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Brain enriched voltage-gated sodium channel (VGSC) Na v 1.2 and Na v 1.6 are critical for electrical signaling in the central nervous system. Previous studies have extensively characterized cell-type specific expression and electrophysiological properties of these two VGSCs and how their differences contribute to fine-tuning of neuronal excitability. However, due to lack of reliable labeling and imaging methods, the sub-cellular localization and dynamics of these homologous Na v 1.2 and Na v 1.6 channels remain understudied. To overcome this challenge, we combined genome editing, super-resolution and live-cell single molecule imaging to probe subcellular composition, relative abundances and trafficking dynamics of Na v 1.2 and Na v 1.6 in cultured mouse and rat neurons and in male and female mouse brain. We discovered a previously uncharacterized trafficking pathway that targets Na v 1.2 to the distal axon of unmyelinated neurons. This pathway utilizes distinct signals residing in the intracellular loop 1 (ICL1) between transmembrane domain I and II to suppress the retention of Na v 1.2 in the axon initial segment (AIS) and facilitate its membrane loading at the distal axon. As mouse pyramidal neurons undergo myelination, Na v 1.2 is gradually excluded from the distal axon as Na v 1.6 becomes the dominant VGSC in the axon initial segment and nodes of Ranvier. In addition, we revealed exquisite developmental regulation of Na v 1.2 and Na v 1.6 localizations in the axon initial segment and dendrites, clarifying the molecular identity of sodium channels in these subcellular compartments. Together, these results unveiled compartment-specific localizations and trafficking mechanisms for VGSCs, which could be regulated separately to modulate membrane excitability in the brain. SIGNIFICANCE STATEMENT Direct observation of endogenous voltage-gated sodium channels reveals a previously uncharacterized distal axon targeting mechanism and the molecular identity of sodium channels in distinct subcellular compartments.

Direct Observation of Compartment-Specific Localization and Dynamics of Voltage-Gated Sodium Channels