Affinage

SCN10A

Sodium channel protein type 10 subunit alpha · UniProt Q9Y5Y9

Length
1956 aa
Mass
220.6 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SCN10A encodes Nav1.8, a tetrodotoxin-resistant, slowly inactivating voltage-gated sodium channel selectively expressed in primary sensory (DRG) neurons, where it amplifies excitability near the action-potential threshold and is specifically required for neuropathic, inflammatory, and visceral pain signaling (PMID:9839820, PMID:10393873, PMID:39378238). Dynamic-clamp analysis establishes that Nav1.8 open probability vastly exceeds that of Nav1.7 at threshold voltages and that reducing Nav1.8 conductance raises rheobase and damps subthreshold oscillations, defining its role as a threshold-amplifying conductance that cooperates functionally with Nav1.7 (PMID:39378238). Channel surface density and gating are tuned at multiple levels: an ER-retention RRR motif in the first intracellular loop limits surface expression and is masked by the β3 subunit, while β1 and β4 subunits reshape current density and gating (PMID:18782866, PMID:21562192); KIF5B kinesin binds the Nav1.8 N-terminus to drive anterograde axonal transport (PMID:24198377); calmodulin binds a C-terminal IQ motif to sustain current and limit frequency-dependent inhibition (PMID:16598065); and PKCε directly phosphorylates S1452 to potentiate currents and lower the activation threshold (PMID:22426212). Channel function is further modulated by PKA and PKC signaling (PMID:14657190), TNFα/TNFR1-driven upregulation (PMID:20638792), CXCL13/CXCR5/p38 signaling (PMID:27708397), and α2A-adrenergic Gi/o–cAMP–PKA inhibition (PMID:25761941), while NGF maintains its steady-state expression in sensory neurons (PMID:10036280). Gain-of-function mutations that impair inactivation (G1662S, T790A) increase β4-mediated resurgent currents and render DRG neurons hyperexcitable, producing painful small-fiber neuropathy (PMID:24006052, PMID:30617209). In the heart, Nav1.8 contributes to late sodium current and intracardiac neuronal firing (PMID:22723299, PMID:22723301), and an intronic enhancer within the SCN10A locus physically contacts the SCN5A promoter to control cardiac Nav1.5 expression and conduction, while a short cardiac SCN10A transcript driven from this enhancer-promoter augments Nav1.5 current and influences atrial conduction (PMID:22706305, PMID:24642470, PMID:33910361). Beyond its canonical conductance, Nav1.8 has a non-ionic role in keratinocytes, binding SOD2 to modulate ROS and inflammation (PMID:35952475).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 High

    Established that SCN10A encodes a bona fide tetrodotoxin-resistant sodium channel selectively expressed in sensory neurons, defining its candidate role in nociception.

    Evidence Molecular cloning from human lumbar DRG and heterologous expression in Xenopus oocytes with electrophysiology; mouse gene structure determined by genomic sequencing

    PMID:9143495 PMID:9839820

    Open questions at the time
    • Functional contribution to native pain pathways not yet tested in vivo
    • Regulation of cell-specific expression not resolved
  2. 1999 High

    Showed that Nav1.8 is specifically required for neuropathic, inflammatory, and visceral pain and that its expression is maintained by NGF and lost after axotomy, separating sensory regulation from transcription.

    Evidence Intrathecal antisense knockdown with mismatch controls in multiple rat pain models, in vivo NGF immunization, in situ hybridization, immunohistochemistry, and patch clamp

    PMID:10036280 PMID:10393873 PMID:11606657 PMID:11790477 PMID:9482802 PMID:9532581

    Open questions at the time
    • Molecular trafficking machinery for injury-induced redistribution unidentified
    • Channel-intrinsic biophysical basis of hyperexcitability not yet defined
  3. 2003 High

    Demonstrated that Nav1.8 currents are bidirectionally modulated by PKA and PKC signaling and identified εPKC as the specific PKC isozyme, linking the channel to intracellular kinase pathways.

    Evidence Xenopus oocyte expression with two-electrode voltage clamp and isozyme-specific PKC peptide activators/inhibitors; yeast two-hybrid interactome screen with pull-down validation

    PMID:12591166 PMID:14657190

    Open questions at the time
    • Phosphorylation sites mediating kinase effects not yet mapped
    • Functional consequences of interactome partners uncharacterized
  4. 2006 High

    Identified calmodulin as a direct C-terminal IQ-motif partner needed to sustain Nav1.8 current density and limit frequency-dependent inhibition, defining a Ca2+/CaM regulatory module.

    Evidence Native DRG co-immunoprecipitation, calmodulin-binding peptide, IQ/DE mutagenesis, and patch clamp in Nav1.8-null neurons

    PMID:16598065

    Open questions at the time
    • Ca2+ dependence of CaM regulation not fully dissected
    • Structural basis of IQ-motif interaction unresolved
  5. 2008 High

    Defined the trafficking control of Nav1.8 surface expression by an ER-retention RRR motif masked by the β3 subunit, explaining accessory-subunit control of current amplitude.

    Evidence RRR-motif mutagenesis, co-immunoprecipitation mapping the β3 interaction domain, and surface-expression assays in heterologous cells

    PMID:18782866

    Open questions at the time
    • Endogenous regulation of β3 availability in neurons not addressed
    • Cellular trafficking route downstream of ER exit not mapped
  6. 2011 High

    Systematically resolved subunit-specific effects of β1, β3, and β4 on Nav1.8 density and gating and established gain-of-function in vivo phenotypes, broadening Nav1.8 roles to autonomic and CNS functions.

