SCN8A

Available structures

Ortholog search: PDBe RCSB

List of PDB id codes
3WFN

Identifiers

Aliases

SCN8A, CERIII, CIAT, EIEE13, MED, NaCh6, Nav1.6, PN4, sodium voltage-gated channel alpha subunit 8

External IDs

MGI: 103169 HomoloGene: 7927 GeneCards: SCN8A

Targeted by Drug

saxitoxin^[1]

Gene ontology
Molecular function	• nucleotide binding • sodium channel activity • voltage-gated ion channel activity • ion channel activity • ATP binding • protein binding • voltage-gated sodium channel activity
Cellular component	• voltage-gated sodium channel complex • integral component of membrane • membrane • node of Ranvier • cytoplasmic, membrane-bounded vesicle • Z disc • axon initial segment • cytoplasmic vesicle • plasma membrane
Biological process	• membrane depolarization during action potential • peripheral nervous system development • sodium ion transport • regulation of ion transmembrane transport • ion transport • nervous system development • ion transmembrane transport • transmembrane transport • transport • myelination • neuronal action potential • regulation of postsynaptic membrane potential • sodium ion transmembrane transport
Sources:Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

Entrez


6334


20273

Ensembl


ENSG00000196876


ENSMUSG00000023033

UniProt


Q9UQD0


Q9WTU3

RefSeq (mRNA)


NM_001177984 NM_014191 NM_175894


NM_001077499 NM_011323

RefSeq (protein)


NP_001171455.1 NP_055006.1


NP_001070967.1 NP_035453.2

Location (UCSC)

Chr 12: 51.59 – 51.81 Mb

Chr 15: 100.87 – 101.05 Mb

PubMed search

^[2]

^[3]

Wikidata

View/Edit Human

View/Edit Mouse

Sodium channel, voltage gated, type VIII, alpha subunit also known as SCN8A or Na_v1.6 is a membrane protein encoded by the SCN8A gene.^[4] Na_v1.6 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.^[5]^[6]^[7]

Structure

Na_v1.6 is encoded by the SC8NA 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. SC8NA is regulated by exons 5N/5A and 18N/18A. 5N/5A and 18N/18A exons encode S3-S4 transmembrane segments that form an intracellular loop.

Function

Like other sodium ion channels, Na_v1.6 facilitates action potential propagation when the membrane potential is depolarized 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,^[8] 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.^[9]

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.^[9] 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 summated at the axon hillock 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.^[6]

Na_V1.6 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 acetycholine reduce 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.^[8] Phosphorylated regulation in sodium channels helps to slow inactivation. However, Na_V1.6 channels lacks adequate protein kinase sites. Phosphorylation sites Ser573 and Ser687 found in other sodium channels are not well conserved in Na_V1.6, leading to the channels ability to consistently and quickly fire following inactivation.^[10]

Clinical significance

The first known mutation in humans was discovered by Krishna Veeramah and Michael Hammer in 2012.^[11] 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.^[6] However, in MS models, sodium channel conversion from mature Na_v1.6 to Na_v1.2 is observed ^[12]

References

↑ "Drugs that physically interact with Sodium channel protein type 8 subunit alpha view/edit references on wikidata".
↑ "Human PubMed Reference:".
↑ "Mouse PubMed Reference:".
↑ "Entrez Gene: SCN8A sodium channel, voltage gated, type VIII, alpha subunit".
↑ Caldwell JH, Schaller KL, Lasher RS, Peles E, Levinson SR (May 2000). "Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses". Proceedings of the National Academy of Sciences of the United States of America. 97 (10): 5616–20. doi:10.1073/pnas.090034797. PMC 25877. PMID 10779552.
1 2 3 Boiko T, Rasband MN, Levinson SR, Caldwell JH, Mandel G, Trimmer JS, Matthews G (April 2001). "Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon". Neuron. 30 (1): 91–104. PMID 11343647.
↑ Tzoumaka E, Tischler AC, Sangameswaran L, Eglen RM, Hunter JC, Novakovic SD (April 2000). "Differential distribution of the tetrodotoxin-sensitive rPN4/NaCh6/Scn8a sodium channel in the nervous system". Journal of Neuroscience Research. 60 (1): 37–44. doi:10.1002/(SICI)1097-4547(20000401)60:13.0.CO;2-W. PMID 10723066.
1 2 Chen Y, Yu FH, Sharp EM, Beacham D, Scheuer T, Catterall WA (August 2008). "Functional properties and differential neuromodulation of Na(v)1.6 channels". Molecular and Cellular Neurosciences. 38 (4): 607–15. doi:10.1016/j.mcn.2008.05.009. PMC 3433175. PMID 18599309.
1 2 Freeman SA, Desmazières A, Fricker D, Lubetzki C, Sol-Foulon N (February 2016). "Mechanisms of sodium channel clustering and its influence on axonal impulse conduction". Cellular and Molecular Life Sciences. 73 (4): 723–35. doi:10.1007/s00018-015-2081-1. PMC 4735253. PMID 26514731.
↑ Chen Y, Yu FH, Sharp EM, Beacham D, Scheuer T, Catterall WA (August 2008). "Functional properties and differential neuromodulation of Na(v)1.6 channels". Molecular and Cellular Neurosciences. 38 (4): 607–15. doi:10.1016/j.mcn.2008.05.009. PMC 3433175. PMID 18599309.
↑ Veeramah KR, O'Brien JE, Meisler MH, Cheng X, Dib-Hajj SD, Waxman SG, Talwar D, Girirajan S, Eichler EE, Restifo LL, Erickson RP, Hammer MF (March 2012). "De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP". American Journal of Human Genetics. 90 (3): 502–10. doi:10.1016/j.ajhg.2012.01.006. PMC 3309181. PMID 22365152.
↑ Craner, Matthew J.; Newcombe, Jia; Black, Joel A.; Hartle, Caroline; Cuzner, M. Louise; Waxman, Stephen G. (2004-05-25). "Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger". Proceedings of the National Academy of Sciences of the United States of America. 101 (21): 8168–8173. doi:10.1073/pnas.0402765101. ISSN 0027-8424. PMC 419575. PMID 15148385.

