Description: sodium channel, voltage-gated, type IV, alpha subunit
Gene: Scn4a
Alias: nav1.4, scn4a

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Nav1.4 is a transmembrane protein of 1836 amino acids with an 84% aa sequence similarity to other voltage gated sodium channels expressed in the CNS [2140] [878]. Nav1.4 is encoded by the gene scn4a and is primarily expressed in skeletal muscle cells and is responsible for the initiation of action potential in those tissues [817].

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scn4a, the gene encoding for Nav1.4, is located on chromosome 17 at position 23-25 (17q23-25) in humans and is composed of 24 exons [2140].

Species NCBI gene ID Chromosome Position
Human 6329 17 34364
Mouse 110880 11 48041
Rat 25722 10 49734

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No alternative splicing events have been reported in humans but some scn4a variants have been identified in other species (rats, mouse, zebrafish) [2140] [2141].

Species NCBI accession Length (nt)
Human NM_000334.4 7805
Mouse NM_133199.2 6598
Rat NM_013178.2 6959

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Protein Isoforms

Nav1.4 is a glycosylated transmembrane protein of 1836 amino acids with a molecular weight of around 260 kDa [2140]. The amino acid sequence of the protein has 84% similarity to other voltage gated sodium channels expressed in the CNS [2140] [878].

Species Uniprot ID Length (aa)
Human P35499 1836
Mouse Q9ER60 1841
Rat P15390 1840


Length (nt)
Length (aa)

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Post-Translational Modifications

Like most mammalian proteins, Nav1.4 is subject to a series of post translational modifications (PTM).
Glycosylation can have a large impact on the gating properties of Nav1.4. N­-linked glycans and O­-linked glycans are often terminated by sialic acids, whose negative charge has been shown to shift the voltage dependence of activation and inactivation toward hyperpolarized potentials. This results in enhanced rates of fast inactivation, and reduced rates of recovery from fast inactivation [2142]
Phosphorylation can also induce a negative shift in the voltage dependence of inactivation for Nav1.4. Phosphorylation by PKC was shown to reduce peak Na+ currents by approximately 90%. This resulted in a -15 mV shift in the midpoint of steady-state inactivation and caused a slight speeding of inactivation [2143]
Reactive oxygen species (ROS) have also been implicated in the regulation of Nav1.4 activity. For example, Chloramine-T is a specific oxidant to sulphur-containing residues and can alter protein function through the oxidation of methionine residues. Chloramine-T has been found to remove more than 50% of Nav1.4 inactivation, with negligible impact on current activation [2144].
As Nav1.4 does not contain a PY motif, it is not targeted for ubiquitination. Instead, degradation is thought to occur via an alternative process that has yet to be elucidated [2145].


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Visual Representation of Nav1.4 Structure
Methodology for visual representation of structure available here

Like all voltage gated sodium channels, Nav1.4 is made up of a single protein comprised of 4 homologous domains (DI-DIV). Each domain is made up of 6 transmembrane subunits (S1-S6). 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 Nav1.4 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. Nav1.4 then returns to its resting state following the hyperpolarization of the cell membrane [2115].
The structure of human Nav1.4, in complex with Navβ1, was resolved via cryo-electron microscopy, giving us a detailed insight to the structural features of Nav1.4. Structural resolution of the ion channel highlighted certain features such as an asymmetric selectivity filter (narrowest part of the open channel pore) and an up conformation for voltage sensing domains 1-4, as well as confirmed the structural basis for fast inactivation [2146].

The approximative size/surface of Nav1.4 can be determined via the resolved or predicted structures.

Nav1.4 Predicted AlphaFold Size

Species Area (Å2) Ref Link
Human 11200.99254 hNav1.4 AlphaFold
Mouse 9868.680196 mNav1.4 AlphaFold
Rat 11566.72567 rNav1.4 AlphaFold

Methodology for AlphaFold size prediction and Disclaimer available here

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The electrophysiological properties of Nav1.4 are similar to those of the CNS channels (Nav 1.1, 1.2, 1.3, 1.6) [881].