    Evidence β-subunit chimera coexpression with patch clamp; ENU-derived hypermorphic Possum mouse with EEG/ECG and behavioral phenotyping; tdTomato genetic tracing of Nav1.8 neurons

    PMID:21562192 PMID:21618224 PMID:22087007

    Open questions at the time
    • Molecular basis of β-subunit gating effects on Nav1.8 not at residue resolution
    • Mechanism linking Nav1.8 to autonomic cardiac regulation unresolved
  7. 2012 High

    Identified PKCε-mediated phosphorylation at S1452 as a direct molecular switch potentiating Nav1.8 and driving pain, and established Nav1.8 contributions in cardiac tissue via late sodium current and intracardiac neurons.

    Evidence Proteomic screen and S1452A mutagenesis with patch clamp and Scn10a-null behavioral assays; selective blocker A-803467 in mouse/rabbit cardiomyocytes and intracardiac neurons; intronic enhancer ChIP/4C and transgenic reporter studies

    PMID:22426212 PMID:22706305 PMID:22723299 PMID:22723301

    Open questions at the time
    • Relative cardiomyocyte vs. neuronal sources of cardiac Nav1.8 signal debated within these datasets
    • Mechanism of enhancer-driven SCN5A control not yet causally deleted at this stage
  8. 2013 High

    Established KIF5B as the kinesin motor driving anterograde axonal transport of Nav1.8 and characterized the first patient gain-of-function mutation impairing inactivation.

    Evidence Reciprocal co-immunoprecipitation mapping the KIF5B stalk interaction, knockdown/overexpression, surface assays, and patch clamp; voltage/current clamp of the G1662S small-fiber neuropathy variant

    PMID:24006052 PMID:24198377

    Open questions at the time
    • Regulation of KIF5B–Nav1.8 cargo loading not defined
    • Penetrance and full mutation spectrum in neuropathy not established here
  9. 2014 High

    Demonstrated that the SCN10A intronic enhancer physically contacts and controls SCN5A expression and cardiac conduction, and that Nav1.8 physically co-associates with Nav1.5 to modulate cardiac sodium current.

    Evidence 4C-seq chromatin conformation, BAC transgenic enhancer deletion, human eQTL/conduction correlation; HEK coexpression with patch clamp and co-immunoprecipitation of Nav1.8 and Nav1.5; A-fiber inflammation studies with ambroxol

    PMID:24606981 PMID:24642470 PMID:24998131

    Open questions at the time
    • Stoichiometry of Nav1.8–Nav1.5 association unknown
    • Whether enhancer effect operates purely in cis at all developmental stages unresolved
  10. 2016 High

    Mapped extrinsic and transcriptional regulators of Nav1.8 — TNFR1, CXCR5/p38, and the translational repressor TCF4 — linking inflammatory and developmental signals to channel abundance and neuronal excitability.

    Evidence TNFR1-knockout and recombinant TNFα studies; Cxcr5-knockout with p38 inhibition and behavioral assays; in utero electroporation with iTRAP and Tcf4 mouse models with pharmacological rescue; α2A-AR/Gi/o/cAMP/PKA pharmacological dissection

    PMID:20638792 PMID:25761941 PMID:26971948 PMID:27708397

    Open questions at the time
    • Integration of multiple signaling inputs on a single channel pool not addressed
    • Direct vs. indirect transcriptional/translational control mechanisms only partially resolved
  11. 2019 High

    Defined the molecular origin of pathogenic Nav1.8 resurgent currents, showing β4-subunit open-channel block converts inactivation-impairing mutations into hyperexcitability.

    Evidence Patch clamp of DRG neurons expressing G1662S and T790A with β4 siRNA knockdown

    PMID:30617209

    Open questions at the time
    • Structural basis of β4-mediated open-channel block not determined
    • Endogenous β4 regulation in pain states unaddressed
  12. 2021 High

    Demonstrated a cardiac short SCN10A transcript driven from the intronic enhancer-promoter that augments Nav1.5 current and shapes atrial conduction independently of SCN5A expression levels.

    Evidence CRISPR/Cas9 enhancer disruption with transcriptomics, atrial patch clamp, ECG, and eQTL analysis; transfection of Nav1.8-short with Nav1.5

    PMID:33910361

    Open questions at the time
    • Mechanism by which Nav1.8-short augments Nav1.5 current not defined
    • Tissue specificity of the short-isoform promoter not fully mapped
  13. 2024 High

    Quantified Nav1.8's threshold-amplifying contribution relative to Nav1.7 and characterized state-dependent pharmacology of clinical Nav1.8 inhibitors, advancing both physiology and drug development.

    Evidence Dynamic clamp with kinetic modeling in DRG neurons against a gain-of-function Nav1.7 background; state-dependent patch-clamp pharmacology of VX-548 and VX-150

    PMID:39322410 PMID:39378238

    Open questions at the time
    • In vivo translation of reverse use-dependent pharmacology to analgesia not addressed in these datasets
    • Quantitative Nav1.7/Nav1.8 cooperativity across diverse neuron subtypes not generalized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse trafficking, kinase, calmodulin, and accessory-subunit inputs are integrated to set Nav1.8 surface density and gating in specific neuron and cardiac cell types, and the structural basis of its non-ionic SOD2-binding function, remain open.
  • No structural model integrating regulatory motifs (RRR, IQ, S1452) with subunit binding
  • Non-channel SOD2/ROS function characterized in a single study
  • Cell-type-specific weighting of competing regulatory pathways unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-397014 Muscle contraction 3 R-HSA-112316 Neuronal System 2 R-HSA-9609507 Protein localization 2
Partners
CALM1KIF5BSCN1BSCN3BSCN4BSCN5ASOD2

