MUTUALLY EXCLUSIVE EXON SPLICING OF TYPE-III BRAIN SODIUM CHANNEL-ALPHA SUBUNIT RNA GENERATES DEVELOPMENTALLY-REGULATED ISOFORMS IN RAT-BRAIN

We have identified two exons of the type III rat brain sodium channel a subunit gene that undergo mutually exclusive alternative RNA splicin g to produce mRNAs coding either for an isoform predominant in neonata l brain (IIIN) or a different isoform (IIIA) predominant in the adult. These exons are 92 base pairs in length and encode amino acids 203-23 2, which correspond to part of the S3 and most of the S4 transmembrane segments within domain I and the extracellular loop between them. Des pite 21 nucleotide differences between the exons, only a single amino acid at position 209 is altered, specifying either aspartic acid (IIIA ) or serine (IIIN). As evidence that these isoforms are generated via alternative splicing, we demonstrate that both exons are encoded withi n the type III gene. The nucleotide sequences of the neonatal and adul t type III exons and the intervening intron as well as the development al regulation of this splicing are nearly identical in the type II sod ium channel gene. The conservation of the exon/intron structure and of the developmentally regulated patterns of expression of the type II a nd III sodium channel genes suggests that alternative mRNA splicing of this exon may play a substantial role in modulating sodium channel fu nction during brain development by alteration of a single amino acid.