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Electrophysiological and developmental implications of Na+ channel-splice variants

Dear Editor, We would like to make comments on a recent publication in the Journal of Neurogenetics (Wang et al.; J Neurogenet, 22, 1 19, 2008). Voltage-gated sodium-channel a-subunits (VGSCas), a multigene family of nine members (Nav1.1 Nav1.9), manifest tissue-selective expression profiles (Diss et al., 2004). Nav1.5/SCN5A is the primary VGSCa expressed in cardiac muscle. Alternative splicing is an important mechanism in generating further diversity among VGSCas, and one such splicing involves the inclusion of two alternative forms of exon-6 (5?-genomic and 3?-genomic) encoding the D1:S3 segment and D1:S3/S4 extracellular linker regions of the channel (Diss et al., 2004). A recent article by Wang et al. (2008) reports on the D1:S3 spicing of Nav1.5, which has been of interest to us for some years (Fraser et al., 2003, 2005; Chioni et al., 2005; Brackenbury et al., 2007; Onkal et al., 2008). Wang et al. (2008) have demonstrated the mRNA expression levels of the Nav1.5 D1:S3 splice variant in a range of adult human tissues. It was concluded that ‘‘neonatal’’/exon 6A is limited to the central nervous system (CNS), whereas ‘‘adult’’/exon6 Nav1.5 expression occurred outside the CNS (especially in the cardiac muscle). This is the first study characterizing the expression of D1:S3 ‘‘neonatal’’/exon 6A variant of Nav1.5 mRNA in a wide range of human tissues. However, we feel that there is further scope in the evaluation of the reported results, as follows: 1. Electrophysiological consequences of D1:S3 Nav1.5 splicing. In their Discussion, Wang et al. (2008) considered, with insight, whether the structural difference between adult (called ‘‘exon 6’’ in their paper) and neonatal (called ‘‘exon 6A’’) Nav1.5 could be of functional (i.e., electrophysiological) significance. Although the authors could not be aware at the time of the publication, this possibility has been tested in our laboratory recently, confirming their speculation (Onkal et al., 2008). Thus, we have demonstrated that D1:S3 adult and neonatal splice variants of Nav1.5 do, indeed, differ extensively in their electrophysiological characteristics. In particular, the neonatal channel has much slower overall kinetics and, consequently, a prolonged current, allowing greater influx of Na . This J. Neurogenetics, 22: 187 191 Copyright # 2008 Informa UK Ltd. ISSN: 0167-7063 print/1563-5260 online DOI: 10.1080/01677060802248637