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Human SCN10A (hPN3) was cloned from lumbar DRG and shown to encode a functional voltage-gated sodium channel that is highly tetrodotoxin-resistant when expressed in Xenopus oocytes, with high sequence identity to rat PN3/SNS and similar tissue distribution restricted to DRG. Molecular cloning, heterologous expression in Xenopus oocytes, electrophysiology Pain High 9839820
1997 The mouse Scn10a gene (SNS) was structurally characterized: 27 exons spanning ~90 kb on chromosome 9, with exon-intron boundaries conserved with the human skeletal muscle VGSC gene, providing the genomic basis for understanding cell-specific expression. Genomic library screening, molecular cloning, gene structure analysis Genomics High 9143495
1998 After peripheral nerve injury (CCI or transection), PN3/Nav1.8 protein redistributes from DRG neuronal cell bodies to peripheral axons, accumulating at the site of injury; mRNA levels in DRG do not change, indicating translocation of pre-synthesized protein rather than altered transcription. Immunohistochemistry, in situ hybridization, patch-clamp electrophysiology in nerve-injured rats The Journal of neuroscience High 9482802
1997 SNS/Nav1.8 mRNA levels in DRG are not substantially altered by local Freund's adjuvant inflammation or systemic NGF treatment in vivo, but drop >60% after axotomy; suggesting SNS expression does not underlie inflammatory hyperexcitability but is regulated by axon-target contact. In situ hybridization, immunohistochemistry, in vivo rat pain models Molecular and cellular neurosciences Medium 9532581
1999 In vivo NGF deprivation (via immunization) selectively reduces TTX-resistant sodium current density and SNS mRNA in IB4-negative (TrkA-expressing) DRG neurons, demonstrating that NGF maintains steady-state Nav1.8 expression and TTX-R currents in adult sensory neurons. In vivo NGF immunization, patch-clamp electrophysiology, in situ hybridization Journal of neurophysiology High 10036280
1999 Intrathecal antisense knockdown of PN3/SNS (but not NaN/SNS2) prevents hyperalgesia and allodynia in both chronic nerve injury and tissue injury pain models in rats, establishing Nav1.8 as specifically required for neuropathic and inflammatory pain signaling. Intrathecal antisense oligodeoxynucleotide administration, behavioral pain assays in rat models Proceedings of the National Academy of Sciences High 10393873
2002 Intrathecal antisense knockdown of Nav1.8 in DRG neurons reduces TTX-resistant sodium current density and reverses neuropathic pain from spinal nerve injury without affecting non-noxious sensation or acute pain responses. Intrathecal antisense ODN, immunohistochemistry, patch-clamp, behavioral assays Pain High 11790477
2001 Nav1.8 antisense knockdown in DRG neurons reduces TTX-resistant sodium currents in bladder afferents and abolishes acetic acid-induced bladder hyperactivity (visceral pain), demonstrating that Nav1.8 mediates visceral nociceptor activation. Intrathecal antisense ODN, patch-clamp of labeled bladder afferents, cystometry, Fos immunohistochemistry The Journal of neuroscience High 11606657
2003 Nav1.8 is differentially modulated by PKA and PKC: PKA activation potentiates Nav1.8 currents in a dose-dependent manner (effect prevented by chloroquine, suggesting trafficking contribution), while PKC activation (via PMA) reduces Nav1.8 peak currents and shifts steady-state activation by 14 mV depolarizing; the PKC effect is mediated specifically by εPKC isozyme. Xenopus oocyte expression, two-electrode voltage clamp, PKC-isozyme-specific peptide activators/inhibitors Journal of neurophysiology High 14657190
2004 Rat Nav1.8 can be stably expressed in the DRG-derived neuroblastoma cell line ND7-23, producing TTX-resistant Na+ currents with gating kinetics closely resembling native DRG TTX-R currents; β1 and β3 accessory subunits are endogenously expressed in ND7-23 and may assist Nav1.8 expression. Stable heterologous expression, whole-cell patch clamp, RT-PCR, pharmacological profiling Neuropharmacology High 14975698
2006 Calmodulin co-immunoprecipitates with endogenous Nav1.8 from native DRG neurons via a conserved IQ motif in the C-terminus. Disrupting calmodulin binding (via IQ/DE mutation or calmodulin-binding peptide) reduces Nav1.8 current density by ~50-65% and markedly enhances frequency-dependent inhibition of the current, without affecting voltage dependence of activation or inactivation. Co-immunoprecipitation from native DRG, calmodulin-binding peptide treatment, IQ/DE mutagenesis, patch clamp in Nav1.8-null DRG neurons Journal of neurophysiology High 16598065
2008 Nav1.8 contains an ER-retention/retrieval signal (RRR motif) in its first intracellular loop that restricts surface expression. The β3 subunit promotes surface expression of Nav1.8 by its intracellular C-terminus interacting with the first intracellular loop of Nav1.8 and masking this RRR motif; mutation of RRR increases surface expression and abolishes β3-mediated effects. Mutagenesis of RRR motif, co-immunoprecipitation, surface expression assays, heterologous expression Journal of cell science High 18782866
2003 Using yeast two-hybrid screening of a DRG cDNA library with Nav1.8 intracellular domains, 28 interacting proteins were identified, including β-actin, moesin, inositol polyphosphate 5-phosphatase, TAO2 kinase, VDAC3, tetraspanin, dynein intermediate and light chain; pull-down assays confirmed interaction of several proteins with Nav1.8 in vivo. Yeast two-hybrid screen, co-immunoprecipitation/pull-down assays, in situ hybridization Brain research. Molecular brain research Medium 12591166
2011 The β1-subunit increases Nav1.8 current density 2.3-fold and shifts activation and inactivation in the hyperpolarizing direction; β4-subunit causes larger shifts in activation (-16.7 mV) and inactivation but does not alter current density; β3-subunit reduces Nav1.8 current density by 31% without gating changes. Chimera experiments show the intracellular C-terminal domain of β1 is required for regulation of Nav1.8 expression and gating. Heterologous coexpression, whole-cell patch clamp, β-subunit chimera constructs Journal of neurophysiology High 21562192
