Channelpedia

Nav1.6

Description: sodium channel, voltage gated, type VIII, alpha subunit
Gene: Scn8a     Synonyms: nav1.6, scn8a

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Introduction

Sodium channel, voltage gated, type VIII, alpha subunit also known as SCN8A or Nav1.6 is a protein which in humans is encoded by the SCN8A gene. It is a voltage-gated sodium channel.

The ion channel was discovered by John Caldwell and colleagues at the University of Colorado Health Sciences Center in the rat, and by Miriam Meisler and colleagues at the University of Michigan Medical School in the mouse.

This is the most abundantly expressed isoform in the CNS during adulthood [834].

From http://en.wikipedia.org/wiki/Nav1.6

Experimental data

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Gene

The amino acid sequence of Nav1.6 is 84% identical to the sequences of Nav1.1 and Nav1.2, but it is more distant from those two than they are to each other (Goldin et al., 2000). [52]

RGD ID Chromosome Position Species
3638 7 139686180-139794282 Rat
736507 15 100701114-100876360 Mouse
1351349 12 51985020-52202307 Human

Scn8a : sodium channel, voltage gated, type VIII, alpha subunit

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Transcript

Acc No Sequence Length Source
NM_019266 n/A n/A NCBI
NM_001077499 n/A n/A NCBI
NM_011323 n/A n/A NCBI
NM_014191 n/A n/A NCBI
NM_001177984 n/A n/A NCBI
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Ontology

Accession Name Definition Evidence
GO:0005886 plasma membrane The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins. IDA
GO:0016021 integral to membrane Penetrating at least one phospholipid bilayer of a membrane. May also refer to the state of being buried in the bilayer with no exposure outside the bilayer. When used to describe a protein, indicates that all or part of the peptide sequence is embedded in the membrane. IDA
GO:0001518 voltage-gated sodium channel complex A sodium channel in a cell membrane whose opening is governed by the membrane potential. IDA
GO:0016020 membrane Double layer of lipid molecules that encloses all cells, and, in eukaryotes, many organelles; may be a single or double lipid bilayer; also includes associated proteins. IEA
GO:0030425 dendrite A neuron projection that has a short, tapering, often branched, morphology, receives and integrates signals from other neurons or from sensory stimuli, and conducts a nerve impulse towards the axon or the cell body. In most neurons, the impulse is conveyed from dendrites to axon via the cell body, but in some types of unipolar neuron, the impulse does not travel via the cell body. IEA
GO:0043025 neuronal cell body The portion of a neuron that includes the nucleus, but excludes all cell projections such as axons and dendrites. IEA
GO:0005624 membrane fraction That fraction of cells, prepared by disruptive biochemical methods, that includes the plasma and other membranes. IEA
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Interaction

Ankyrin-G

Experiments where cDNA encoding hNav1.6 was transfected into tsA201 cells - which do not express endogenous ankyrin - show that ankyrin-G negatively regulates persistent sodium current (Ina-p) through the hNav1.6 channel. Hence it is possible that ankyrin-G regulates neuronal excitability not only through clustering Nav channels, but also through modifying gating behaviors of Nav1.6 channels[50]. Ankyrins have an important role in clustering NaV1.6 into nodes of Ranvier and axon initial segments [1390].

Calmodulin

No evidence was found that CaM modulates the voltage dependence of activation or inactivation of either Nav1.4 or Nav1.6 channels. But changes in the intracellular calcium ion concentration altered the inactivation kinetics of NaV1.6 currents via a CaM-dependent mechanism. This means CaM can regulate the properties of VGSCs in isoform-specific ways and via calcium-dependent and calcium-independent mechanisms.[53]

Tetrodotoxin

Nav1.6 is TTX sensitive (non selective) [1376]

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Protein

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Structure

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Distribution

Nav1.6 is present in the somata and diffusely along unmyelinated fibers arising from small DRG neurons [51].

