Splice Variants of NaV1.7 Sodium Channels Have Distinct β Subunit-Dependent Biophysical Properties

Genes encoding the alpha subunits of neuronal sodium channels have evolutionarily conserved sites of alternative splicing but no functional differences have been attributed to the splice variants. Here, using Na(V)1.7 as an exemplar, we show that the sodium channel isoforms are functionally distinct when co-expressed with beta subunits. The gene, SCN9A, encodes the alpha subunit of the Na(V)1.7 channel, and contains both sites of alternative splicing that are highly conserved. In conditions where the intrinsic properties of the Na(V)1.7 splice variants were similar when expressed alone, co-expression of beta 1 subunits had different effects on channel availability that were determined by splicing at either site in the alpha subunit. While the identity of exon 5 determined the degree to which beta 1 subunits altered voltage-dependence of activation (P = 0.027), the length of exon 11 regulated how far beta 1 subunits depolarised voltage-dependence of inactivation (P = 0.00012). The results could have a significant impact on channel availability, for example with the long version of exon 11, the co-expression of beta 1 subunits could lead to nearly twice as large an increase in channel availability compared to channels containing the short version. Our data suggest that splicing can change the way that Na-V channels interact with beta subunits. Because splicing is conserved, its unexpected role in regulating the functional impact of beta subunits may apply to multiple voltage-gated sodium channels, and the full repertoire of beta subunit function may depend on splicing in alpha subunits.