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

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The tetrodotoxin-sensitive (TTX-S) channel Nav1.3 is abundantly expressed in neuronal tissues during embryonic and neonatal stages of development [2101] and is rare in adult tissues [46].

After axonal transection, Nav1.3 is upregulated in dorsal root ganglia (DRG) neurons adding to the evidence that upregulation of Nav1.3 may play a role in rendering axotomized DRG neurons hyperexcitable, thus contributing to neuropathic pain [1393]. It is thought that the fast activation and inactivation kinetics of Nav1.3, together with its rapid repriming kinetics and persistent current component, contributes to the development of spontaneous ectopic discharges and sustained rates of firing characteristics of injured sensory nerves [1394].

In humans, individuals with Nav1.3 mutations have altered neurodevelopment features, including gain-of-function mutations generating cortical malformations [2101] and infantile encephalopathy [1401].

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Experiments on sodium channels in GH3 cells (a clonal line of rat pituitary cells) showed that nimodipine treatment caused a moderate reduction (approx. 30%) of the mRNA for Na v 1.2 and a marked reduction (approx. 70%) of the mRNA for Na v 1.3. Treatment with Bay K 8644 produced 90–130% increases in these same mRNAs, in contrast.[353]

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



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

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Coexpression of the rat Nav1.3 and human Nav1.3 alpha subunits in combination with their conspecific beta1 and beta2 subunits in Xenopus laevis oocytes gave channels that reacted very differently to the pyrethroid insecticide tefluthrin.[42]


Contactin/F3, a cell adhesion molecule, causes Nav1.3 channels in HEK 293 cells to increases the amplitude of the current threefold without changing the biophysical properties of the channel. But removing contactin from the cell surface of cotransfected cells does not reduce the elevated levels of the Nav1.3 current. [45]

Beta 3 Subunit

Coexpression of beta3 subunits had significant effects on the kinetic and voltage-dependent properties of Nav1.3 currents in HEK 293 cells, whereas coexpression of beta1 and beta2 subunits had nearly no effect on Nav1.3 properties.[43]

Beta 1 Subunit

But experiments with Nav1.3 sodium channel with the cRNA of rat DRG expressed in oocytes show that the β1 subunit modifies the functional properties of the Nav1.3 sodium channel. Co-expression of β1 subunits increased the peak current of the Nav1.3 channel significantly, accelerated inactivation and slightly shifted the activation G-V curve to more hyperpolarized potentials.[44]


Nav1.3 is TTX sensitive [1376]



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The alpha subunit (260 kDa) is large, forming functional sodium channels when expressed in mammalian cells or Xenopus oocytes. The properties of these channels are altered following coexpression with the modulatory beta subunits (33–36 kDa).[41].The beta subunits are structurally homologous and form single transmembrane glycoproteins with short intracellular loops and immunoglobulin-like extracellular segments.[44]

Individual α and β-subunit genes are expressed in complex tissue-specific and developmentally regulated patterns to generate a wide combinatorial variety of channels with distinct properties. For example, the neuronal channel α-subunit Nav1.3 and the β3-subunit: the tissue-specific expression patterns of Nav1.3 correlate closely with β3, and the subunits show parallel expression patterns throughout development. Moreover, the expression of these two proteins is up-regulated in rat dorsal root ganglion neurons after nerve damage which suggests that the β3-subunit may play an important role in the selective regulation of Nav1.3 in both physiological and pathological situations.(Extracted from [359])

β3 is composed of an extracellular V-type immunoglobulin (Ig) domain, a single α-helical transmembrane domain, and a short intracellular domain. Mutations that affect the structure of the Ig domain modify gating behavior. The role of the intracellular domain has been difficult to assess because its deletion led to a β3-subunit that failed to bind the α-subunit.(Extracted from [359])

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Nav1.3 is predominantly expressed during pre-myelination stages of development in somatodendritic and axonal compartments of embryonic neurons. In rodents, the expression is attenuated after birth [1370] while in humans, the channel is highly expressed in somatodendritic compartment of myelinated neurons [1398]. In the developing human brain, NaV1.3 is enriched to both dividing cell types and newly born migrating neurons [2101].

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Nav1.3 isoforms are abundantly expressed in the developing cenral nervous system of rats and humans [42]. In the developing human brain, NaV1.3 is enriched to both dividing cell types and newly born migrating neurons [2101].

Nav1.3 channels are abundantly expressed in neuronal tissues during embryonic and neonatal stages of development[46]. In the adult human central nervous system is widely expressed but is normally absent, or present at low levels, in adult peripheral nervous system. Axotomy or other forms of nerve damage lead to the reexpression of NaV1.3 and the associated beta-3 subunit in sensory neurons, but not in primary motor neurons [1395][1396].

Nav1.3-like immunoreactivity (-LI) neurons were found in the cerebral cortex, hippocampal formation, colliculi, and mesencephalic reticular formation. Na v 1.3-LI was observed in fiber tracts such as the corpus callosum, anterior commissure, corticofugal fibers, lateral lemniscus, and cerebellar peduncles. Na v 1.3-LI was found to be particularly intense in sensory nerve tracts such as the mesencephalic trigeminal tract, vestibulospinal tract, or spinal trigeminal tract. Na v 1.3-LI was abundant in white matter and the dorsal roots of the spinal cord. In the spinal cord grey matter, Na v 1.3-LI fibers terminate in the deep laminae of the dorsal horn and in the ventral horn. Na v 1.3-LI was found in motoneurons as well as in ventral roots. Hence Na v 1.3 is present at the protein level in the adult rat. [331]

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Mouse models:
SCN3A -/- : shows a normal response to neurophatic pain [1402]

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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]

The function of human Nav 1.3 K subtype, stably expressed in Chinese hamster ovary cells, changes when modulating subunits L1, L2 and L3 in the following way according to electrophysiological measurements: Without any L subunits, human Nav 1.3 form channels that inactivated rapidly (inactivation tau is around 0.5 ms at 0 mV) and almost completely by the end of 190ms-long depolarizations. Using an intracellular solution with aspartate as the main anion, the midpoint for channel activation is roughly -312 mV. The midpoint for inactivation, determined using 100 ms conditioning pulses, is around -347 mV. The time constant for repriming of inactivated channels at 380 mV was found to be around 6 ms. Coexpression of L1 or L3 did not affect inactivation time course or the voltage dependence of activation, but shifted the inactivation curve around 10 mV negative, and slowed the repriming rate approximately three-fold. L2 was not found to affect channel properties, either by itself or in combination with L1 or L3. [350]

The increase in Nav1.3 expression after nerve inury has been correlated with the appearance of a novel TTX-S current in injured DRG neurons, characterized by a more rapid recovery from inactivation (repriming) than that seen in the normal DRG. The phenotypic change in Nav1.3 expression and repriming kinetics is reversed by intrathecal delivery of glial cell derived neurotrophic factor (GDNF) and/or neurotrophic growth factor (NGF), which also abolishes the hyperalgesia and allodynia produced in a model of neuropathic pain [1394].



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).



Contributors: Rajnish Ranjan, Michael Schartner

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