Affinage

SCN4A

Sodium channel protein type 4 subunit alpha · UniProt P35499

Length
1836 aa
Mass
208.1 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SCN4A encodes Nav1.4, the principal voltage-gated sodium channel α-subunit of adult skeletal muscle, responsible for initiating and propagating action potentials required for muscle contraction. The channel undergoes mechanistically coupled fast inactivation (mediated by the DIII–IV IFM motif) and slow inactivation (regulated by the II–III loop at Ser-906 and modulated by the β1 subunit's extracellular Ig domain), with calmodulin constitutively bound at the C-terminal IQ motif to regulate inactivation voltage-dependence and surface trafficking, and sialic acids on N- and O-glycans electrostatically tuning gating (PMID:8968581, PMID:18270170, PMID:12898257, PMID:18941776, PMID:25450184). Gain-of-function mutations that enhance activation window currents or impair inactivation cause myotonia or periodic paralysis, while loss-of-function mutations—including null alleles that are lethal in homozygous knockout mice—reduce action potential amplitude causing congenital myasthenic syndrome or myopathy; specific S4 arginine substitutions create pathological gating pore currents that depolarize resting membrane potential and trigger hypokalemic paralytic attacks (PMID:19015483, PMID:26700687, PMID:27048647, PMID:18824591, PMID:21881211). The inner vestibule formed by D1-S6 (N434), D3-S6 (L1280, F1278), and D4-S6 residues constitutes overlapping binding sites for local anesthetics, veratridine, and pyrethroids (PMID:12626674, PMID:12761351, PMID:11502895).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1996 High

    Establishing that fast and slow inactivation are mechanistically coupled resolved whether these were independent processes: removing fast inactivation (IFM→QQQ) paradoxically accelerated slow inactivation, showing that fast inactivation normally reduces slow inactivation probability.

    Evidence On-cell macropatch recording from Xenopus oocytes co-expressing Nav1.4 α and β1 with IFM motif mutagenesis

    PMID:8968581

    Open questions at the time
    • Structural basis for the coupling between the DIII–IV loop and the slow inactivation gate was not resolved
    • Whether coupling is direct or allosteric through the pore domain was not determined
  2. 2001 High

    Mapping neurotoxin and insecticide binding sites on the D3-S6 helix revealed that pyrethroid (deltamethrin) and batrachotoxin receptors occupy opposite faces of the same helix, establishing domain-specific pharmacological topology of the inner pore.

    Evidence Systematic site-directed mutagenesis of D3-S6 residues with voltage clamp in HEK cells using deltamethrin and batrachotoxin

    PMID:11502895

    Open questions at the time
    • No structural visualization of toxin-bound conformations
    • Contributions of other S6 segments to pyrethroid sensitivity were not fully addressed
  3. 2003 High

    Multiple studies converged to define the inner vestibule pharmacology and disease-linked gating mechanisms: veratridine and local anesthetics share overlapping binding determinants at N434/L1280/F1579; L1280 directly contacts bupivacaine enantiomers; S906 in the II–III loop tunes slow inactivation; and the V1442E mutation demonstrated that enhanced inactivation causes myasthenic loss-of-function while P1158S showed temperature-dependent gain-of-function causing cold-induced paralysis.

    Evidence Site-directed mutagenesis with voltage clamp in HEK cells; pharmacological characterization with VTD, bupivacaine enantiomers; computer simulations of mutant gating at different temperatures

    PMID:12626674 PMID:12761351 PMID:12766226 PMID:12898257 PMID:14557559

    Open questions at the time
    • No high-resolution structure of the Nav1.4 inner vestibule to confirm residue orientations
    • Slow inactivation structural gate identity beyond S906 contribution remained unknown
    • Temperature-dependence mechanism of P1158S at the atomic level was not resolved
  4. 2006 Medium

    The β1 subunit's role in gating was linked to sialylation-dependent surface charge: β1 potentiates extracellular Ca²⁺-dependent shifts in activation through its highly sialylated extracellular domain, establishing that glycosylation of auxiliary subunits tunes voltage sensing.