Nav1.4 activates rapidly in response to depolarization and conducts a large inward Na+ current, driving the rapid upstroke of the action potential [2147]. Fast inactivation quickly kicks in following the channel opening, with the protein returning to its resting state after repolarization. Like other voltage gated sodium channels, upon prolonged depolarization, Nav1.4 channels progressively enter the slow inactivation (SI) state from which they are also slow to recover. In Nav1.4, this SI mechanisms are thought to be controlled by the immobilization of the voltage sensing domains following a prolonged depolarization [2148].

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Single Channel Unitary Conductance

Single channel unitary conductance is determined experimentally.
For Nav1.4, there have been recordings of single channel unitary conductance values with some degree of variance between experiments:

  • 24.9 pS - cRNA-injected Xenopus oocytes [2149]
  • 52 pS - cRNA injected Xenopus oocytes [2150]
  • 17.6 ± 0.2 pS - HEK [2151]
  • 22 pS - HEK [2152]


A single kinetic model for all human voltage-gated sodium channels (Balbi et al, 2017)
Origin : HEK cells   |   Recording temperature: RT
Temperature dependence: Q10   |   Formalism: Markov
States: C1, C2, O1, O2, I1, I2   |   Implementation: NEURON
Simulation (Nav14_a.mod):
Nav1.4 Balbi 2017

Membrane Systems Group 2022
Origin : Mouse scn4a   |   Host cell: CHO
Recording temperature: 25 C   |   Formalism: Hodgkin-Huxley
Gates: m, h   |   Implementation: NEURON
Simulation (Nav14__mCHO25c.mod):

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Expression and Distribution

Tissue and cellular

Nav1.4 is predominantly expressed in skeletal muscles [2153] [2117].
Within skeletal muscles, Nav1.4 is expressed in the plasma membranes of both the transverse tubules and the sarcolemma [2147]. The distribution within these muscular tissues also varies, with the density of Nav1.4 being around 20 times higher at the neuromuscular junction (NMJ). This is a result of local mRNA accumulation, which ensures the proper transmission of the motoneuron action potential to the muscle fiber [2140] [2147].


In rodents, scn4a expression increases just after birth [2140]. However, Nav1.4 expression is relatively low in rat neonatal skeleton muscles but highly expressed in adult rat skeletal muscles [881].

Expression modulation

Androgens may also play a role in the regulation of scn4a expression as mice with genes for modified androgens have been shown to have decreased scn4a expression levels. These mice also eventually die as a result of their neuro-muscular condition. Further research is needed to definitively confirm the role of androgens in scn4a expression and the exact molecular mechanisms of interaction [2158].

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CNS Sub-cellular Distribution

As Nav1.4 is predominantly expressed in muscle cells, their CNS sub-cellular distribution has not yet been characterized.

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Muscle Action Potential Initiator

Given its location, Nav1.4 is responsible for almost all of the inward Na+ current that generates the action potential in skeletal muscles, leading to muscle contraction [2147].

The crucial role of Nav1.4 in muscular action potential generation is highlighted by the numerous channelopathies that arise when the channel is deregulated. Mutations in Nav1.4 disrupt channel activity by impairing either fast and/or slow inactivation, or voltage-gating mechanism, resulting in pathologically enhanced or reduced muscle excitability. Known Nav1.4 channelopathies include [2154] [2147]:

  • Congenital myasthenic syndrome
  • Congenital myopathy with hypotonia
  • Hyperkalaemic periodic paralysis
  • Hypokalaemic periodic paralysis
  • Normokalemic Periodic Paralysis
  • Paramyotonia congenita
  • Potassium-aggravated myotonia
  • Sodium channel myotonia
  • Rhabdomyolysis [2155]

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Nav1.4 may interact with β subunits through specific binding sites. To date, evidence of only interactions with Navβ1 and Navβ4 has been identified.

