Ions carry transsarcolemmal currents that contribute importantly to electrical activity in cardiac myocytes, where the influx of Naþ ions plays an especially unique and critical role. The sodium current (INa), is not only responsible for initial cardiac action-potential depolarization, but also the influx of Naþ ions into the cytoplasm, which helps to generate the prolonged depolarization characteristics of the action-potential plateau. The magnitude and kinetics of INa are controlled in a complex manner by both membrane potential and intracellular metabolites. Such Naþ-preferring voltage-dependent channels are present in a wide variety of electrically excitable membranes of cardiac and skeletal muscles, nerves, and other tissues. The voltage-gated cardiac Naþ channel has been extensively studied by electrophysiological approaches, so that we have accumulated a large amount of information on the biophysical properties of this channel during the last thirty years. Mutations of the human voltage-gated cardiac Naþ-channel gene that cause several forms of inherited diseases have been identified. The underlying defects in the Naþ-channel-related disease state include aberrant regulation of channel function, resulting in lethal ventricular tachyarrhythmias and so on. This review article will cover certain aspects involved in the structure and regulation of the cardiac sarcolemmal voltage-gated Naþ channel in physiological and particularly in pathophysiological conditions. In 1984, in order to clarify the primary structure of the Naþ channel, Numa and colleagues used partial sequences from purified eel electroplax Naþ channels to clone the cDNA for the eel Naþ-channel -subunit. Using this probe, they cloned three Naþ-channel -subunits from the rat brain. The rat heart isoform (rHt) and its human counterpart (hHt) were cloned thereafter. The -subunit of the cardiac Naþ channel has been reported to be 240 kDa. A schematic diagram of the proposed membrane topology for the -subunit of the cardiac Naþ channel is shown in Figure 1. The -subunit consists of four large homologous membrane domains (I-IV). Each domain is comprised of six putative -helices (S1-S6). The channel’s pore is assumed to extend between segments S5 and S6. Studies with molecular-biological techniques, particularly site-directed mutagenesis of Naþ-channel proteins and functional expression mutant channels have pinpointed regions that are involved in different functions of the channel. Between each of the six transmembrane segments and particularly between each of the four larger domains are extensive regions that fold out from the membrane. Highly charged S4 segments of each domain transduce the transmembrane electrical voltage by moving across the transmembrane electrical field. This movement causes conformational changes that result in an opening or gating of the Naþ-conducting pathway. The opening of the channel, also called ‘‘activation’’, allows Naþ ions to passively enter the cell down the Naþconcentration gradient to depolarize the membrane. The Nand C-termini, as well as the linkers between segments alternate between intracellular and extracellular surfaces. The ball and chain mechanism was first proposed for the explanation of the sodium channel inactivation (Figure 1). The idea of the ball and chain inactivation in the Naþ channel is simple: when the channel is open, a peptide ball (composed of amino acid residues), tethered on the membrane by a chain, wanders randomly around the channel pore. Further studies have shown that the inactivation of sodium channels involves rather a hinged lid than a ball on chain, but this did not decrease the significance of the model.
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Jun 14, 2012
Chaojian Wang + 4
Open Access
