Abstract
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(v)1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Changes in Na(v)1.6 expression and function profoundly impact the input-output properties of neurons in normal and pathological conditions. While mutations in Na(v)1.6 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(v)1.6 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(v)1.6 function. However, there is still more to be learned about how these different modes of modulation interact. Here, we examine the role of Na(v)1.6 in neuronal function and provide a thorough review of this channel's complex regulatory mechanisms and how they may contribute to neuromodulation.