2012 PKCε directly phosphorylates Nav1.8 at residue S1452, identified by proteomic screen. PKCε-mediated phosphorylation increases Nav1.8 currents, lowers activation voltage threshold, and produces a depolarizing shift in inactivation. Alanine substitution at S1452 blocks PKCε modulation. PKCε activator peptide ψεRACK produces mechanical hyperalgesia in wild-type but not Scn10a−/− mice. Proteomic screen, site-directed mutagenesis (S1452A), patch clamp in sensory neurons, Scn10a knockout mice, in vivo behavioral assays The Journal of clinical investigation High 22426212
2012 Scn10a/Nav1.8 transcripts are present in mouse heart and the selective Nav1.8 blocker A-803467 (which does not affect Nav1.5 current) blocks late sodium current and shortens action potentials in mouse and rabbit cardiomyocytes, suppressing early afterdepolarizations, indicating Nav1.8 contributes to cardiac late sodium current. RT-PCR of mouse heart, patch clamp in isolated cardiomyocytes, pharmacological block with A-803467 Circulation research High 22723299
2012 Nav1.8 is functionally expressed in intracardiac ganglia neurons (not in ventricular myocytes): immunolabeling shows Nav1.8 in intracardiac but not ventricular myocytes; A-803467 reduces Na+ current density and shifts inactivation in intracardiac neurons but has no effect on myocyte Na+ current or action potential upstroke, while markedly reducing action potential firing frequency in intracardiac neurons. Immunohistochemistry, immunocytochemistry, patch clamp in intracardiac neurons vs. myocytes, pharmacological blockade Circulation research High 22723301
2013 KIF5B kinesin directly interacts with the N-terminus of Nav1.8 (via the 511-620 aa stalk domain of KIF5B), as shown by co-immunoprecipitation. KIF5B overexpression increases Nav1.8 current density and surface expression (requiring intact ATP hydrolysis and cargo-binding); KIF5B knockdown reduces Nav1.8 current density. KIF5B promotes anterograde transport of Nav1.8 to axons and increases Nav1.8 accumulation and neuronal excitability in axons, effects abolished by disrupting the KIF5B–Nav1.8 interaction. Co-immunoprecipitation, knockdown and overexpression in ND7-23 and DRG neurons, patch clamp, surface expression assay, brefeldin A treatment, KIF5B domain mutants The Journal of neuroscience High 24198377
2012 An intronic enhancer within the Scn10a locus directly interacts with the Scn5a promoter (shown by 4C-seq in mouse heart tissue); deletion of this enhancer in BAC transgenic mice abolishes Scn5a cardiac expression. The common SCN10A variant rs6801957 (within the enhancer) disrupts TBX3/TBX5 binding and reduces cardiac enhancer activity in vivo. ChIP-seq for TBX3/NKX2-5/GATA4/p300, luciferase enhancer assays, transgenic mice, in vivo enhancer activity reporter The Journal of clinical investigation High 22706305
2014 High-resolution 4C-seq shows the cardiac enhancer within SCN10A intron physically contacts the SCN5A promoter in mouse heart. Engineered deletion of this enhancer in BAC transgenic mice eliminates Scn5a cardiac expression. The common variant rs6801957 within the enhancer correlates with reduced SCN5A expression and slower cardiac conduction in humans. 4C-seq chromatin conformation, BAC transgenic enhancer deletion, SCN5A expression quantification, human genetics The Journal of clinical investigation High 24642470
2014 Coexpression of wild-type SCN10A with wild-type SCN5A in HEK cells nearly doubles sodium channel current compared to SCN5A alone. SCN10A Brugada syndrome mutants (R14L and R1268Q) coexpressed with SCN5A reduce sodium current by 79-84%. Co-immunoprecipitation demonstrates physical co-association of Nav1.8 and Nav1.5 at the plasma membrane. Heterologous coexpression in HEK cells, patch clamp, co-immunoprecipitation Journal of the American College of Cardiology High 24998131
2013 The Nav1.8 G1662S mutation found in painful small fiber neuropathy patients impairs fast inactivation, depolarizing the V1/2 of inactivation by ~7 mV. Expression of G1662S in DRG neurons renders them hyperexcitable. Voltage clamp analysis of mutant channel in heterologous cells, current clamp in DRG neurons Journal of neurology, neurosurgery, and psychiatry High 24006052
2019 Two Nav1.8 gain-of-function mutations (G1662S and T790A) that impair inactivation greatly increase TTX-resistant resurgent sodium currents in DRG neurons. T790A Nav1.8 enhances DRG neuron excitability, produces early afterdepolarizations and prolongs action potentials. siRNA knockdown of β4 subunit reduces TTX-resistant resurgent Nav1.8 currents by 56% and reduces excitability of T790A-expressing neurons, indicating β4 mediates open-channel block that generates resurgent Nav1.8 currents. Patch clamp of DRG neurons expressing mutant channels, siRNA knockdown of β4 subunit, current and voltage clamp The Journal of neuroscience High 30617209
2003 Ectopic expression of Nav1.8 cDNA in cerebellar Purkinje cells in vitro increases action potential amplitude and duration, decreases conglomerate action potentials, and promotes sustained pacemaker-like firing, demonstrating that Nav1.8's depolarized inactivation and slow repriming perturb normal Purkinje cell firing patterns. Biolistic cDNA transfection into cerebellar Purkinje cells in vitro, patch clamp electrophysiology Brain research Medium 12493611
2011 Nav1.8-expressing neurons are genetically traced using tdTomato reporter mice; Nav1.8-positive vagal afferents innervate gastrointestinal mucosa, myenteric plexus, liver, and pancreas and make neuroendocrine appositions with enteroendocrine cells, establishing Nav1.8 as marking visceral afferents with metabolic/gastrointestinal functions. Cre-LoxP genetic tracing with fluorescent reporter, immunohistochemistry, anatomical mapping The Journal of comparative neurology Medium 21618224
2014 Nav1.8 is up-regulated and anterogradely transported to peripheral axons of large myelinated Aβ-fiber DRG neurons during CFA-induced chronic inflammation. TTX-R Nav1.8 peak current density is enhanced in Aβ-fiber neurons after inflammation, and voltage-dependent activation shifts in the hyperpolarizing direction. The Nav1.8-preferring blocker ambroxol reduces Nav1.8 current potentiation and blocks CFA-induced mechanical allodynia. Immunohistochemistry, RT-PCR, patch clamp of large DRG neurons, in vivo pharmacological block with ambroxol Journal of neuroinflammation High 24606981
