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

作者：Jiaying Qiu, Pei Wu, Yu Zhang, Yali Li, Chunli Xia, Siwan Peng, Junjie Sun · 发表于：Annals of Medicine · 年份：2026 · DOI：10.1080/07853890.2026.2645735 · 研究领域：Ion channel regulation and function、Cardiac electrophysiology and arrhythmias、Ion Channels and Receptors

BACKGROUND: 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. INTRODUCTION: 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. DISCUSSION: 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. CONCLUSIONS: By integrating mechanistic insig...