    Evidence Whole-cell patch clamp of Nav1.4 ± β1 in HEK293 cells with Ca²⁺ titration

    PMID:16432696

    Open questions at the time
    • Identity of specific sialylated residues on β1 responsible for the effect was not determined
    • Whether β1 sialylation affects slow inactivation coupling was not tested
  5. 2008 High

    Three advances reshaped understanding of Nav1.4 regulation and disease: calmodulin was established as a constitutive ancillary subunit binding the IQ motif to modulate inactivation and trafficking; the β1 Ig domain was shown to independently impede slow inactivation; and HypoPP-associated R666 mutations were demonstrated to create gating pore currents—anomalous cation leak through the voltage sensor domain—as the molecular basis of hypokalemic paralysis.

    Evidence FRET and CaM-fusion constructs in mammalian cells; β1 domain-deletion mutagenesis with patch clamp; voltage clamp of R666 mutants in heterologous cells with barrier model fitting

    PMID:18270170 PMID:18824591 PMID:18941776 PMID:19015483

    Open questions at the time
    • Whether CaM binding is Ca²⁺-dependent at physiological [Ca²⁺] in muscle fibers was unclear
    • In vivo demonstration of gating pore currents had not yet been achieved
    • Whether β1 Ig domain contacts the pore or acts allosterically on slow inactivation was not resolved
  6. 2011 High

    Two findings extended the gating pore and glycosylation mechanisms: knock-in mice carrying R669H validated that gating pore currents cause paralytic attacks under low-K⁺ challenge in vivo, with concurrent loss-of-function reducing AP amplitude; and polysialic acid versus sialic acid were shown to shift gating in opposite directions through electrostatic mechanisms.

    Evidence Knock-in mouse model with ex vivo muscle recordings and pharmacological challenge; Nav1.4 expression in CHO sialylation-deficient mutant lines with patch clamp

    PMID:21606664 PMID:21881211

    Open questions at the time
    • Mechanism by which Na⁺/K⁺-ATPase modulates recovery from paralysis was not fully dissected
    • Whether polySia is present on native muscle Nav1.4 at physiological levels was not confirmed
  7. 2012 High

    Histidine-scanning of S4 arginines across all four voltage-sensor domains revealed domain-specific resting-state topologies: DI, DII, and DIII S4 segments are accessible to proton conduction at rest, while DIV has a longer hydrophobic septum preventing gating pore formation, explaining why disease-causing gating pore mutations cluster in DI–DIII.

    Evidence Arginine-to-histidine mutagenesis in all four domains with proton current measurements and molecular dynamics simulations

    PMID:23134726

    Open questions at the time
    • No experimental structure of the resting-state VSD to directly validate the MD models
    • Whether the DIV septum length difference is conserved across Nav isoforms was not tested
  8. 2013 Medium

    The C-terminal EF-hand-like region was identified as a Ca²⁺-sensitive regulator of inactivation: the myotonia mutation F1705I rendered inactivation Ca²⁺-dependent (unlike wild-type human Nav1.4), with species differences in the EFL explaining divergent Ca²⁺ sensitivity between human and rat channels.

    Evidence Patch clamp of wild-type and mutant human/rat Nav1.4 with Ca²⁺ and CaM manipulation in heterologous cells

    PMID:24324661

    Open questions at the time
    • Whether native muscle fibers show EFL-mediated Ca²⁺-dependent inactivation changes was not demonstrated
    • Structural basis for species-specific Ca²⁺ sensitivity in the EFL was not resolved
  9. 2014 Medium

    Both N-glycan and O-glycan sialylation within the D1S5–S6 linker were shown to contribute comparably to electrostatic gating modulation, and a knock-in mouse model revealed that Nav1.4 dysfunction activates AMPK and produces systemic metabolic consequences beyond excitability defects.

    Evidence Nav1.4 expression in CHO lines with selective glycosylation deficiencies; ENU-mutagenesis knock-in mouse with metabolic characterization

    PMID:25348630 PMID:25450184

    Open questions at the time
    • Whether AMPK activation is a direct consequence of reduced muscle activity or an independent signaling pathway was not resolved
    • Specific O-glycosylation sites on D1S5–S6 linker were not mapped
  10. 2015 High

    The phenotypic spectrum of SCN4A was extended in both directions: recessive null/hypomorphic mutations were shown to cause severe congenital myopathy and fetal hypokinesia through complete loss of channel function, while Nav1.4 knockout mice confirmed that homozygous loss is lethal and heterozygous loss produces latent myasthenia without compensatory Nav1.5 upregulation; separately, a pore mutation (G1537S) causing altered ion selectivity segregated with essential tremor and epilepsy.

