Voltage-Gated Sodium Channel Dysfunction in Epilepsy: Zebrafish Models for Therapeutics

Voltage-gated sodium channels (VGSCs) play pivotal roles in cellular function, particularly in the regulation of electrical signaling. Structural defects in these channels cause deleterious effects in a myriad of cell types, leading to various diseases, like epilepsy, cardiac arrythmias, kidney disease, and certain cancers. Over the past decade, significant efforts have been geared toward developing drugs that target the pore domains of these channels, called pore-blocking agents. This approach has seen several setbacks, commonly due to the lack of isoform-specific binding. Alternative targeting strategies are being used to reduce or eliminate the side effects of pore-blocking agents. Transgenic mouse models have proven useful in such studies, and subtype-selective inhibitors were developed. The zebrafish model system was also used to explore neurological, cardiovascular, and metabolic diseases caused by voltage-gated sodium channel dysfunction. Here, we delve into the growing literature on the structure and function of voltage-gated sodium channels, their role in epilepsy and its comorbidities, and the advancement in the use of zebrafish as a model system to explore these channels as therapeutic targets.