2010 TNF-α upregulates Nav1.3 and Nav1.8 in uninjured DRG neurons following motor fiber injury (L5-VRT). Peri-sciatic recombinant TNF-α application without nerve injury is sufficient to upregulate both channels in vivo and in cultured DRG neurons. TNF receptor 1 knockout mice show significantly reduced channel upregulation after L5-VRT, demonstrating TNF-α acts through TNFR1 to regulate Nav1.8 expression. Western blot, immunofluorescence, peri-sciatic TNF-α administration, TNFR1 knockout mice, in vitro DRG culture Pain High 20638792
2016 CXCL13 acting via CXCR5 receptor on DRG neurons activates p38 MAP kinase, which increases Nav1.8 current density; Nav1.8 co-expresses with CXCR5, and Nav1.8 blockade reduces CXCL13-induced neuronal hyperexcitability and pain hypersensitivity. Co-immunolabeling, patch clamp of DRG neurons, Cxcr5 knockout mice, p38 inhibitor, intrathecal injections, behavioral assays Scientific reports High 27708397
2015 Dexmedetomidine (DEX) suppresses Nav1.8 TTX-resistant currents in small DRG neurons via α2A-adrenergic receptor-Gi/o-adenylate cyclase-cAMP-PKA signaling pathway. The Gi/o inhibitor pertussis toxin, AC activator forskolin, membrane-permeable cAMP analogue, and α2A-AR antagonist all block DEX-induced Nav1.8 inhibition, establishing the mechanistic linkage. Whole-cell patch clamp, pharmacological dissection with receptor antagonists, G-protein inhibitors, AC activators and cAMP analogues, immunohistochemistry Molecular brain High 25761941
2016 TCF4 (Transcription Factor 4) represses Scn10a translation in rat prefrontal neurons; suppression of Tcf4 increases Scn10a translation (identified by iTRAP), attenuates neuronal spiking, and increases afterhyperpolarization. Nav1.8 channel pharmacological blockade rescues the excitability deficit, establishing TCF4 as a transcriptional repressor of Scn10a affecting neuronal intrinsic excitability. In utero electroporation, translating ribosome affinity purification (iTRAP), pharmacological rescue, Tcf4+/tr mouse model Neuron High 26971948
2021 Cardiomyocytes express a short SCN10A transcript (Scn10a-short, last 7 exons) transcribed from an intronic enhancer-promoter. CRISPR/Cas9 disruption of this enhancer in mice reduces Scn10a-short expression in atria and ventricles, reduces cardiac sodium current in atrial cardiomyocytes, causes atrial conduction slowing and arrhythmia, while Scn5a expression is unaffected. In transfection experiments, NaV1.8-short increases NaV1.5-mediated sodium current. CRISPR/Cas9 genome editing, transcriptomic analysis, patch clamp, ECG, eQTL analysis Circulation High 33910361
2009 Human and rat Nav1.8 channels have distinct inactivation properties: human Nav1.8 shows more hyperpolarized voltage-dependence of inactivation, faster inactivation development, slower recovery from fast inactivation, and faster recovery from slow inactivation compared to rat Nav1.8. Several compounds (A-803467, V102862, ralfinamide, tetracaine, 227c89) preferentially inhibit the inactivated state; A-803467 and V102862 are most potent, with A-803467 showing greater inactivated-state affinity for human than rat channels. Heterologous expression in ND7/23 cells, whole-cell patch clamp, pharmacological characterization Neuropharmacology High 19371587
2024 VX-548 (suzetrigine) inhibits human Nav1.8 channels with an IC50 of 0.27 nM and VX-150 active metabolite with IC50 of 15 nM, both showing unusual 'reverse use-dependence' where inhibition is relieved by repeated depolarizations. Reinhibition rate is proportional to drug concentration, consistent with voltage-sensor-resting-state binding; the relief occurs at ~40 ms time constant independent of concentration, indicating drug dissociation from activated channels. Whole-cell patch clamp of human Nav1.8, state-dependent pharmacological analysis, concentration-response experiments Molecular pharmacology High 39322410
2022 Nav1.8 in keratinocytes directly binds SOD2, preventing its deacetylation and mitochondrial localization, thereby reducing SOD2 activity and causing ROS accumulation; this promotes pro-inflammatory mediator production (IL-1β, IL-6). Nav1.8 knockdown (but not a Nav1.8 channel blocker) eliminates excess ROS and attenuates TNFα-induced inflammation, indicating this is a non-ionic channel function. Nav1.8 knockdown, transcriptome sequencing, co-immunoprecipitation with SOD2, ROS measurement, inflammatory cytokine assays, in vivo mouse skin inflammation models Redox biology Medium 35952475
2011 Hypermorphic (gain-of-function) Possum mutation in Scn10a enhances Nav1.8 sodium currents and neuronal excitability in DRG neurons, increases cold sensitivity, and produces a complex neurobehavioral phenotype (tonic immobility on scruffing) with electroencephalographic changes and sinus bradycardia abrogated by atropine, implicating Nav1.8 in central nervous system functions and cardiac autonomic regulation beyond nociception. ENU mutagenesis, patch clamp of DRG neurons, EEG, ECG, behavioral phenotyping, atropine pharmacology Proceedings of the National Academy of Sciences High 22087007
2024 Dynamic clamp experiments show Nav1.8 channel open-probability exceeds Nav1.7WT open-probability ninefold at the AP threshold voltage (-21.9 mV) in DRG neurons. Reducing Nav1.8 conductance by 25-50% increases rheobase and reduces firing probability in DRG neurons expressing gain-of-function Nav1.7L848H (IEM), and reduces subthreshold membrane potential oscillations, demonstrating Nav1.8 amplifies excitability near AP threshold and interacts functionally with Nav1.7 in neuropathic pain. Dynamic clamp in DRG neurons, kinetic modeling of Nav1.8, gain-of-function Nav1.7 mutation (IEM model) The Journal of general physiology High 39378238
2014 Common SCN10A haplotypes carrying I962V+V1073A+L1092P or I962V+V1073A are associated with shorter PR intervals and show significantly larger Nav1.8 late current fractions (20.2% and 22.4% vs. 11.7% wild-type), while P1045T haplotype associated with longer PR interval has smaller late current (6.4%), establishing a direct link between Nav1.8 late current and cardiac conduction velocity. SCN10A sequencing in 3699 individuals, heterologous expression of haplotype variants, whole-cell patch clamp measuring late current Circulation. Genomic and precision medicine High 29752399

