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 Nav1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Changes in Nav1.6 expression and function profoundly impact the input-output properties of neurons in normal and pathological conditions. While mutations in Nav1.6 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 Nav1.6 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 Nav1.6 function. However, there is still more to be learned about how these different modes of modulation interact. Here, we examine the role of Nav1.6 in neuronal function and provide a thorough review of this channel’s complex regulatory mechanisms and how they may contribute to neuromodulation.
Highlights
A well-functioning and healthy brain is dependent on the ability of neurons to integrate and relay impulses
These impulses are mediated by the activity of voltage-gated sodium channels (Navs) by controlling the initiation and propagation of electrical signals, which are fine-tuned by myriad signaling events to contribute as critical regulators of neuronal excitability [1]
While cerebellar Purkinje neurons isolated from Scn8a null mice display a 35% decrease in the transient sodium current, they display an even larger 70% reduction in the persistent current in addition to reduced repetitive firing capabilities compared to WT littermates [80]
Summary
A well-functioning and healthy brain is dependent on the ability of neurons to integrate and relay impulses. 10–60 μM in length (depending on cell type) located at the proximal end of the axon and maintains neuronal polarity by functioning as a physiological and physical bridge between somatodendritic and axonal compartments This region is characterized by a high density of ion channels, scaffolding proteins, kinases, and other critical proteins that orchestrate. Studies have shown that Nav 1.6 contains the targeting motif |(V/A)P(I/L)AXXE(S/D)D| located in the second intracellular loop (L2) that allows channels to bind AnkG and concentrate Nav 1.6 within these axonal compartments [57,58,59,60,61] This targeting strategy is not unique to Nav 1.6 and localizes Nav 1.2, voltage-gated potassium channels, cell adhesion molecules, and other regulatory proteins to the AIS [56,62,63,64]. Nav 1.6 appears to be the predominant Nav localized to axonal and dendritic compartments, thereby providing exquisite control over input-output properties of neurons
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