Description: sodium channel, voltage-gated, type III, alpha
Gene: Scn3a     Synonyms: nav1.3, scn3a

Edit - History


Nav1.3 is a tetrodotoxin-sensitive (TTX-S) voltage gated sodium ion channel. It is coded by SCN3A and is composed of around 2000 amino acid residues. Nav1.3 is abundantly expressed in neuronal tissues during early development stages of development [2101] and is rare in adult tissues [46].

Edit - History


Nav1.3 is encoded by the gene SCN3A present at the position 2q24.3 in the human genome. The length of SCN3A gene is of 120 kb and contains 31 exons. [2112]

RGD ID Chromosome Position Species
3635 3 - Rat
736602 2 65295175-65405549 Mouse
736601 2 165944030-166060577 Human

Scn3a : sodium channel, voltage-gated, type III, alpha

Edit - History


Across multiple species, the expression of SCN3A is at its highest neonatally and post-birth, with expression of the ion channel dropping off over an organism’s lifetime [2113].
Multiple alternative splice SCN3A variants have also been observed [2112]. For example, exon 5 splicing differs depending on the developmental stage. SCN3A neonatal exon (5N) is only expressed in early development and switches to adult exon (5A) in the mature cortex [2113]. Exon 12 encodes a region of the DI-DII intracellular loop containing important phosphorylation sites that modulate channel kinetics. Alternative splicing of exon 12 leads to 4 Nav1.3 isoforms (12v1, 12v2, 12v3, 12v4) in humans and 3 isoforms, (NaCh III, NaCh IIIa, NaCh IIIb) in rats [41].

Acc No Sequence Length Source
NM_013119 n/A n/A NCBI
NM_018732 n/A n/A NCBI
NM_001081676 n/A n/A NCBI
NM_001081677 n/A n/A NCBI
NM_006922 n/A n/A NCBI



Accession Name Definition Evidence
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:0001518 voltage-gated sodium channel complex A sodium channel in a cell membrane whose opening is governed by the membrane potential. IEA

Edit - History


Though it can function independently, the α subunit Nav1.3 often interacts with one or more β subunits through specific binding sites.

Navβ1 [Nav1.3] [Navβ1] complex expressed in xenopus oocytes was shown to increase peak current and shift in activation/inactivation activity, with a decrease in activation time and an increase in inactivation. This highlights the increased activation properties of the interaction and the potential of increased neuronal firing [44].
​​Navβ2 When [Nav1.3] [Navβ2] complex is expressed in mammalian systems, little to no effect was observed on the kinetics or current densities. However, when the same complex was expressed in DRG cells, a depolarizing shift in activation and faster recovery from inactivation was observed. This suggests that other interactions within the native cells are involved in the modulation of Nav1.3 activity in complex with Navβ2 [2114].
​​Navβ3 Navβ3 has been shown to be co-localised with Nav1.3 during the same stages of development in rats. Furthermore, ​​Navβ3 was shown to interact with Nav1.3 resulting in slower inactivation rates and a hyperpolarization shift in the voltage dependence of activation and inactivation [46].

Tetrodotoxin (TTX) sensitivity is a key factor for differentiating ion channels. Nav1.3 is sensitive to tetrodotoxin, a toxin found in pufferfish. TTX works as a pore blocker to the ion channel by forming electrostatic interactions with the negatively charged vestibule of the Nav channel. This physically blocks the entrance to the pore, effectively stopping the flow of ions and current [2111].

Many studies have demonstrated the interactions between Nav1.3 and various compounds with the potential to modulate its activity. Certain of these compounds could be of pharmacological interest for further drug development.

Edit - History


Edit - History


Like all voltage gated sodium channels, Nav1.3 is made up of a single protein comprised of 4 homologous domains (DI-DIV). Each domain is made up of 6 transmembrane subunits. S1-4 form the voltage sensing domain (VSD) whereas the S5-6 form the pore module (PM). The S4 subunit of each domain contains a series of positively charged residues. When membrane depolarization occurs, these charged residues cause the movement of the S4 subunit, inducing a conformational change in S5-S6, opening of the channel and allowing the entry of sodium ions into the cell. Soon after opening, rapid inactivation of Nav1.3 is instigated by the binding of the IFM motif, found in the loop between D3 and D4, to a hydrophobic receptor site next to the S6 in D4. This binding causes the shift of S6, allosterically closing the channel, thus deactivating the channel [2115]. Nav1.3 then returns to its resting state following the hyperpolarization of the cell membrane [2116].

Edit - History


On a subcellular level, Nav1.3 was shown to be predominantly localized at the neuronal soma and proximal dendrites in the human brain [1398].

Edit - History


Nav1.3 is mainly expressed in the electrically excitable cells of the central nervous system (CNS) but is present at lower levels in other tissues and non-excitable cells [2117] [367].
In the developing fetal brain, SCN3A is present in the cortical plate, outer subventricular zone, intermediate zone and at lower expression levels in the ventricular zone [2101].
Nav1.3 is widely expressed in the adult human central nervous system, in areas such as thalamus, amygdala, cerebellum, but is normally absent, or present at low levels, in the adult peripheral nervous system, such as the spinal chord and the heart. Via immunostaining of adult human brain tissue, Nav1.3 was found most present in the cerebral cortex with highest levels in the cerebellum. Nav1.3 was also identified in the gray matter of the middle frontal gyrus, middle temporal gyrus, and the sensory and motor cortex. Nav1.3 was also found present in the deep brain nuclei, the hippocampal structures and the insular cortex [1398].