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 350 11790477
2003 The TTX-resistant sodium channel Nav1.8 (SNS/PN3): expression and correlation with membrane properties in rat nociceptive primary afferent neurons. The Journal of physiology 298 12794175
1998 Distribution of the tetrodotoxin-resistant sodium channel PN3 in rat sensory neurons in normal and neuropathic conditions. The Journal of neuroscience : the official journal of the Society for Neuroscience 290 9482802
1999 A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain. Proceedings of the National Academy of Sciences of the United States of America 259 10393873
2012 Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system. Pain 228 22703890
2005 Nociceptor-specific gene deletion using heterozygous NaV1.8-Cre recombinase mice. Pain 228 15621361
2000 Diversity of expression of the sensory neuron-specific TTX-resistant voltage-gated sodium ion channels SNS and SNS2. Molecular and cellular neurosciences 225 10845770
2000 Drosophila SNS, a member of the immunoglobulin superfamily that is essential for myoblast fusion. Genes & development 213 10859168
2021 ZnS-SnS@NC Heterostructure as Robust Lithiophilicity and Sulfiphilicity Mediator toward High-Rate and Long-Life Lithium-Sulfur Batteries. ACS nano 208 33764730
2014 Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome. Journal of the American College of Cardiology 180 24998131
2000 Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states. Pain 175 10692601
2012 Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer. The Journal of clinical investigation 157 22706305
2010 TNF-α contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury. Pain 151 20638792
2014 A common genetic variant within SCN10A modulates cardiac SCN5A expression. The Journal of clinical investigation 145 24642470
2012 Blocking Scn10a channels in heart reduces late sodium current and is antiarrhythmic. Circulation research 144 22723299
2009 Sns and Kirre, the Drosophila orthologs of Nephrin and Neph1, direct adhesion, fusion and formation of a slit diaphragm-like structure in insect nephrocytes. Development (Cambridge, England) 138 19515699
1997 Regulation of expression of the sensory neuron-specific sodium channel SNS in inflammatory and neuropathic pain. Molecular and cellular neurosciences 130 9532581
2001 Developmental expression of the TTX-resistant voltage-gated sodium channels Nav1.8 (SNS) and Nav1.9 (SNS2) in primary sensory neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 122 11487631
2012 Functional Nav1.8 channels in intracardiac neurons: the link between SCN10A and cardiac electrophysiology. Circulation research 115 22723301
2017 Electroacupuncture Attenuates CFA-induced Inflammatory Pain by suppressing Nav1.8 through S100B, TRPV1, Opioid, and Adenosine Pathways in Mice. Scientific reports 112 28211895
2009 SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples. Cancer chemotherapy and pharmacology 110 19169685
2001 The involvement of the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3/SNS) in a rat model of visceral pain. The Journal of neuroscience : the official journal of the Society for Neuroscience 103 11606657
2009 Abnormal expression of voltage-gated sodium channels Nav1.7, Nav1.3 and Nav1.8 in trigeminal neuralgia. Neuroscience 102 19699781
2009 Increased peripheral nerve excitability and local NaV1.8 mRNA up-regulation in painful neuropathy. Molecular pain 100 19320998
2003 Modulation of Nav1.7 and Nav1.8 peripheral nerve sodium channels by protein kinase A and protein kinase C. Journal of neurophysiology 99 14657190
2016 Sodium channel Nav1.8: Emerging links to human disease. Neurology 96 26747884
2016 Optogenetic Silencing of Nav1.8-Positive Afferents Alleviates Inflammatory and Neuropathic Pain. eNeuro 96 27022626
2013 The G1662S NaV1.8 mutation in small fibre neuropathy: impaired inactivation underlying DRG neuron hyperexcitability. Journal of neurology, neurosurgery, and psychiatry 92 24006052
2011 Genetic tracing of Nav1.8-expressing vagal afferents in the mouse. The Journal of comparative neurology 92 21618224
2004 SNS: Adhesive properties, localization requirements and ectodomain dependence in S2 cells and embryonic myoblasts. Mechanisms of development 89 15511638
2004 Heterologous expression and functional analysis of rat Nav1.8 (SNS) voltage-gated sodium channels in the dorsal root ganglion neuroblastoma cell line ND7-23. Neuropharmacology 87 14975698
2015 Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study. Cardiovascular research 84 25691538
2016 Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1. Neuron 81 26971948
1998 A tetrodotoxin-resistant voltage-gated sodium channel from human dorsal root ganglia, hPN3/SCN10A. Pain 77 9839820
1999 In vivo NGF deprivation reduces SNS expression and TTX-R sodium currents in IB4-negative DRG neurons. Journal of neurophysiology 74 10036280
