Affinage

SCN3A

Sodium channel protein type 3 subunit alpha · UniProt Q9NY46

Length
2000 aa
Mass
226.3 kDa
Annotated
2026-04-28
75 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SCN3A encodes the voltage-gated sodium channel α subunit Nav1.3, which generates rapidly activating, fast-inactivating, tetrodotoxin-sensitive sodium currents with rapid repriming kinetics and large ramp currents that contribute to neuronal and neuroendocrine excitability (PMID:11487618, PMID:25172946). Channel biophysical properties are modulated by auxiliary β1 and β3 subunits that shift inactivation and slow repriming (PMID:12220575, PMID:20675377), by contactin which increases surface expression and current density (PMID:15317864), and by calmodulin binding to the C-terminal domain (PMID:16912065); transcriptionally, SCN3A is regulated by CpG methylation at its promoter via MBD2, FTO, and SIRT1-dependent histone acetylation, and post-transcriptionally by GAPDH binding to its 3′ UTR and by miR-96 and miR-30b (PMID:25459751, PMID:27816501, PMID:38828629, PMID:24234845). After nerve or spinal cord injury, TNF-α acting through TNFR1, NF-κB, and p38 MAPK/JNK pathways re-induces Nav1.3 in adult sensory and thalamic neurons, driving hyperexcitability and neuropathic pain that is reversed by antisense knockdown (PMID:14523090, PMID:20638792, PMID:20858468). Gain-of-function SCN3A variants that increase persistent current and hyperpolarize activation cause epileptic encephalopathy and polymicrogyria through disrupted cortical neuronal migration, while loss-of-function trafficking-deficient variants also increase seizure susceptibility, establishing SCN3A as a cause of developmental and epileptic encephalopathy with malformations of cortical development (PMID:30146301, PMID:32515017, PMID:28235671).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    Establishing the core biophysical identity of Nav1.3 — its rapid repriming, slow closed-state inactivation, and large ramp currents — defined the channel as distinct from other Nav isoforms and explained its potential for generating subthreshold depolarizations.

    Evidence Whole-cell patch clamp of Nav1.3 in HEK293 cells and SNS-null DRG neurons with TTX-resistant mutagenesis

    PMID:11487618

    Open questions at the time
    • Contribution of endogenous cellular factors to repriming differences not identified
    • No in vivo validation of ramp current relevance
  2. 2002 High

    Demonstrating that β1 and β3 (but not β2) subunits shift Nav1.3 inactivation negatively and slow repriming revealed how auxiliary subunits tune channel availability, resolving why native Nav1.3 currents differ from heterologously expressed α-subunit-alone currents.

    Evidence Stable transfection and whole-cell electrophysiology in CHO cells with multiple β subunit combinations; extended by NMR/CD structural analysis of β3 intracellular domain in 2010

    PMID:12220575 PMID:20675377

    Open questions at the time
    • Structural basis of β1–Nav1.3 interaction not resolved
    • In vivo stoichiometry of α–β complexes unknown
  3. 2003 High

    Showing that Nav1.3 upregulation in dorsal horn neurons after spinal cord injury is functionally required for hyperexcitability and pain — and that antisense knockdown reverses both — established Nav1.3 as a causal driver of central neuropathic pain.

    Evidence Antisense ODN knockdown with reversal controls, electrophysiology, and behavioral pain assays in rat SCI model; replicated in thalamic neurons in 2005

    PMID:14523090 PMID:16109750

    Open questions at the time
    • Genetic knockout confirmation in pain models not yet performed at this stage
    • Mechanism of injury-induced transcriptional re-activation not identified
  4. 2004 High

    Identifying contactin as a physical partner that increases Nav1.3 surface density threefold without altering gating revealed a trafficking-based mechanism for regulating channel abundance at the membrane.

    Evidence Co-immunoprecipitation from native brain and transfected HEK293 cells; GST pulldown of N- and C-termini; patch clamp showing increased current density

    PMID:15317864

    Open questions at the time
    • Whether contactin-Nav1.3 interaction occurs at nodes of Ranvier in vivo not shown
    • Binding site on Nav1.3 not mapped at residue resolution
  5. 2006 High

    Demonstrating calmodulin binding to the Nav1.3 C-terminus and showing that CaM inhibition suppresses Na+ currents established calcium-dependent regulation of Nav1.3 channel activity in a non-neuronal cell type (renal pericytes).

    Evidence GST pulldown, co-immunoprecipitation, and patch clamp with CaM inhibitors in isolated DVR pericytes

    PMID:16912065

    Open questions at the time
    • CaM binding site residues not mapped
    • Physiological relevance of Ca²⁺-dependent activation shift in vivo unclear
  6. 2008 High

    The first disease-associated SCN3A variant (K354Q) was identified in pediatric epilepsy and shown to increase persistent current, opening the question of whether Nav1.3 gain-of-function causes human epilepsy.

    Evidence Patient screening and electrophysiology initially in SCN5A backbone chimera, then validated in native Nav1.3 in hippocampal neurons in 2010 showing spontaneous firing and paroxysmal depolarizing shifts

    PMID:18242854 PMID:20420834

    Open questions at the time
    • Single family — segregation data limited
    • Population frequency of K354Q not fully established at the time
  7. 2010 High

    Identifying the TNF-α → TNFR1 → NF-κB / p38 MAPK / JNK signaling cascade as the pathway re-inducing Nav1.3 in adult DRG neurons after injury resolved the upstream molecular mechanism of injury-induced Nav1.3 upregulation.