External links

"SCN8A Website and Registry". University of Arizona.

PDB gallery

1byy: SODIUM CHANNEL IIA INACTIVATION GATE

Membrane transport protein: ion channels (TC 1A)

Ca²⁺: Calcium channel

Ligand-gated	Inositol trisphosphate receptor 1 2 3 Ryanodine receptor 1 2 3

Voltage-gated	L-type/Ca_vα 1.1 1.2 1.3 1.4 N-type/Ca_vα2.2 P-type/Ca_vα 2.1 Q-type/Ca_vα2.1 R-type/Ca_vα2.3 T-type/Ca_vα 3.1 3.2 3.3 α₂δ-subunits 1 2 β-subunits β1 β2 β3 β4 γ-subunits γ1 γ2 γ3 γ4 Cation channels of sperm 1 2 3 4 Two-pore channel 1 2

Na⁺: Sodium channel

Constitutively active	Epithelial sodium channel α β γ δ

Proton-gated	Amiloride-sensitive cation channel 1 2 3 4

Voltage-gated	Na_vα 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 7A Na_vβ 1 2 3 4

K⁺: Potassium channel

Calcium-activated	BK channel α1 β1 β2 β3 β4 SK channel SK1 SK2 SK3 IK channel IK1 K_Ca 1.1 2.1 2.2 2.3 3.1 4.1 4.2 5.1

Inward-rectifier	K_ATP K_ir 1.1 2.1 2.2 2.3 2.4 2.6 GIRK/K_ir 3.1 3.2 3.3 3.4 K_ir 4.1 4.2 5.1 6.1 6.2 7.1

Tandem pore domain	K2P 1 2 3 4 5 6 7 9 10 12 13 15 16 17 18

Voltage-gated	K_vα1-6 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 2.1 2.2 3.1 3.2 3.3 3.4 4.1 4.2 4.3 5.1 6.1 6.2 6.3 6.4 K_vα7-12 7.1 7.2 7.3 7.4 7.5 8.1 8.2 9.1 9.2 9.3 10.1 10.2 11.1/hERG 11.2 11.3 12.1 12.2 12.3 K_vβ 1 2 3 KCNIP 1 2 3 4 minK/ISK minK/ISK-like MiRP 1 2 3 Shaker gene

Miscellaneous

Cl⁻: Chloride channel	Calcium-activated chloride channels Anoctamin ANO1 Bestrophin 1 2 Chloride Channel Accessory 1 2 3 4 CFTR CLCN 1 2 3 4 5 6 7 KA KB CLIC 1 2 3 4 5 6 L1 CLNS 1A 1B

H⁺: Proton channel	HVCN1

M⁺: CNG cation channel	α 1 2 3 4 β 1 2 3 HCN FC 1 2 3 4

M⁺: TRP cation channel	TRPA (1) TRPC 1 2 3 4 4AP 5 6 7 TRPM 1 2 3 4 5 6 7 8 TRPML 1 2 3 TRPN TRPP 1 2 TRPV 1 2 3 4 5 6

H₂O (+ solutes): Porin	Aquaporin 0 1 2 3 4 5 6 7 8 9 Voltage-dependent anion channel 1 2 3 General bacterial porin family

Cytoplasm: Gap junction	Connexin: A GJA1 GJA3 GJA4 GJA5 GJA8 GJA9 GJA10 B GJB1 GJB2 GJB3 GJB4 GJB5 GJB6 GJB7 C GJC1 GJC2 GJC3 D GJD2 GJD3 GJD4) Innexin

By gating mechanism

Ion channel class	Ligand-gated Light-gated Voltage-gated Stretch-activated

see also disorders

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

This article is issued from Wikipedia - version of the 11/29/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.