    Evidence Whole-cell patch clamp of multiple loss-of-function mutants in HEK293 cells; exon-12-deletion knockout mice with ex vivo electrophysiology; whole-exome sequencing with functional characterization of G1537S

    PMID:26427606 PMID:26700687 PMID:27048647

    Open questions at the time
    • Whether partial Nav1.4 loss-of-function is compensated by other sodium channels in specific muscle types was not tested
    • Brain expression of Nav1.4 and its contribution to tremor/epilepsy require direct electrophysiological confirmation
  11. 2020 Medium

    Further mechanistic refinement showed that EF-hand-like motif deletions/substitutions impair fast inactivation causing nondystrophic myotonia, and that Nav1.4 mutations can generate resurgent sodium currents (in the presence of Navβ4 peptide) providing a mechanism for repetitive firing in myotonia.

    Evidence Patch clamp of EFL mutants in heterologous cells; V445M mutant co-expressed with Navβ4 peptide in CHO cells analyzing resurgent currents

    PMID:32129495 PMID:32276507

    Open questions at the time
    • Whether Navβ4-mediated resurgent currents occur in native skeletal muscle fibers is not established
    • Structure of the EFL in the context of the full-length channel is not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive biophysical characterization, a high-resolution structure of the full-length human Nav1.4 in multiple gating states with bound CaM and β subunits is lacking; the structural basis of slow inactivation, the mechanism coupling EFL Ca²⁺ sensing to the inactivation gate, and whether Nav1.4 has functional roles in non-skeletal muscle tissues (heart, brain) remain unresolved.
  • No cryo-EM structure of human Nav1.4 in the slow-inactivated state
  • Mechanism linking gating pore currents to downstream metabolic (AMPK) activation is unknown
  • Functional significance of SCN4A expression in cardiac tissue is not established by direct electrophysiology

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 7 GO:0140299 molecular sensor activity 2
Localization
GO:0005886 plasma membrane 7
Pathway
R-HSA-1643685 Disease 6 R-HSA-112316 Neuronal System 5 R-HSA-397014 Muscle contraction 3
Partners
CALM1HCN2SCN1BSCN4B