[Nav1.4] [Navβ1] co-expression impacts both fast and slow inactivation compared to Nav1.4 expression alone. Fast inactivation is mildly disrupted with a 5 mV rightward shift. Following a 30 second depolarization, the voltage dependence of slow inactivation is shifted to the right (depolarized) and channel recovery is faster [2156].
[Nav1.4] [Navβ4] co-expression has been shown to lead to a modest negative shift in the voltage dependence of activation [406]. However, given the limited research on Nav1.4 and Navβ interactions, aside from Navβ1, further research is needed to determine the full extent of the role of Navβ on the channel.

There is clear evidence that the gating regulation and expression of Nav subunits relies on a variety of accessory and regulatory proteins. Despite this understanding, very little is known about proteins that interact with Nav1.4. However, some interactions, with Ankyrin-G, syntrophin, and Calmodulin (CaM), have been observed [2140].
Calmodulin is a small ubiquitous eukaryotic Ca2+-sensing regulatory protein. CaM can induce changes in target proteins via its binding to them and in response to changes in calcium concentration. Association with CaM is essential for the functional expression of Nav1.4. Disruptions of the interaction lead to a 99% reduction in Nav1.4 current amplitude [53]. Ca2+-sensing properties means that its activity can also be modulated based off of Ca2+ concentrations. Indeed, NaV1.4 exhibits a unique CaM mediated Ca2+-dependent inactivation (CDI). Under increased [Ca2+] levels, bulk Na+ current is reduced by approximately 30% [2157].

Nav1.4 channels are sensitive to nanomolar concentrations of tetrodotoxin (TTX), like the CNS channels. They are also sensitive to nanomolar concentrations of μ-conotoxin, which specifically interacts with Nav1.4 [881]

For additional resources on potential drug and compound interactions:

  • Known and predicted drug interactions with Nav1.4
  • Known and predicted animal toxin interactions with Nav1.4

- History


Loussouarn G et al. Physiological and Pathophysiological Insights of Nav1.4 and Nav1.5 Comparison.
Front Pharmacol, 2015, 6 (314).


Goldin AL et al. Nomenclature of voltage-gated sodium channels.
Neuron, 2000 Nov , 28 (365-8).

Bendahhou S et al. Serine-1321-independent regulation of the mu 1 adult skeletal muscle Na+ channel by protein kinase C.
Proc. Natl. Acad. Sci. U.S.A., 1995 Dec 19 , 92 (12003-7).

Kassmann M et al. Oxidation of multiple methionine residues impairs rapid sodium channel inactivation.
Pflugers Arch., 2008 Sep , 456 (1085-95).

Pei Z et al. Posttranslational Modification of Sodium Channels.
Handb Exp Pharmacol, 2018, 246 (101-124).


Goldin AL Diversity of mammalian voltage-gated sodium channels.
Ann. N. Y. Acad. Sci., 1999 Apr 30 , 868 (38-50).

Cannon SC Sodium Channelopathies of Skeletal Muscle.
Handb Exp Pharmacol, 2018, 246 (309-330).

Chahine M et al. Functional expression and properties of the human skeletal muscle sodium channel.
Pflugers Arch., 1994 May , 427 (136-42).

Carle T et al. Gating defects of a novel Na+ channel mutant causing hypokalemic periodic paralysis.
Biochem. Biophys. Res. Commun., 2006 Sep 22 , 348 (653-61).

Simkin D et al. Mechanisms underlying a life-threatening skeletal muscle Na+ channel disorder.
J. Physiol. (Lond.), 2011 Jul 1 , 589 (3115-24).

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

Mantegazza M et al. Sodium channelopathies of skeletal muscle and brain.
Physiol Rev, 20211001, 101 (1633-1689).


Ben-Johny M et al. Conservation of Ca(2+)/Calmodulin Regulation across Na and Ca(2+) Channels.
Cell, 2014 Jun 19 , 157 (1657-70).

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



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