2015 Methylglyoxal mediates streptozotocin-induced diabetic neuropathic pain via activation of the peripheral TRPA1 and Nav1.8 channels. Metabolism: clinical and experimental 73 26975538
2009 The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model. Molecular cancer therapeutics 69 19372566
2018 Characteristics of sensory neuronal groups in CGRP-cre-ER reporter mice: Comparison to Nav1.8-cre, TRPV1-cre and TRPV1-GFP mouse lines. PloS one 67 29864146
2014 Roles of ASIC3, TRPV1, and NaV1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia. Molecular pain 66 24957987
2014 SCN10A/Nav1.8 modulation of peak and late sodium currents in patients with early onset atrial fibrillation. Cardiovascular research 62 25053638
2009 SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo. Cancer chemotherapy and pharmacology 59 19649632
2011 Localisation of SCN10A gene product Na(v)1.8 and novel pain-related ion channels in human heart. International heart journal 58 21646736
2005 Reduced thermal sensitivity and Nav1.8 and TRPV1 channel expression in sensory neurons of aged mice. Neurobiology of aging 57 15979214
2022 Nav1.8 in keratinocytes contributes to ROS-mediated inflammation in inflammatory skin diseases. Redox biology 55 35952475
2015 Common and rare variants in SCN10A modulate the risk of atrial fibrillation. Circulation. Cardiovascular genetics 53 25691686
1999 Abnormal expression of SNS/PN3 sodium channel in cerebellar Purkinje cells following loss of myelin in the taiep rat. Neuroreport 53 10321459
1997 Cloning and characterization of a mouse sensory neuron tetrodotoxin-resistant voltage-gated sodium channel gene, Scn10a. Genomics 53 9143495
2019 Increased Resurgent Sodium Currents in Nav1.8 Contribute to Nociceptive Sensory Neuron Hyperexcitability Associated with Peripheral Neuropathies. The Journal of neuroscience : the official journal of the Society for Neuroscience 51 30617209
2016 CXCL13/CXCR5 enhances sodium channel Nav1.8 current density via p38 MAP kinase in primary sensory neurons following inflammatory pain. Scientific reports 49 27708397
2011 Regulation of Nav1.6 and Nav1.8 peripheral nerve Na+ channels by auxiliary β-subunits. Journal of neurophysiology 49 21562192
2007 SNS-032 prevents tumor cell-induced angiogenesis by inhibiting vascular endothelial growth factor. Neoplasia (New York, N.Y.) 49 17534442
2008 The voltage-gated Na+ channel Nav1.8 contains an ER-retention/retrieval signal antagonized by the beta3 subunit. Journal of cell science 48 18782866
2014 Functional up-regulation of Nav1.8 sodium channel in Aβ afferent fibers subjected to chronic peripheral inflammation. Journal of neuroinflammation 47 24606981
2013 KIF5B promotes the forward transport and axonal function of the voltage-gated sodium channel Nav1.8. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 24198377
2012 PKCε phosphorylation of the sodium channel NaV1.8 increases channel function and produces mechanical hyperalgesia in mice. The Journal of clinical investigation 45 22426212
2006 Calmodulin regulates current density and frequency-dependent inhibition of sodium channel Nav1.8 in DRG neurons. Journal of neurophysiology 45 16598065
2000 SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS letters 45 10675548
2024 State-Dependent Inhibition of Nav1.8 Sodium Channels by VX-150 and VX-548. Molecular pharmacology 40 39322410
2016 SCN10A Mutation in a Patient with Erythromelalgia Enhances C-Fiber Activity Dependent Slowing. PloS one 40 27598514
2021 Pain behavior in SCN9A (Nav1.7) and SCN10A (Nav1.8) mutant rodent models. Neuroscience letters 39 33775738
2011 Hypermorphic mutation of the voltage-gated sodium channel encoding gene Scn10a causes a dramatic stimulus-dependent neurobehavioral phenotype. Proceedings of the National Academy of Sciences of the United States of America 38 22087007
2003 Expression of Nav1.8 sodium channels perturbs the firing patterns of cerebellar Purkinje cells. Brain research 38 12493611
2002 Origins of gene, genetic code, protein and life: comprehensive view of life systems from a GNC-SNS primitive genetic code hypothesis. Journal of biosciences 38 11937687
2024 Interplay of Nav1.8 and Nav1.7 channels drives neuronal hyperexcitability in neuropathic pain. The Journal of general physiology 36 39378238
2021 Variant Intronic Enhancer Controls SCN10A-short Expression and Heart Conduction. Circulation 36 33910361
2019 A cellular model of Brugada syndrome with SCN10A variants using human-induced pluripotent stem cell-derived cardiomyocytes. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 36 31106349
2012 Increased expression of tetrodotoxin-resistant sodium channels Nav1.8 and Nav1.9 within dorsal root ganglia in a rat model of bone cancer pain. Neuroscience letters 35 22342308
2001 Sodium channel beta1 and beta2 subunits parallel SNS/PN3 alpha-subunit changes in injured human sensory neurons. Neuroreport 35 11234750