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 The V1442E mutation in SCN4A (Nav1.4) markedly enhances fast inactivation close to the resting potential and causes enhanced use-dependent inactivation on high-frequency stimulation, resulting in failure to generate action potentials and a myasthenic phenotype; demonstrated by expression of genetically engineered channels in HEK cells. Whole-cell patch clamp in HEK293 cells expressing mutant Nav1.4 channels; mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 12766226
1996 Fast and slow inactivation of Skm1 (Nav1.4) are mechanistically coupled: abolishing fast inactivation by IFM1303QQQ mutation in the DIII-IV inactivation loop allows slow inactivation to occur more quickly and completely, demonstrating that fast inactivation reduces the probability of subsequent slow inactivation; slow inactivation remains intact even when fast inactivation is removed. On-cell macropatch recording from Xenopus oocytes co-expressing Skm1 alpha and beta1 subunits; site-directed mutagenesis of IFM motif Biophysical journal High 8968581
2008 Calmodulin (CaM) associates constitutively with the C-terminus of Nav1.4 via the IQ motif in a conformation-independent manner (shown by FRET in mammalian cells). Mutation of the IQ motif reduces surface expression of Nav1.4 and eliminates CaM modulation of gating. A single CaM fused to the C-terminus is sufficient to modulate Na+ current and shift the voltage dependence of inactivation, establishing CaM as an ancillary subunit that facilitates channel trafficking and regulates inactivation. FRET, mutagenesis of IQ motif, CaM-fusion constructs with variable glycine linkers, whole-cell patch clamp in mammalian cells The Journal of general physiology High 18270170
2012 Single histidine substitutions of S4 arginine residues in each voltage sensor domain (VSD) of Nav1.4 produce proton leak currents (gating pore currents) that report the resting-state position of each S4 segment. DI/R1H, DII/R1H, and DIII/R2H produce leak currents indicating accessible positions, while DIV S4 residues do not produce appreciable proton currents due to a longer hydrophobic septum that prevents water from forming a proton conduction pathway, revealing domain-specific resting state topologies. Site-directed mutagenesis with histidine substitutions, whole-cell patch clamp proton current measurements, molecular dynamics simulations of resting-state VSD structures Proceedings of the National Academy of Sciences of the United States of America High 23134726
2008 Three HypoPP-associated missense mutations at R666 (R672 in human) in the domain II S4 segment of Nav1.4 create accessory ionic permeation pathways (gating pore currents) permeable to K+ and Na+, exhibiting inward rectification and saturation consistent with a barrier model with a single cation binding site near the external surface; R666H creates a proton-selective gating pore. These low-amplitude inward currents at resting potential are proposed to cause pathological depolarization during paralytic attacks. Whole-cell voltage clamp of mutant Nav1.4 channels expressed in heterologous system; barrier model fitting The Journal of general physiology High 18824591
2011 Knock-in mice carrying the NaV1.4-R669H (ortholog of human R672H) HypoPP mutation show transient loss of muscle excitability and weakness under low-K+ challenge. Affected fibers exhibit an anomalous inward current at hyperpolarized potentials (gating pore current) consistent with a leaky voltage sensor as the trigger for paralytic attacks, plus reduced action potential amplitude indicating concurrent loss-of-function. Recovery is sensitive to Na+/K+-ATPase inhibition by ouabain. Knock-in mouse model; ex vivo muscle fiber recordings; low-K+ and high-K+ challenge; pharmacological ouabain treatment The Journal of clinical investigation High 21881211
