Voltage-gated Sodium Channels: Structure, Function and Channelopathies

Zifan Pei, Yanling Pan, Theodore R. Cummins, Pei, Zifan, Pan, Yanling, Cummins, Theodore R.

Voltage-gated sodium channels (VGSCs) are critical determinants of excitability. The properties of VGSCs are thought to be tightly controlled. However, VGSCs are also subjected to extensive modifications. Multiple posttranslational modifications that covalently modify VGSCs in neurons and muscle have been identified. These include, but are not limited to, phosphorylation, ubiquitination, palmitoylation, nitrosylation, glycosylation, and SUMOylation. Posttranslational modifications of VGSCs can have profound impact on cellular excitability, contributing to normal and abnormal physiology. Despite four decades of research, the complexity of VGSC modulation is still being determined. While some modifications have similar effects on the various VGSC isoforms, others have isoform-specific interactions. In addition, while much has been learned about how individual modifications can impact VGSC function, there is still more to be learned about how different modifications can interact. Here we review what is known about VGSC posttranslational modifications with a focus on the breadth and complexity of the regulatory mechanisms that impact VGSC properties.