Molecular insights into voltage-gated sodium channels in excitable cells: pathophysiological roles and emerging therapeutic targets

Voltage-gated sodium channels (VGSCs; Nav1.1-Nav1.9) are necessary for the initiation and propagation of action potentials in neurons, cardiac muscle and skeletal muscle. Because of their functional importance, VGSCs have become promising candidates for drug development in the brain, heart, and pain. The aim of this review is to highlight the structure, physiological role and pathological involvement of VGSCs in several different diseases, such as epilepsy, arrhythmias, chronic pain and cancer. Clinically established VGSC-targeting drugs are discussed, as well as recent evidence that shows an involvement of VGSCs in tumor progression and metastasis. Lack of selectivity, blood-brain barrier penetration, and regulatory complexities are among the challenges faced by VGSC-targeted therapy, as discussed in the review. Other challenges with VGSC-targeted therapy, such as high isoform homology, limited selectivity, blood-brain barrier penetration, and regulatory complexities, are also discussed in the review. In addition, new isoform-specific modulation strategies, innovative drug delivery devices, and new therapeutic approaches are highlighted. In summary, VGSCs are interesting but complex therapeutic targets, and future progress in selective targeting and drug delivery will likely increase their potential use across a variety of neurological, cardiovascular, and oncological disorders.