2015 Recessive loss-of-function SCN4A mutations causing fully non-functional or reduced-activity Nav1.4 channels are sufficient to cause severe congenital myopathy and fetal hypokinesia. In vitro functional assessment in HEK293 cells demonstrated that each mutation either abolished or markedly reduced channel activity, showing that different degrees of loss-of-function attenuate the skeletal muscle action potential amplitude below the threshold needed for normal muscle contraction. Whole exome sequencing; whole-cell patch clamp in HEK293 cells expressing mutant Nav1.4; clinical correlation Brain : a journal of neurology High 26700687
2016 Heterozygous Nav1.4 null mice (exon 12 deletion) have half-normal sodium current density in skeletal muscle, no compensatory upregulation of fetal Nav1.5, and manifest latent myasthenia with a right-shifted force-stimulus relation without periodic paralysis. Homozygous null mice die by postnatal day 2, establishing that Nav1.4 is essential for postnatal muscle excitability. Knockout mouse model (exon 12 deletion); ex vivo muscle electrophysiology; Western blot for Nav1.5 Brain : a journal of neurology High 27048647
2003 Veratridine (VTD) binds within the inner vestibule of Nav1.4 at a site that overlaps extensively with the local anesthetic receptor (residues N434 in D1-S6, L1280 in D3-S6, F1579 in D4-S6). Triple cysteine substitution (N434C/L1280C/F1579C) abolishes VTD-induced persistent opening but converts VTD into a high-affinity channel blocker, indicating receptor-bound VTD stabilizes the open conformation and reduces unitary conductance from the inner vestibule. Site-directed mutagenesis; whole-cell voltage clamp of mutant Nav1.4 in HEK cells; pharmacological characterization with VTD, amitriptyline, bupivacaine The Journal of physiology High 12626674
2003 Residue L1280 in D3-S6 of Nav1.4 directly interacts with bupivacaine enantiomers in the inactivated channel state. Substitutions at L1280 with aromatic groups increase inactivated-state block, while positively charged substitutions decrease it; several substitutions (L1280E, L1280N, L1280Q, L1280R) confer stereoselectivity for R(+)-bupivacaine, the opposite of the N434R effect in D1-S6, indicating L1280 and N434 face each other in the pore. Site-directed mutagenesis; whole-cell voltage clamp of mutant Nav1.4 in HEK293T cells; pharmacological analysis with bupivacaine enantiomers Molecular pharmacology High 12761351
2001 A phenylalanine residue at D3-S6 position F1278 of Nav1.4 is critical for pyrethroid (deltamethrin) action. The double mutant I687M/F1278I renders channels greatly resistant to deltamethrin while retaining batrachotoxin (BTX) sensitivity, and the adjacent residues S1276 and L1280 are critical for BTX action, placing the deltamethrin and BTX receptors on opposite surfaces of the D3-S6 helix. Site-directed mutagenesis; whole-cell voltage clamp in HEK cells; pharmacological characterization with deltamethrin and batrachotoxin Molecular pharmacology High 11502895
2006 The beta1 subunit modulates Nav1.4 gating by increasing negative surface charge density near the voltage-sensing machinery. Co-expression of beta1 potentiates the shift of half-activation potentials induced by changes in extracellular Ca2+ concentration without affecting Ca2+ binding to the open or closed pore, attributable to the highly sialylated nature of the beta1 subunit. Whole-cell patch clamp of Nav1.4 ± beta1 subunit in HEK293 cells; extracellular Ca2+ titration experiments Experimental brain research Medium 16432696
2008 Co-expression of the beta1 subunit impedes slow inactivation of Nav1.4 in HEK cells, right-shifting the voltage dependence and hastening recovery from slow inactivation. This effect depends on the extracellular Ig-like domain of beta1 but is independent of its intracellular C-terminal tail and is independent of the negative coupling between fast and slow inactivation. Whole-cell patch clamp of Nav1.4 ± beta1 in HEK cells; beta1 domain deletion mutants Pflugers Archiv : European journal of physiology Medium 18941776