2014 PKC-NF-κB are involved in CCL2-induced Nav1.8 expression and channel function in dorsal root ganglion neurons. Bioscience reports 33 24724624
2013 Correlation of Nav1.8 and Nav1.9 sodium channel expression with neuropathic pain in human subjects with lingual nerve neuromas. Molecular pain 33 24144460
2003 Sensory neuron proteins interact with the intracellular domains of sodium channel NaV1.8. Brain research. Molecular brain research 33 12591166
2002 Nerve fibers in lumbar spine structures and injured spinal roots express the sensory neuron-specific sodium channels SNS/PN3 and NaN/SNS2. Spine 32 11805657
2019 Targeting the Nav1.8 ion channel engenders sex-specific responses in lysophosphatidic acid-induced joint neuropathy. Pain 31 30211781
2016 Modulation of Nav1.8 by Lysophosphatidic Acid in the Induction of Bone Cancer Pain. Neuroscience bulletin 30 27631681
2015 Novel SCN10A variants associated with Brugada syndrome. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 29 25842276
2012 NaV1.8 channels are expressed in large, as well as small, diameter sensory afferent neurons. Channels (Austin, Tex.) 29 23064159
2023 SNS alleviates depression-like behaviors in CUMS mice by regluating dendritic spines via NCOA4-mediated ferritinophagy. Journal of ethnopharmacology 28 37028613
2015 Dexmedetomidine inhibits Tetrodotoxin-resistant Nav1.8 sodium channel activity through Gi/o-dependent pathway in rat dorsal root ganglion neurons. Molecular brain 27 25761941
2010 Responses in mantle cell lymphoma cells to SNS-032 depend on the biological context of each cell line. Cancer research 27 20663900
2000 Expression of sodium channel SNS/PN3 and ankyrin(G) mRNAs in the trigeminal ganglion after inferior alveolar nerve injury in the rat. Experimental neurology 27 10915577
2019 An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo. Nature communications 26 31666509
2018 Common Coding Variants in SCN10A Are Associated With the Nav1.8 Late Current and Cardiac Conduction. Circulation. Genomic and precision medicine 26 29752399
2008 Increased nerve fiber expression of sensory sodium channels Nav1.7, Nav1.8, And Nav1.9 in rhinitis. The Laryngoscope 26 18197135
2005 Short hairpin RNA-mediated selective knockdown of NaV1.8 tetrodotoxin-resistant voltage-gated sodium channel in dorsal root ganglion neurons. Anesthesiology 26 16192776
2004 Upregulation and colocalization of p75 and Nav1.8 in Purkinje neurons in experimental autoimmune encephalomyelitis. Neuroscience letters 25 15464262
2016 Sodium channel diversity in the vestibular ganglion: NaV1.5, NaV1.8, and tetrodotoxin-sensitive currents. Journal of neurophysiology 24 26936982
2016 Contrasting Nav1.8 Activity in Scn10a-/- Ventricular Myocytes and the Intact Heart. Journal of the American Heart Association 24 27806966
2014 The endocannabinoid anandamide inhibits voltage-gated sodium channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 in Xenopus oocytes. Anesthesia and analgesia 24 24557103
2014 Histamine upregulates Nav1.8 expression in primary afferent neurons via H2 receptors: involvement in neuropathic pain. CNS neuroscience & therapeutics 24 24990156
2012 Genetic polymorphisms of SCN10A are associated with functional dyspepsia in Japanese subjects. Journal of gastroenterology 24 22618805
2022 SNS-023 sensitizes hepatocellular carcinoma to sorafenib by inducing degradation of cancer drivers SIX1 and RPS16. Acta pharmacologica Sinica 23 36261513
2016 Channelopathy-related SCN10A gene variants predict cerebellar dysfunction in multiple sclerosis. Neurology 23 26740675
2022 Photogenerated reactive oxygen species and hyperthermia by Cu3SnS4 nanoflakes for advanced photocatalytic and photothermal antibacterial therapy. Journal of nanobiotechnology 22 35443708
2021 Transcriptional inhibition by CDK7/9 inhibitor SNS-032 suppresses tumor growth and metastasis in esophageal squamous cell carcinoma. Cell death & disease 22 34741018
2018 Anticancer and radiosensitizing effects of the cyclin-dependent kinase inhibitors, AT7519 and SNS‑032, on cervical cancer. International journal of oncology 22 29901072
2015 Antihyperalgesic effects of ProTx-II, a Nav1.7 antagonist, and A803467, a Nav1.8 antagonist, in diabetic mice. Journal of experimental pharmacology 22 27186141
2020 Long-term multicentre experience of adjuvant radiotherapy for pN3 squamous cell carcinoma of the penis. BJU international 21 33249744
2016 Biallelic SCN10A mutations in neuromuscular disease and epileptic encephalopathy. Annals of clinical and translational neurology 21 28078312
2009 SNS-032 prevents hypoxia-mediated glioblastoma cell invasion by inhibiting hypoxia inducible factor-1alpha expression. International journal of oncology 21 19287962
2009 Functional and pharmacological properties of human and rat NaV1.8 channels. Neuropharmacology 20 19371587

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