Nav1.6 is the main Nav subunit in the somatodendritic compartments of CA1 PCs with a very dramatic drop (by a factor of 40 to 70) in density from nodes of Ranvier and AISs to somata, and a distance-dependent decrease in density along the proximodistal axis of the dendritic tree [362]. NaV1.2 populates immature nodes of Ranvier in hypomyelinated axons and is completely replaced by NaV1.6 at mature nodes along compact myelinated axons.[47]

Nav1.6 subunit is present in hippocampal CA1 PC proximal and distal dendrites. A gradual decrease in Nav1.6 density along the proximodistal axis of the dendritic was detected without any labelling in dendritic spines. This characteristic subcellular distribution of the Nav1.6 subunit identify this molecule as a key substrate enabling dendritic excitability [362]; in fact, Nav1.6 channels at axon initial segments contribute to persistent Na(+) current and ensure a high degree of temporal precision in repetitive firing of CG cells [365]. In cells where the Kv1.1 and Kv1.2 subunits are coexpressed with the Nav1.6 subunit, their subcellular distributions are correlated.[329]

This isoform is present in both sensory and motor pathways, and its subcellular distribution includes axons, nodes, dendrites, cell bodies, and pre- and post-synaptic sites [834].

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Expression

Nav1.6 was detected during the embryonic period in brain, and levels increased shortly after birth and peaked by 2-weeks of age. This is the most abundantly expressed isoform in the CNS during adulthood [834]. Is the most abundant channel at mature nodes of Ranvier in myelinated axons in the CNS (replacing Nav1.2) [1450] and PNS [1451].

NaV1.6 is broadly expressed in the nervous system in a variety of cells including Purkinje cells, motor neurons, pyramidal and granule neurons, glial cells and Schwann cells and is enriched at the nodes of Ranvier [1414]. Nav1.6 channels have been also detected in immune cells, such microglia and macrophagues [1449] and in cultured microglia, Nav1.6 is the most prominently expressed sodium channel [1392]. .

There is no rostral-caudal gradient of Nav1.6 mRNA, but it is present in a somato-dendritic distribution in output neurons of [834], [329],[48],[49]:
* Cerebellum
* Cerebral cortex
* Hippocampus
* Purkinje cells in the cerebellar granule cell layer
* Globus pallidus

Nav1.6 is also expressed in:
* Spinal cord [369]
* Utricular hair cells (early postnatal period) [410]
* Corti organ [414]
* Smooth muscle myocytes (plasmalemma)[1415]

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Functional

The functional role of NaV1.6 subunits have been assessed in mutant mice lacking NaV1.6 channels, for example in cerebellar and globus pallidus neurons, and dorsal root and trigeminal ganglion cells. The findings support that NaV1.6 subunits mediate resurgent and persistent Na+ currents in these cells with a resulting effect on repetitive firing behavior. Further, NaV1.6 subunits have a hyperpolarized voltage of activation compared with other Na channel isoforms. Experiments and simulations indicate a critical role for NaV1.6 in setting the low spike threshold at the AIS of CA1 pyramidal neurons. [48]

Nav1.6 channels with resurgent gating are critical for fast spiking in globus pallidus neurons, as in Purkinje neurons. The location and density of these channels (not their resurgence) is what underlies their role in pacemaking.[49]

Electrical stimulation therapies to treat Parkinson's desease are unlikely to functionally inactivate neurons possessing Nav1.6 Na channels with prominent resurgent gating. [49]

Threshold electrotonus responses from peripheral myelinated axons of Scn8amed mice are abnormal due to the lack of a Nav1.6-mediated persistent sodium current in myelinated axons.[360]

In HEK-293 cells, the Nav1.6 persistent current was measured to be 3–5% of the peak transient current, a value matching the ratio between peak and persistent open probability in single-channel recording. The cellattached configuration showed that the molecular mechanism of the whole-cell persistent current is a consequence of single Nav1.6 channels reopening.[363]

Nav1.6 channels at axon initial segments contribute to persistent Na+ current and ensure a high degree of temporal precision in repetitive firing of CG cells.[365]

Channelopathies

Mutation in SCN8A is not a common cause of human disease although a patient with a heterozygous mutation in SCN8A that caused a C-terminal truncation of NaV1.6 (loss of channel function) has been related with [1416]:
* Cerebelar atrophy
* Ataxia
* Mental retardation
It have been found changes in the expression of Nav1.6 in multiple sclerosis and mice with autoimmune encephalomyelitis [404].

