page_title: SCN8A
section_title: Function
hierarchical_section_title: SCN8A / Function
caption_attribution_description: English: Crystal Structure of Nav1.6 IQ motif in complex with apo-CaM
context_page_description: Sodium channel, voltage gated, type VIII, alpha subunit also known as SCN8A or Naᵥ1.6 is a membrane protein encoded by the SCN8A gene. Naᵥ1.6 is one sodium channel isoform and is the primary voltage-gated sodium channel at the nodes of Ranvier. The channels are highly concentrated in sensory and motor axons in the peripheral nervous system and cluster at the nodes in the central nervous system.
context_section_description: Like other sodium ion channels, Naᵥ1.6 facilitates action potential propagation when the membrane potential is depolarized by an influx of Na⁺ ions. However, Naᵥ1.6 is able to sustain repetitive excitation and firing. The high frequency firing characteristic of Naᵥ1.6 is caused by a persistent and resurgent sodium current. This characteristic is caused by slow activation of the sodium channel following repolarization, which allows a steady-state sodium current after the initial action potential propagation. The steady-state sodium current contributes to the depolarization of the following action potential. Additionally, the activation threshold of Naᵥ1.6 is lower compared to other common sodium channels such as Naᵥ1.2. This feature allows Naᵥ1.6 channels to rapidly recover from inactivation and sustain a high rate of activity.
  Naᵥ1.6 is expressed primarily in the nodes of Ranvier in myelinated axons but is also highly concentrated at the distal end of the axon hillock, cerebellar granule cells and Purkinje neurons and to a lower extent in non-myelinated axons and dendrites. Given the location of Naᵥ1.6, the channel contributes to the firing threshold of a given neuron, as the electrical impulses from various inputs are summed at the axon hillock in order to reach firing threshold before propagating down the axon. Other sodium channel isoforms are expressed at the distal end of the axon hillock, including Naᵥ1.1 and Naᵥ1.2.
  NaV1.6 channels demonstrate resistance against protein phosphorylation regulation. Sodium channels are modulated by protein kinase A and protein kinase C (PKC) phosphorylation, which reduce peak sodium currents. Dopamine and acetylcholine decrease sodium currents in hippocampal pyramidal neurons through phosphorylation. Similarly, serotonin receptors in the prefrontal cortex are regulated by PKC in order to reduce sodium currents. Phosphorylated regulation in sodium channels helps to slow inactivation. However, NaV1.6 channels lacks adequate protein kinase sites. Phosphorylation sites at amino acid residues Ser573 and Ser687 are found in other sodium channels but are not well conserved in NaV1.6. The lack of serine residues lead to the channel's ability to consistently and quickly fire following inactivation.
  NaV1.6 is conversely regulated by Calmodulin (CaM). CaM interacts with the isoleucine-glutamine (IQ) motif of NaV1.6 in order to inactivate the channel. The IQ motif folds into a helix when interacting with CaM and CaM will inactivate NaV1.6 depending on the concentration of calcium. The NaV1.6 IQ demonstrates moderate affinity for CaM compared to other sodium channel isoforms such as NaV1.6. The difference in CaM affinity contributes to NaV1.6's resistance to inactivation.
caption: Nav1.6 IQ motif in complex with CaM[12]
exif: {"Image ExifOffset": "28", "EXIF ImageDescription": "ImageSource=RCSB PDB; StructureID=3wfn; DOI=http://dx.doi.org/10.2210/pdb3wfn/pdb;"}