Novel mRNA isoforms of the sodium channels Na(v)1.2, Na(v)1.3 and Na(v)1.7 encode predicted two-domain, truncated...

The expression of voltage-gated sodium channels is regulated at multiple levels, and in this study we addressed the potential for alternative splicing of the Na(v)1.2, Na(v)1.3, Na(v)1.6 and Na(v)1.7 mRNAs. We isolated novel mRNA isoforms of Na(v)1.2 and Na(v)1.3 from adult mouse and rat dorsal root ganglia (DRG), Na(v)1.3 and Na(v)1.7 from adult mouse brain, and Na(v)1.7 from neonatal rat brain. These alternatively spliced isoforms introduce an additional exon (Na(v)1.2 exon 17A and topologically equivalent Na(v)1.7 exon 16A) or exon pair (Na(v)1.3 exons 17A and 17B) that contain an in-frame stop codon and result in predicted two-domain, truncated proteins. The mouse and rat orthologous exon sequences are highly conserved (94-100% identities), as are the paralogous Na(v)1.2 and Na(v)1.3 exons (93% identity in mouse) to which the Na(v)1.7 exon has only 60% identity. Previously, Na(v)1.3 mRNA has been shown to be upregulated in rat DRG following peripheral nerve injury, unlike the downregulation of all other sodium channel transcripts. Here we show that the expression of Na(v)1.3 mRNA containing exons 17A and 17B is unchanged in mouse following peripheral nerve injury (axotomy), whereas total Na(v)1.3 mRNA expression is upregulated by 33% (P=0.003), suggesting differential regulation of the alternatively spliced transcripts. The alternatively spliced rodent exon sequences are highly conserved in both the human and chicken genomes, with 77-89% and 72-76% identities to mouse, respectively. The widespread conservation of these sequences strongly suggests an additional level of regulation in the expression of these channels, that is also tissue-specific.