Mouse models:
- Scn8a+/+ [368]
- Scn8a+/- [368]
- Scn8a-/- [368]
- Nav1.6 null [49]
- Snc8amed [1417]
- Scn9atg [1418]

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Kinetics

NaV1.6 subunits at the AIS have a significant contribution to its role as spike trigger zone and shape repetitive discharge properties of CA1 pyramidal neurons.[48]
Nav1.6 is a fast activating and fast inactivating channel that can also produce a persistent or non-inactivating current which can account for ~5% of the transient current [1392].

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Model

[1] Nav1.6 (Model ID = 33)

Animalrat
CellType L5PC
Age 21 Days
Temperature23.0°C
Reversal 50.0 mV
Ion Na +
Ligand ion
Reference A L Goldin et. al; J. Neurosci. 1998 Aug 15
mpower 1.0
mInf 1.0000/(1+ exp(-0.03937*4.2*(v - -17.000)))
mTau 1
127

MOD - xml - channelML

References

47

Goldin AL. et al. Role of the terminal domains in sodium channel localization.
Channels (Austin), 2009 May-Jun , 3 (171-80).

48

Royeck M. et al. Role of axonal NaV1.6 sodium channels in action potential initiation of CA1 pyramidal neurons.
J. Neurophysiol., 2008 Oct , 100 (2361-80).

50

Shirahata E. et al. Ankyrin-G regulates inactivation gating of the neuronal sodium channel, Nav1.6.
J. Neurophysiol., 2006 Sep , 96 (1347-57).

52

Zhou W. et al. Use-dependent potentiation of the Nav1.6 sodium channel.
Biophys. J., 2004 Dec , 87 (3862-72).

288

Goldin AL. et al. Functional analysis of the mouse Scn8a sodium channel.
J. Neurosci., 1998 Aug 15 , 18 (6093-102).

329

Nusser Z. et al. Cell-type-dependent molecular composition of the axon initial segment.
J. Neurosci., 2008 Dec 31 , 28 (14329-40).

366

Couraud F. et al. Nav1.1 is predominantly expressed in nodes of Ranvier and axon initial segments.
Mol. Cell. Neurosci., 2008 Oct , 39 (180-92).

403

Meeks JP. et al. Action potential initiation and propagation in CA3 pyramidal axons.
J. Neurophysiol., 2007 May , 97 (3460-72).

834

Goldin AL. et al. Resurgence of sodium channel research.
Annu. Rev. Physiol., 2001 , 63 (871-94).

1390

Wood JN. et al. Neurological perspectives on voltage-gated sodium channels.
Brain, 2012 Sep , 135 (2585-612).

362

Nusser Z. et al. Molecular identity of dendritic voltage-gated sodium channels.
Science, 2010 May 14 , 328 (906-9).

1417

Duchen LW. et al. Hereditary motor end-plate disease in the mouse: light and electron microscopic studies.
J. Neurol. Neurosurg. Psychiatr., 1970 Apr , 33 (238-50).

1392

Black JA. et al. Sodium channels and microglial function.
, 2011 Oct 1 , ().

365

Osorio N. et al. Persistent Nav1.6 current at axon initial segments tunes spike timing of cerebellar granule cells.
J. Physiol. (Lond.), 2010 Feb 15 , 588 (651-70).

1451

Rasband MN. et al. Early events in node of Ranvier formation during myelination and remyelination in the PNS.
Neuron Glia Biol., 2006 May , 2 (69-79).

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Credits

Editor : Admin.

Contributors : Rajnish Ranjan, Michael Schartner

To cite : [Editor], [Contributors]. Accessed on [Date] Channelpedia , http://channelpedia.epfl.ch/ionchannels/125