2011 Polysialic acid (polySia) and sialic acid (Sia) attached to Nav1.4 differentially regulate channel gating: loss of Sia shifts voltage-dependent activation and steady-state inactivation to more depolarized potentials and affects recovery from fast inactivation; loss of polySia shifts these parameters in the opposite direction. Both modifications act through electrostatic mechanisms at the channel surface. Expression of Nav1.4 in CHO cell mutants deficient in sialylation or polysialylation; whole-cell patch clamp; immunoblot gel shift analysis Pharmacology Medium 21606664
2014 Sialic acids attached to both N-glycans and O-glycans within the Nav1.4 D1S5-S6 linker modulate channel gating through electrostatic mechanisms, with similar relative contributions from each glycan type. Preventing either N-glycan or O-glycan sialylation shifts all voltage-dependent parameters to intermediate values between full and no sialylation. Expression of Nav1.4 in CHO cell lines with selective loss of N-glycan or O-glycan sialylation; whole-cell patch clamp; immunoblot gel shift Biochimica et biophysica acta Medium 25450184
2003 The P1158S mutation in SCN4A (Nav1.4) causes hyperpolarizing shifts in voltage dependence of both activation and inactivation at cold temperature and slows inactivation rate, mechanistically explaining both cold-induced paralysis (at low potassium) and myotonia (at normal potassium) as demonstrated by patch clamp and computer simulation. Amphotericin B perforated patch clamp at 22°C and 32°C in tsA201 cells; computer simulation incorporating mutant gating parameters Neurology Medium 14557559
2003 The II-III loop of Nav1.4 (residue Ser-906) is important for slow inactivation: substitutions at S906 with varying hydrophobicity systematically shift steady-state slow inactivation voltage dependence and alter recovery kinetics, with hydrophobic residues enhancing and polar residues destabilizing the slow-inactivated state. Site-directed mutagenesis; whole-cell patch clamp in heterologous expression system Pflugers Archiv : European journal of physiology Medium 12898257
2013 Ca2+ and calmodulin regulate Nav1.4 inactivation gating through the EF-hand-like (EFL) region of the C-terminus. The myotonia mutation F1705I in human Nav1.4 renders inactivation gating Ca2+-sensitive (unlike wild-type human Nav1.4), slows INa decay in a Ca2+-dependent manner, and shifts the V1/2 of inactivation with CaM overexpression, with species differences in Ca2+ sensitivity attributable to sequence divergence in the EFL region. Whole-cell patch clamp of wild-type and mutant human and rat Nav1.4 in heterologous cells; Ca2+ and CaM manipulation experiments; mutagenesis PloS one Medium 24324661
2020 Mutations in the EF hand-like motif of the Nav1.4 C-terminus (E1702del, E1702K, T1700_E1703del) impair fast inactivation as demonstrated by whole-cell patch clamp, establishing that the C-terminal EF hand-like region is important for regulating fast inactivation and that its disruption causes nondystrophic myotonia. Whole-cell patch clamp recording of heterologously expressed mutant Nav1.4 channels Muscle & nerve Medium 32129495
2008 The novel I141V mutation in the first transmembrane segment (S1) of domain I of Nav1.4 causes a -12.9 mV hyperpolarizing shift in voltage dependence of activation (approximately twofold increase in window current) and a -8.7 mV shift of slow inactivation with accelerated entry, establishing gain-of-function in activation as the mechanism of myotonia and enhanced slow inactivation as a protective factor against depolarization-induced paralysis. Whole-cell patch clamp of mutant Nav1.4 in HEK293 cells Neurology Medium 19015483
2015 The recessive p.R1454W mutation in SCN4A causes enhanced fast and slow inactivation, slower recovery from inactivated states, and frequency-dependent regulation of Nav1.4, resulting in loss-of-function and a combined myasthenic syndrome/periodic paralysis phenotype by decreasing channel availability for action potential generation at the neuromuscular junction. Whole-cell patch clamp in mammalian cell background (heterologous expression); genetic testing Neurology Medium 26659129
