Distribution and function of sodium channel subtypes in human atrial myocardium

Abstract

<p>Voltage-gated sodium channels composed of a pore-forming alpha subunit and auxiliary beta subunits are responsible for the upstroke of the action potential in cardiac muscle. However, their localization and expression patterns in human myocardium have not yet been clearly defined. We used immunohistochemical methods to define the level of expression and the subcellular localization of sodium channel alpha and beta subunits in human atrial myocytes. Na(v)1.2 channels are located in highest density at intercalated disks where beta 1 and beta 3 subunits are also expressed. Na(v)1.4 and the predominant Na(v)1.5 channels are located in a striated pattern on the cell surface at the z-lines together with beta 2 subunits. Na(v)1.1, Na(v)1.3, and Na(v)1.6 channels are located in scattered puncta on the cell surface in a pattern similar to beta 3 and beta 4 subunits. Na(v)1.5 comprised approximately 88% of the total sodium channel staining, as assessed by quantitative immunohistochemistry. Functional studies using whole cell patch-clamp recording and measurements of contractility in human atrial cells and tissue showed that TTX-sensitive (non-Na(v)1.5) alpha subunit isoforms account for up to 27% of total sodium current in human atrium and are required for maximal contractility. Overall, our results show that multiple sodium channel alpha and beta subunits are differentially localized in subcellular compartments in human atrial myocytes, suggesting that they play distinct roles in initiation and conduction of the action potential and in excitation-contraction coupling. TTX-sensitive sodium channel isoforms, even though expressed at low levels relative to TTX-sensitive Na(v)1.5, contribute substantially to total cardiac sodium current and are required for normal contractility. This article is part of a Special Issue entitled "Na+ Regulation in Cardiac Myocytes". (C) 2013 Elsevier Ltd. All rights reserved.</p>