Sodium channel protein type 8 subunit alpha also known as Na
v1.6 is a membrane
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
encoded by the ''SCN8A''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Na
v1.6 is one sodium channel isoform and is the primary
voltage-gated sodium channel
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...
at each
node of Ranvier
In neuroscience and anatomy, nodes of Ranvier ( ), also known as myelin-sheath gaps, occur along a myelinated axon where the axolemma is exposed to the extracellular space. Nodes of Ranvier are uninsulated and highly enriched in ion channels, al ...
. 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.
Structure
Na
v1.6 is encoded by the SCN8A gene which contains 27 exons and measures 170 kb. The voltage gated sodium channel is composed of 1980 residues. Like other sodium channels, Na
v1.6 is a monomer composed of four homologous domains (I-IV) and 25 transmembrane segments. SCN8A encodes S3-S4 transmembrane segments which form an intracellular loop.
Function
Like other
sodium ion channels
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...
, Na
v1.6 facilitates action potential propagation when the
membrane potential
Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...
is
depolarized
In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...
by an influx of Na
+ ions. However, Na
v1.6 is able to sustain repetitive excitation and firing. The high frequency firing characteristic of Na
v1.6 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 Na
v1.6 is lower compared to other common sodium channels such as Na
v1.2. This feature allows Na
v1.6 channels to rapidly recover from inactivation and sustain a high rate of activity.
Na
v1.6 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 Na
v1.6, the channel contributes to the firing threshold of a given neuron, as the electrical impulses from various inputs are summed at the
axon hillock
The axon hillock is a specialized part of the cell body (or soma) of a neuron that connects to the axon. It can be identified using light microscopy from its appearance and location in a neuron and from its sparse distribution of Nissl substance. ...
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 Na
v1.1 and Na
v1.2.
Na
V1.6 channels demonstrate resistance against protein phosphorylation regulation. Sodium channels are modulated by
protein kinase A
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
and
protein kinase C
In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
(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, Na
V1.6 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 Na
V1.6. The lack of serine residues lead to the channel's ability to consistently and quickly fire following inactivation.
Na
V1.6 is conversely regulated by Calmodulin (CaM). CaM interacts with the isoleucine-glutamine (IQ) motif of Na
V1.6 in order to inactivate the channel. The IQ motif folds into a helix when interacting with CaM and CaM will inactivate Na
V1.6 depending on the concentration of calcium. The Na
V1.6 IQ demonstrates moderate affinity for CaM compared to other sodium channel isoforms such as Na
V1.6. The difference in CaM affinity contributes to Na
V1.6's resistance to inactivation.
Clinical significance
The first known mutation in humans was discovered by Krishna Veeramah and Michael Hammer in 2012.
The genome of a child demonstrating epileptic encephalopathy was sequenced and revealed a ''de novo'' missense mutation, p.Asn1768Asp. The missense mutations in Na
v1.6 increased channel function by increasing the duration of the persistent sodium current and prevented complete inactivation following hyperpolarization. 20% of the initial current persisted 100 ms after hyperpolarization resulting in hyperexcitability of the neuron and increasing the likelihood of premature or unintentional firing. In addition to epileptic encephalopathy, the patient presented with developmental delay, autistic features, intellectual disability and ataxia.
Sodium channel conversion has been implicated in the demyelination of axons related multiple sclerosis (MS). In early stages of myelination, immature Na
v1.2 channels outnumber Na
v1.6 in axons. However, mature Na
v1.6 channels gradually replace the other channels as myelination continues, allowing increased conduction velocity given the lower threshold of Na
v1.6.
However, in MS models, sodium channel conversion from mature Na
v1.6 to Na
v1.2 is observed.
See also
*
Sodium channel
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...
*
''paralytic'' - SCN8A ortholog in ''
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
''
References
Further reading
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External links
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{{NLM content
Sodium channels