2008 Adenoviral overexpression of skeletal muscle Nav1.4 (SkM1) in depolarized epicardial border zones of infarcted canine myocardium restores action potential upstroke velocity (Vmax) at depolarized membrane potentials and reduces inducible sustained ventricular tachyarrhythmia, because Nav1.4 activates at more negative potentials than cardiac SCN5A and thus remains functional in partially depolarized tissue. Adenoviral gene transfer; in vivo epicardial mapping and programmed stimulation; in vitro microelectrode studies; immunohistochemistry; computational modeling Circulation High 19103989
2010 Adenoviral expression of Nav1.4 (SkM1) in murine ventricular myocardium increased action potential Vmax and conduction velocity under hyperkalemic and ischemic conditions, and reduced incidence and duration of reperfusion ventricular tachycardia, demonstrating that Nav1.4's more negative activation threshold preserves conduction when cardiac Nav1.5 is inactivated by depolarization. Adenoviral injection; in vivo coronary ligation/reperfusion model; ex vivo multisite microelectrode mapping; Western blot; simulated ischemia (elevated K+, acidosis) Cardiovascular research High 20823275
2013 Co-injection of HCN2 and Nav1.4 (SkM1) adenoviral constructs into left bundle branches of AV-blocked dogs produces stable biological pacemaker activity at physiological rates. Nav1.4 contributes by hyperpolarizing the action potential threshold in isolated LV preparations, improving the efficiency of HCN2-driven spontaneous depolarizations and allowing stable autonomous pacing without electronic backup. Adenoviral gene transfer in vivo; in vivo Holter/ECG monitoring; in vitro isolated LV action potential recordings; AP threshold measurements Journal of the American College of Cardiology Medium 23395072
2014 A novel SCN4A mutation (p.I588V) in a patient with myotonia and periodic paralysis causes metabolic abnormalities in a mouse knock-in model (draggen mice, equivalent mutation p.I582V), including AMPK activation associated with immobility attacks, revealing that Nav1.4 dysfunction has downstream systemic metabolic consequences beyond direct electrophysiological effects. N-ethyl-N-nitrosourea mutagenesis mouse model; in vivo metabolic and behavioral characterization; AMPK activity measurements Brain : a journal of neurology Medium 25348630
2020 The V445M missense mutation in Nav1.4 causes a hyperpolarizing shift of activation and inactivation curves with increased window current, and when co-expressed with the Navβ4 peptide, generates larger resurgent Na+ currents with a delayed time to peak compared to wild-type, providing a mechanism for repetitive firing and recurrent myotonia. Whole-cell patch clamp in CHO cells expressing mutant Nav1.4 ± Navβ4 peptide; analysis of transient, persistent, and resurgent Na+ currents International journal of molecular sciences Medium 32276507
2015 The SCN4A pore mutation p.Gly1537Ser segregates with essential tremor and epilepsy susceptibility in a large Spanish family. Patch clamp analysis revealed that this mutation produces more rapid kinetics at near-threshold potentials, alters ion selectivity to allow K+ and NH4+ conductance through the pore, with the aberrant cation flux proposed to contribute to tremor and increased seizure susceptibility. Whole exome sequencing; site-directed mutagenesis; patch clamp electrophysiology; mouse and human brain expression analysis Human molecular genetics Medium 26427606
2015 The SCN4A p.P72L mutation (in the cytoplasmic N-terminus of Nav1.4, a region with no previously reported mutations) causes a -5 mV hyperpolarizing shift of the voltage dependence of activation, increasing cell excitability and potentially enhancing the myotonic phenotype of a DM2 patient carrying this variant. Whole-cell voltage-clamp analysis in tsA201 cells expressing mutant Nav1.4 Neuromuscular disorders : NMD Low 25660391
2003 The paramyotonia congenita SCN4A mutation R1448C is expressed in normal human heart (SCN4A alpha-subunit mRNA detected by RT-PCR), and affected family members show repolarization abnormalities on ECG, establishing that SCN4A is expressed in cardiac tissue and may contribute to cardiac electrophysiology. RT-PCR of human heart tissue; clinical ECG analysis in mutation carriers Neurology Low 12552059

