The axon initial segment (AIS) and nodes of Ranvier are the sites of action potential initiation and regeneration in axons. Although the basic molecular architectures of AIS and nodes, characterized by dense clusters of Na+ and K+ channels, are similar, firing patterns vary among cell types. Neuronal firing patterns are established by the collective activity of voltage-gated ion channels and can be modulated through interaction with auxiliary subunits. Here, we report the neuronal expression pattern and subcellular localization of Navβ4, the modulatory Na+ channel subunit thought to underlie resurgent Na+ current. Immunostaining of rat tissues revealed that Navβ4 is strongly enriched at the AIS of a select set of neuron types, including many characterized by high-frequency firing, and at nodes of Ranvier in the PNS and some nodes in the CNS. By introducing full-length and mutant GFP-tagged Navβ4 into cultured neurons, we determined that the AIS and nodal localization of Navβ4 depends on its direct interaction with Na+ channel α subunits through an extracellular disulfide bond. Based on these results, we propose that differences in the specific composition of the Na+channel complexes enriched at the AIS and nodes contribute to the diverse physiologies observed among cell types.
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