# Alternative splicing in voltage-gated sodium channels: mechanisms, regulatory networks and therapeutic implications

## TL;DR

Alternative splicing in sodium channels expands their function, and correcting splicing defects could treat related diseases.

## Contribution

This review systematically catalogs splicing variants in all nine VGSC α-subunits and evaluates their clinical and functional impacts.

## Key findings

- Alternative splicing significantly expands the proteomic and functional diversity of voltage-gated sodium channels.
- Dysregulation of splicing contributes to channelopathies, and antisense oligonucleotides offer a promising therapeutic strategy.
- RNA-binding proteins like Rbfox and Nova2 regulate splicing events in a cell-type-specific manner.

## Abstract

Voltage-gated sodium channels (VGSCs) are fundamental to electrical signalling in excitable cells, and their dysfunction underlies a wide range of channelopathies. While the existence of nine distinct α-subunit genes contributes to VGSC diversity, alternative splicing serves as a significant post-transcriptional mechanism that profoundly expands their proteomic and functional repertoire. Dysregulation of this splicing process is increasingly linked to disease pathogenesis.

This review aims to provide a comprehensive synthesis of the alternative splicing landscape across all nine VGSC α-subunits. It systematically catalogs known splicing variants, details their roles in developmental regulation, tissue-specific expression and fine-tuning of channel biophysics, and examines the regulatory networks controlling these events.

We detail conserved splicing switches (e.g. the 5N/5A exon in neuronal channels) and isoform-specific events across the VGSC family (Nav1.1 to Nav1.9), evaluating their functional and clinical impacts. The regulation of these events by key RNA-binding proteins (RBPs), such as Rbfox and Nova2, within cell-type-specific networks is emphasized. Furthermore, we discuss how splicing dysregulation contributes to channelopathies and evaluate the promising potential of novel therapeutic strategies, particularly antisense oligonucleotides (ASOs), to correct pathogenic splicing defects.

By integrating mechanistic insights with clinical implications, this review establishes alternative splicing as a central theme in VGSC biology and pathophysiology. It highlights the critical need for, and the emerging path towards, precision medicine approaches that target splicing defects for the treatment of VGSC-associated disorders, providing a foundational resource to guide future research and therapeutic development.

Alternative splicing critically expands the functional diversity of voltage-gated sodium channels (VGSCs).Dysregulation of this splicing process is a direct cause of disease, contributing to various channelopathies.Correcting pathogenic splicing defects, notably via antisense oligonucleotides (ASOs), represents a promising precision therapeutic strategy.

Alternative splicing critically expands the functional diversity of voltage-gated sodium channels (VGSCs).

Dysregulation of this splicing process is a direct cause of disease, contributing to various channelopathies.

Correcting pathogenic splicing defects, notably via antisense oligonucleotides (ASOs), represents a promising precision therapeutic strategy.