Trafficking mechanisms underlying Na(v) channel subcellular localization in neurons

Voltage gated sodium channels (Na(v)) play a crucial role in action potential initiation and propagation. Although the discovery of Na(v) channels dates back more than 65 years, and great advances in understanding their localization, biophysical properties, and links to disease have been made, there are still many questions to be answered regarding the cellular and molecular mechanisms involved in Na(v) channel trafficking, localization and regulation. This review summarizes the different trafficking mechanisms underlying the polarized Na(v) channel localization in neurons, with an emphasis on the axon initial segment (AIS), as well as discussing the latest advances regarding how neurons regulate their excitability by modifying AIS length and location. The importance of Na(v) channel localization is emphasized by the relationship between mutations, impaired trafficking and disease. While this review focuses on Na(v)1.6, other Na(v) isoforms are also discussed.