Cardiac sodium channel and inherited arrhythmia syndromes

Time for primary review 32 days. The voltage-gated cardiac sodium channel is responsible for the generation of the rapid upstroke of the myocardial action potential and thereby plays a central role in excitability of myocardial cells. In addition, since the action potential upstroke velocity — in conjunction with the extent of intercellular communication via gap junctions 1 — also determines impulse conduction velocity in cardiac tissue, this channel also plays a vital role in impulse propagation. Mutations in the gene encoding this channel (SCN 5 A ; Section 2. 1) have been linked to three forms of primary electrical disease — the long QT syndrome (LQTS) 2, the Brugada syndrome (BS) 3 and cardiac conduction defects 4. The elucidation of the pathophysiological mechanisms of these mutant Na+ channels would ultimately enable more specific pharmacological intervention in the management of these syndromes and other related arrhythmias. The cardiac Na+ channel (see Ref. 5 for review) is a member of the voltage-dependent family of Na+ channels (see Ref. 6 for review). These channels consist of heteromeric assemblies of an α-subunit, the pore-forming component, the function of which is modulated by association with one or two ancillary β-subunits. ### 2. 1 α-Subunit The human cardiac Na+ channel α-subunit is a heavily glycosylated protein of ∼260 kDa consisting of 2016 amino acid residues 7. It is encoded by the SCN 5 A gene 8, which is located on chromosome 3p21 9. At least 11 other different genes that encode highly homologous sodium channel α-subunit isoforms expressed in the heart, muscle and nervous system have been hitherto identified in man (http: //www. ncbi. nlm. nih. gov/entrez/query. fcgi? db=Nucleotide). They display a modular architecture (Fig. 1), which consists of four internally homologous domains (DI–DIV) each made up of six transmembrane segments (S1–S6). The interdomain linkers and the N- and … * Corresponding author. Tel.: +31-20-566-3265; fax: +31-20-697-5458 a. a. wildeatamc. uva. nl