Trafficking regulates the subcellular distribution of voltage-gated sodium channels in primary sensory neurons

Voltage-gated sodium channels (Na(v)s) comprise at least nine pore-forming α subunits. Of these, Na(v)1.6, Na(v)1.7, Na(v)1.8 and Na(v)1.9 are the most frequently studied in primary sensory neurons located in the dorsal root ganglion and are mainly localized to the cytoplasm. A large pool of intracellular Na(v)s raises the possibility that changes in Na(v) trafficking could alter channel function. The molecular mediators of Na(v) trafficking mainly consist of signals within the Na(v)s themselves, interacting proteins and extracellular factors. The surface expression of Na(v)s is achieved by escape from the endoplasmic reticulum and proteasome degradation, forward trafficking and plasma membrane anchoring, and it is also regulated by channel phosphorylation and ubiquitination in primary sensory neurons. Axonal transport and localization of Na(v)s in afferent fibers involves the motor protein KIF5B and scaffold proteins, including contactin and PDZ domain containing 2. Localization of Na(v)1.6 to the nodes of Ranvier in myelinated fibers of primary sensory neurons requires node formation and the submembrane cytoskeletal protein complex. These findings inform our understanding of the molecular and cellular mechanisms underlying Na(v) trafficking in primary sensory neurons.