Nav1.5, the predominant sodium channel in the mammalian heart, is the main component of the upstroke of the cardiac action potential. Accordingly Nav1.5 dysfunction (via mutation or aberrant expression) underlies numerous inherited cardiac arrhythmias and has a role in cardiac hypertrophy and ischemic heart disease. Heart sodium currents change significantly when cardiomyocytes lose the ability to proliferate in postnatal heart remodelling. Thus, electrophysiological recordings from foetal myocytes exhibit markedly slower kinetics than adult cells (Jacques et al., 1997). We have recently demonstrated the existence of adult and foetal (‘neonatal’) alternative splice forms of Nav1.5 (Fraser et al., 2005). This splicing is regulated postnatally in the heart, with the ‘neonatal’ exon of Nav1.5 transcripts rapidly replaced by the ‘adult’ exon. The kinetics of ‘neonatal Nav1.5’ are markedly slower than those of the adult form suggesting that alternative splicing may be a major mechanism underlying postnatal changes in heart currents (Mattis et al., 2007). Two SCN5A promoters, differentially utilised pre- and postnatally, have recently been found suggesting that SCN5A transcriptional and alternative splicing regulation may be coupled (Shang and Dudley, 2005). Here we show that the Brn-3a transcription factor (expressed in the foetal heart and DRG sensory neurons like Nav1.5) can regulate foetal Nav1.5 expression in vitro and in vivo. Using real-time RT-PCR methods we found Nav1.5 mRNA levels in DRG and whole heart extracts from E13.5 Brn-3a -/- mice were significantly reduced (~2-fold) compared to wild-type litter-mates. This reduction was probably due to Brn-3a acting to promote the transcription of SCN5A since over-expression of Brn-3a in human SH-SY5Y sensory neuron/neuroblastoma cells in vitro increased endogenous Nav1.5 mRNA levels ~2-fold. Importantly, although both neonatal and adult isoforms could be detected only the levels of neonatal Nav1.5 changed with Brn-3a manipulations. This appeared to be due to Brn-3a acting specifically upon the upstream ‘foetal’ SCN5A promoter since the activity of a ‘foetal’ SCN5A promoter-luciferase fusion construct was increased ~2-fold in both primary myocytes and SH-SY5Y cells over-expressing Brn-3a. In conclusion, we show that in the pre-natal heart and DRG Brn-3a regulates the expression of neonatal Nav1.5 specifically by acting upon the ‘foetal’ SCN5A promoter. Our data suggest that SCN5A provides a further example of developmental-specific transcription and alternative splicing coupling (Kornblihtt, 2005).