remainder bound TTX with high affinity (K D =1.5 nM). In confirmation of the idea that there are multiple types of Na channels present under physiological conditions, later work identified the presence of several other Na channel isoforms in addition to the “cardiac Na channel” including the neuronal-type isoforms Na V 1.1 and Na V 1.2 and the skeletal isoform Na V 1.4 [2–7]. The high-capacity and low-affinity binding of TTX is associated with the cardiac Na channel (Na V 1.5) and the low-capacity, high-affinity component was attributed to the combination of neural Na channels (Na V 1.1 and Na V 1.2) and to the skeletal Na channel isoform (Na V 1.4). Because of the relatively low expression levels of the “non-cardiac Na channels” compared to that of the “cardiac Na chan- nel” and the related observation that the “non-cardiac Na channels” contribute only 5–10% of the total Na current at the peak of I Na in a cardiac action potential [2,3,9], their role in cardiac electrophysiology has been largely overlooked and is still not clearly established. One possibility proposed by Maier et al. [8], is that neuronal Na channels are involved in intracellular propagation of the action potential and Journal of Molecular and Cellular Cardiology 53 (2012) 593–598 ⁎ Corresponding author at: Dept. of Physiology and Biophysics, Faculty of Medicine and Health Sciences, University of Sherbrooke, 3001 12th ave, Sherbrooke QC, Canada. Tel.: +1 819 820 6868xt12555; fax: +1 819 820 6887. E-mail address: robert.dumaine@usherbrooke.ca (R. Dumaine). 1 Contributed equally to the realization of this work. 2 New address is Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica NY, 12557. 0022-2828/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.yjmcc.2012.06.012 Contents lists available at SciVerse ScienceDirect Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc