Distinctive Properties and Powerful Neuromodulation of Na_v1.6 Sodium Channels Regulates Neuronal Excitability

Voltage-gated sodium channels (Navs) are critical determinants of cellular excitability. These ion channels exist as large heteromultimeric structures and their activity is tightly controlled. In neurons, the isoform Na_v1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Changes in Na_v1.6 expression and function profoundly impact the input-output properties of neurons in normal and pathological conditions. While mutations in Na_v1.6 may cause channel dysfunction, aberrant changes may also be the result of complex modes of regulation, including various protein-protein interactions and post-translational modifications, which can alter membrane excitability and neuronal firing properties. Despite decades of research, the complexities of Na_v1.6 modulation in health and disease are still being determined. While some modulatory mechanisms have similar effects on other Nav isoforms, others are isoform-specific. Additionally, considerable progress has been made toward understanding how individual protein interactions and/or modifications affect Na_v1.6 function. However, there is still more to be learned about how these different modes of modulation interact. Here, we examine the role of Na_v1.6 in neuronal function and provide a thorough review of this channel's complex regulatory mechanisms and how they may contribute to neuromodulation.