Edit - History


Cellular Function

Like all voltage gated sodium channels, Nav1.3 is responsible for the inward flow of Na+ ions into the neuronal cell in a voltage dependent manner. This depolarizing activity of Nav1.3 is likely involved in the establishment of the action potentials. Given their somatodendritic localization, it is thought that Nav1.3 ion channels participate in the downstream propagation of the action potential as that area controls neuronal excitability via the integration of synaptic impulses [2118]


The other functions of Nav1.3 are highlighted by the different channelopathies that arise when the channel does not function as normal.

Neuropathic Pain
Nav1.3 is thought to play a role in neuropathic chronic pain. Though Nav1.3 expression is generally low in adults, Nav1.3 is re-expressed and up-regulated following spinal cord injury. Nav upregulation leads to the generation of ramp current, enhanced persistent current, and shifts in the activation and inactivation activity. These changes lead to increased firing of the downstream neurons leading to chronic pain in the injured area [2119].
Numerous studies have identified mutations in SCN3A that may be responsible for certain forms of epilepsy. Most mutations result in gain-of-function activity, where mutant channels inactivate slower and have a lower activation threshold. This results in increased misfiring rates. This effect can be hindered via application of sodium channel blockers [2120].
Development and associated disorders
Several studies have observed development disorders, such as cerebral cortex malformations, familial autism, oral motor development, linked to SCN3A. Given that Nav1.3 is predominantly expressed in early development, mutations in SCN3A are likely to lead to issues during this crucial stages. Indeed, altered SCN3A expression disrupts the cerebral cortical development in ferret model experiments. [2101] [[1378].

Edit - History


The Nav1.3 channel mediates a TTX-sensitive current with fast activation and inactivation kinetics, and rapid recovery from inactivation.
Rat brain Nav1.3 sodium channels expressed in human embryonic kidney (HEK) 293 cells generate fast-activating and fast inactivating currents. Recovery from inactivation is relatively quick at negative potentials (<-80 mV) but slow at more positive potentials. Development of closed-state inactivation was slow, and Nav1.3 channels generated large ramp currents in response to slow depolarizations.[43]



Model Nav1.3 (ID=43)       Edit

CellType Neocortical
Age 0 Days
Reversal 50.0 mV
Ion Na +
Ligand ion
Reference [43] T R Cummins et. al; J. Neurosci. 2001 Aug 15
mpower 3.0
m Alpha (0.182 * ((v)- -26))/(1-(exp(-((v)- -26)/9))) If v neq -26
m Beta (0.124 * (-(v) -26))/(1-(exp(-(-(v) -26)/9))) If v neq -26
hpower 1.0
h Inf 1 /(1+exp((v-(-65.0))/8.1))
h Tau 0.40 + (0.265 * exp(-v/9.47))

MOD - xml - channelML



Thimmapaya R et al. Distribution and functional characterization of human Nav1.3 splice variants.
Eur. J. Neurosci., 2005 Jul , 22 (1-9).


Alessandri-Haber N et al. Molecular determinants of emerging excitability in rat embryonic motoneurons.
J. Physiol. (Lond.), 2002 May 15 , 541 (25-39).


Wood JN et al. Voltage-gated sodium channels and pain pathways.
J. Neurobiol., 2004 Oct , 61 (55-71).


Huang X et al. [Expression and function of voltage-gated Na+ channel isoforms in rat sinoatrial node]
Nan Fang Yi Ke Da Xue Xue Bao, 2007 Jan , 27 (52-5).


Black JA et al. Sodium channel activity modulates multiple functions in microglia.
Glia, 2009 Aug 1 , 57 (1072-81).

Rogers M et al. The role of sodium channels in neuropathic pain.
Semin. Cell Dev. Biol., 2006 Oct , 17 (571-81).

Whitaker WR et al. Comparative distribution of voltage-gated sodium channel proteins in human brain.
Brain Res. Mol. Brain Res., 2001 Mar 31 , 88 (37-53).

Weiss LA et al. Sodium channels SCN1A, SCN2A and SCN3A in familial autism.
Mol. Psychiatry, 2003 Feb , 8 (186-94).

Holland KD et al. Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy.
Neurosci. Lett., 2008 Mar 5 , 433 (65-70).

Jiang D et al. Structural Advances in Voltage-Gated Sodium Channels.
Front Pharmacol, 2022, 13 (908867).

Zhang J et al. N-type fast inactivation of a eukaryotic voltage-gated sodium channel.
Nat Commun, 20220517, 13 (2713).

Liao S et al. Structure and Function of Sodium Channel Nav1.3 in Neurological Disorders.
Cell Mol Neurobiol, 2022Mar24, ().

Black JA et al. Noncanonical roles of voltage-gated sodium channels.
Neuron, 2013 Oct 16 , 80 (280-91).

Wang J et al. Distribution and function of voltage-gated sodium channels in the nervous system.
Channels (Austin), 2017Nov02, 11 (534-554).

Hains BC et al. Sodium channel expression and the molecular pathophysiology of pain after SCI.
Prog. Brain Res., 2007 , 161 (195-203).

Edit - History


Contributors: Rajnish Ranjan, Katherine Johnston, Michael Schartner

To cite this page: [Contributors] Channelpedia , accessed on [date]