Nav1.6
Description: sodium channel, voltage gated, type VIII, alpha subunit Gene: Scn8a Synonyms: nav1.6, scn8a
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
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]
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 |
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 |
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]
Protein
Structure
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].
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]
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]
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].
Model
Model Nav1.6 (ID=33) Edit
Animal | rat | |
CellType | L5PC | |
Age | 21 Days | |
Temperature | 23.0°C | |
Reversal | 50.0 mV | |
Ion | Na + | |
Ligand ion | ||
Reference | A L Goldin et. al; J. Neurosci. 1998 Aug 15 | |
mpower | 1.0 | |
m Inf | 1.0000/(1+ exp(-0.03937*4.2*(v - -17.000))) | |
m Tau | 1 |
References
Lee A
et al.
Role of the terminal domains in sodium channel localization.
Channels (Austin),
2009 May-Jun
, 3 (171-80).
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).
Shirahata E
et al.
Ankyrin-G regulates inactivation gating of the neuronal sodium channel, Nav1.6.
J. Neurophysiol.,
2006
Sep
, 96 (1347-57).
Rush AM
et al.
Electrophysiological properties of two axonal sodium channels, Nav1.2 and Nav1.6, expressed in mouse spinal sensory neurones.
J. Physiol. (Lond.),
2005
May
1
, 564 (803-15).
52
Zhou W
et al.
Use-dependent potentiation of the Nav1.6 sodium channel.
Biophys. J.,
2004
Dec
, 87 (3862-72).
Herzog RI
et al.
Calmodulin binds to the C terminus of sodium channels Nav1.4 and Nav1.6 and differentially modulates their functional properties.
J. Neurosci.,
2003
Sep
10
, 23 (8261-70).
288
Smith MR
et al.
Functional analysis of the mouse Scn8a sodium channel.
J. Neurosci.,
1998
Aug
15
, 18 (6093-102).
Lorincz A
et al.
Cell-type-dependent molecular composition of the axon initial segment.
J. Neurosci.,
2008
Dec
31
, 28 (14329-40).
Sittl R
et al.
Sustained increase in the excitability of myelinated peripheral axons to depolarizing current is mediated by Nav1.6.
,
2011
Feb
2
, ().
361
He H
et al.
Molecular determination of selectivity of the site 3 modulator (BmK I) to sodium channels in the CNS: a clue to the importance of Nav1.6 in BmK I-induced neuronal hyperexcitability.
Biochem. J.,
2010
Sep
28
, 431 (289-98).
Chatelier A
et al.
Biophysical characterisation of the persistent sodium current of the Nav1.6 neuronal sodium channel: a single-channel analysis.
Pflugers Arch.,
2010
Jun
, 460 (77-86).
364
Low SE
et al.
Na(v)1.6a is required for normal activation of motor circuits normally excited by tactile stimulation.
Dev Neurobiol,
2010
Jun
, 70 (508-22).
366
Duflocq A
et al.
Nav1.1 is predominantly expressed in nodes of Ranvier and axon initial segments.
Mol. Cell. Neurosci.,
2008
Oct
, 39 (180-92).
367
Mechaly I
et al.
Molecular diversity of voltage-gated sodium channel alpha subunits expressed in neuronal and non-neuronal excitable cells.
Neuroscience,
2005
, 130 (389-96).
370
Raman IM
et al.
Altered subthreshold sodium currents and disrupted firing patterns in Purkinje neurons of Scn8a mutant mice.
Neuron,
1997
Oct
, 19 (881-91).
403
Meeks JP
et al.
Action potential initiation and propagation in CA3 pyramidal axons.
J. Neurophysiol.,
2007
May
, 97 (3460-72).
Goldin AL
Resurgence of sodium channel research.
Annu. Rev. Physiol.,
2001
, 63 (871-94).
Eijkelkamp N
et al.
Neurological perspectives on voltage-gated sodium channels.
Brain,
2012
Sep
, 135 (2585-612).
Lorincz A
et al.
Molecular identity of dendritic voltage-gated sodium channels.
Science,
2010
May
14
, 328 (906-9).
Kearney JA
et al.
Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6).
Hum. Mol. Genet.,
2002
Oct
15
, 11 (2765-75).
Tzoumaka E
et al.
Differential distribution of the tetrodotoxin-sensitive rPN4/NaCh6/Scn8a sodium channel in the nervous system.
J. Neurosci. Res.,
2000
Apr
1
, 60 (37-44).
Chabbert C
et al.
Voltage-gated Na+ channel activation induces both action potentials in utricular hair cells and brain-derived neurotrophic factor release in the rat utricle during a restricted period of development.
J. Physiol. (Lond.),
2003
Nov
15
, 553 (113-23).
Hossain WA
et al.
Where is the spike generator of the cochlear nerve? Voltage-gated sodium channels in the mouse cochlea.
J. Neurosci.,
2005
Jul
20
, 25 (6857-68).
Saleh S
et al.
Electrophysiological and molecular identification of voltage-gated sodium channels in murine vascular myocytes.
J. Physiol. (Lond.),
2005
Oct
1
, 568 (155-69).
Trudeau MM
et al.
Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation.
J. Med. Genet.,
2006
Jun
, 43 (527-30).
Craner MJ
et al.
Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger.
Proc. Natl. Acad. Sci. U.S.A.,
2004
May
25
, 101 (8168-73).
Grieco TM
et al.
Production of resurgent current in NaV1.6-null Purkinje neurons by slowing sodium channel inactivation with beta-pompilidotoxin.
J. Neurosci.,
2004
Jan
7
, 24 (35-42).
Mercer JN
et al.
Nav1.6 sodium channels are critical to pacemaking and fast spiking in globus pallidus neurons.
J. Neurosci.,
2007
Dec
5
, 27 (13552-66).
Duchen LW
Hereditary motor end-plate disease in the mouse: light and electron microscopic studies.
J. Neurol. Neurosurg. Psychiatr.,
1970
Apr
, 33 (238-50).
Kohrman DC
et al.
Insertional mutation of the motor endplate disease (med) locus on mouse chromosome 15.
Genomics,
1995
Mar
20
, 26 (171-7).
Black JA
et al.
Sodium channels and microglial function.
,
2011
Oct
1
, ().
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).
Craner MJ
et al.
Sodium channels contribute to microglia/macrophage activation and function in EAE and MS.
Glia,
2005
Jan
15
, 49 (220-9).
Kaplan MR
et al.
Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier.
Neuron,
2001
Apr
, 30 (105-19).
Schafer DP
et al.
Early events in node of Ranvier formation during myelination and remyelination in the PNS.
Neuron Glia Biol.,
2006
May
, 2 (69-79).
Credits
Contributors: Rajnish Ranjan, Michael Schartner
To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/ionchannels/125/ , accessed on [date]