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. Brain : a journal of neurology 159 11353725
2003 Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proceedings of the National Academy of Sciences of the United States of America 147 12766226
1996 Interaction between fast and slow inactivation in Skm1 sodium channels. Biophysical journal 114 8968581
2015 Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy. Brain : a journal of neurology 104 26700687
1993 A novel SCN4A mutation causing myotonia aggravated by cold and potassium. Human molecular genetics 97 8242056
2012 Gating pore currents and the resting state of Nav1.4 voltage sensor domains. Proceedings of the National Academy of Sciences of the United States of America 74 23134726
2010 Severe neonatal episodic laryngospasm due to de novo SCN4A mutations: a new treatable disorder. Neurology 71 20713951
2008 Epicardial border zone overexpression of skeletal muscle sodium channel SkM1 normalizes activation, preserves conduction, and suppresses ventricular arrhythmia: an in silico, in vivo, in vitro study. Circulation 69 19103989
2011 A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis. The Journal of clinical investigation 67 21881211
2008 Gating pore currents in DIIS4 mutations of NaV1.4 associated with periodic paralysis: saturation of ion flux and implications for disease pathogenesis. The Journal of general physiology 66 18824591
2018 Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study. Lancet (London, England) 65 29605429
2004 New mutations of SCN4A cause a potassium-sensitive normokalemic periodic paralysis. Neurology 65 15596759
2008 In tandem analysis of CLCN1 and SCN4A greatly enhances mutation detection in families with non-dystrophic myotonia. European journal of human genetics : EJHG 59 18337730
2008 Severe neonatal non-dystrophic myotonia secondary to a novel mutation of the voltage-gated sodium channel (SCN4A) gene. American journal of medical genetics. Part A 54 18203179
2015 A recessive Nav1.4 mutation underlies congenital myasthenic syndrome with periodic paralysis. Neurology 52 26659129
2013 HCN2/SkM1 gene transfer into canine left bundle branch induces stable, autonomically responsive biological pacing at physiological heart rates. Journal of the American College of Cardiology 52 23395072
2016 Physiological and Pathophysiological Insights of Nav1.4 and Nav1.5 Comparison. Frontiers in pharmacology 51 26834636
1997 Characterization of SKM1, a Saccharomyces cerevisiae gene encoding a novel Ste20/PAK-like protein kinase. Molecular microbiology 50 9044278
1992 Dinucleotide repeat polymorphisms at the SCN4A locus suggest allelic heterogeneity of hyperkalemic periodic paralysis and paramyotonia congenita. American journal of human genetics 49 1315122
2009 Clinical Diversity of SCN4A-Mutation-Associated Skeletal Muscle Sodium Channelopathy. Journal of clinical neurology (Seoul, Korea) 42 20076800
2015 SCN4A mutation as modifying factor of myotonic dystrophy type 2 phenotype. Neuromuscular disorders : NMD 41 25660391
2004 Absence of ion channels CACN1AS and SCN4A mutations in thyrotoxic hypokalemic periodic paralysis. Thyroid : official journal of the American Thyroid Association 41 15072700
2015 SCN4A pore mutation pathogenetically contributes to autosomal dominant essential tremor and may increase susceptibility to epilepsy. Human molecular genetics 39 26427606
2019 Metformin inhibits cell proliferation in SKM-1 cells via AMPK-mediated cell cycle arrest. Journal of pharmacological sciences 38 31744691
2015 Fucoidan inhibits proliferation of the SKM-1 acute myeloid leukaemia cell line via the activation of apoptotic pathways and production of reactive oxygen species. Molecular medicine reports 38 26324225
2008 Calmodulin regulation of Nav1.4 current: role of binding to the carboxyl terminus. The Journal of general physiology 36 18270170
2003 Cold induces shifts of voltage dependence in mutant SCN4A, causing hypokalemic periodic paralysis. Neurology 36 14557559
2013 Diagnosis and outcome of SCN4A-related severe neonatal episodic laryngospasm (SNEL): 2 new cases. Pediatrics 35 23958773
2003 Veratridine block of rat skeletal muscle Nav1.4 sodium channels in the inner vestibule. The Journal of physiology 35 12626674
1998 Salbutamol treatment in a patient with hyperkalaemic periodic paralysis due to a mutation in the skeletal muscle sodium channel gene (SCN4A). Journal of neurology, neurosurgery, and psychiatry 35 9703181
1995 The SKM-1 leukemic cell line established from a patient with progression to myelomonocytic leukemia in myelodysplastic syndrome (MDS)-contribution to better understanding of MDS. Leukemia & lymphoma 35 8580805
2014 Mutations in SCN4A: a rare but treatable cause of recurrent life-threatening laryngospasm. Pediatrics 34 25311598
2003 Paramyotonia congenita with an SCN4A mutation affecting cardiac repolarization. Neurology 34 12552059
1998 Linkage of malignant hyperthermia and hyperkalemic periodic paralysis to the adult skeletal muscle sodium channel (SCN4A) gene in a large pedigree. American journal of medical genetics 33 9508059
1994 Mutations in the muscle sodium channel gene (SCN4A) in 13 French families with hyperkalemic periodic paralysis and paramyotonia congenita: phenotype to genotype correlations and demonstration of the predominance of two mutations. European journal of human genetics : EJHG 33 8044656
2001 A phenylalanine residue at segment D3-S6 in Nav1.4 voltage-gated Na(+) channels is critical for pyrethroid action. Molecular pharmacology 32 11502895
2015 SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies. European journal of human genetics : EJHG 31 26036855
2003 Point mutations at L1280 in Nav1.4 channel D3-S6 modulate binding affinity and stereoselectivity of bupivacaine enantiomers. Molecular pharmacology 31 12761351
1995 Paramyotonia congenita without paralysis on exposure to cold: a novel mutation in the SCN4A gene (Val1293Ile). Neuroreport 30 8580427
2014 Mechanism of μ-conotoxin PIIIA binding to the voltage-gated Na+ channel NaV1.4. PloS one 29 24676211
2012 Antiproliferative and antitumor effects of azacitidine against the human myelodysplastic syndrome cell line SKM-1. Anticancer research 28 22399596
2010 Expression of skeletal muscle sodium channel (Nav1.4) or connexin32 prevents reperfusion arrhythmias in murine heart. Cardiovascular research 28 20823275
2003 Severe infantile hyperkalaemic periodic paralysis and paramyotonia congenita: broadening the clinical spectrum associated with the T704M mutation in SCN4A. Journal of neurology, neurosurgery, and psychiatry 28 12933953
2014 SPAG6 silencing inhibits the growth of the malignant myeloid cell lines SKM-1 and K562 via activating p53 and caspase activation-dependent apoptosis. International journal of oncology 26 25405588
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