    Evidence Recombinant TNF-α in vivo and in vitro, TNFR1 knockout mice, pharmacological inhibition of p38 MAPK (SB203580), JNK (SP600125), and NF-κB (PDTC)

    PMID:20638792 PMID:20858468 PMID:22129822

    Open questions at the time
    • Direct transcription factor binding to Scn3a promoter not shown
    • Relative contributions of NF-κB vs. MAPK pathways not quantitatively resolved
  8. 2011 Medium

    Mapping the Scn3a promoter identified a critical GC box element and showed that CpG methylation represses transcription, providing the first epigenetic framework for developmental downregulation of Nav1.3.

    Evidence Luciferase reporter assays with truncation and deletion constructs, CpG methylation of promoter regions in PC12, SH-SY5Y, and HEK293 cells

    PMID:21271300

    Open questions at the time
    • Transcription factor binding the GC box not identified
    • In vivo chromatin state not examined at this stage
  9. 2014 High

    Demonstrating that MBD2 binding and CpG methylation at the -39C site control developmental and seizure-related changes in Scn3a expression, and that Nav1.3 is the predominant Na+ channel in pancreatic α-cells required for glucagon secretion, broadened the gene's functional significance beyond neurons.

    Evidence ChIP, luciferase reporters, MBD2 knockdown, mouse seizure model for epigenetics; Scn3a knockout mice with patch clamp and secretion assays for pancreatic function

    PMID:25172946 PMID:25459751

    Open questions at the time
    • Whether epigenetic regulation of Scn3a operates in pancreatic cells is unknown
    • Compensatory channel upregulation in Scn3a-null islets not fully characterized
  10. 2014 Medium

    Identifying miR-96 and subsequently miR-30b as direct post-transcriptional regulators of SCN3A mRNA in DRG neurons, with in vivo knockdown alleviating neuropathic pain, established miRNA-based control as a second layer of SCN3A expression regulation.

    Evidence miR-96 and miR-30b agomir/antagomir delivery intrathecally in CCI and SNL rat models with qPCR, Western blot, and behavioral testing

    PMID:24234845 PMID:28529474

    Open questions at the time
    • Direct 3′ UTR luciferase validation for miR-96 not shown in original study
    • Endogenous miRNA level changes after injury not fully quantified
  11. 2016 Medium

    Showing that GAPDH binds the SCN3A 3′ UTR to stabilize mRNA, that phospho-GAPDH increases in seizures, and that β-hydroxybutyrate disrupts this interaction provided a metabolic-post-transcriptional regulatory mechanism linking ketogenic diet efficacy to Nav1.3 downregulation.

    Evidence RNA-protein binding assays, GAPDH phosphorylation analysis, seizure mouse model, ketogenic diet experiments, luciferase reporters

    PMID:27816501

    Open questions at the time
    • GAPDH binding site in 3′ UTR not mapped at nucleotide resolution
    • Whether GAPDH regulation of SCN3A occurs in human neurons not confirmed
  12. 2016 High

    A loss-of-function SCN3A variant (L247P) was shown to be trafficking-deficient, and Scn3a hypomorphic mice displayed increased seizure susceptibility without spontaneous seizures, demonstrating that both gain- and loss-of-function mechanisms at SCN3A increase seizure risk.

    Evidence Cell surface biotinylation of L247P variant; Scn3a gene-trap hypomorphic mouse with electroconvulsive, flurothyl, and kainic acid seizure threshold testing

    PMID:28235671

    Open questions at the time
    • Mechanism by which reduced Nav1.3 increases seizure susceptibility not fully elucidated
    • Whether L247P affects channel folding vs. ER export not distinguished
  13. 2018 High

    Systematic characterization of gain-of-function SCN3A variants causing epileptic encephalopathy and polymicrogyria — with Nav1.3 shown to be highly expressed in fetal cortical progenitors — established SCN3A as a gene for developmental and epileptic encephalopathy with malformation of cortical development.

    Evidence Patch clamp of multiple mutant channels; developmental expression profiling; ferret in vivo cortical malformation model; clinical-genetic analysis of patients; pharmacological testing with phenytoin and lacosamide

    PMID:29466837 PMID:30146301

    Open questions at the time
    • Whether persistent current directly disrupts progenitor migration or acts via altered network activity not resolved
    • Structural basis for variant clustering in S4–S6 transmembrane segments not modeled
  14. 2020 High

    A systematic genotype-phenotype study of 22 patients confirmed that the majority of pathogenic SCN3A variants show gain of function (increased persistent current and/or hyperpolarized activation), with variants clustering in domains II–IV transmembrane segments, consolidating the genotype-to-mechanism framework.

    Evidence Whole-cell voltage clamp of Nav1.3 variants coexpressed with β1/β2 in HEK-293T cells; structural domain mapping across 22 patients

    PMID:32515017

    Open questions at the time
    • No high-resolution cryo-EM structure of Nav1.3 with disease variants
    • Functional consequences of rare loss-of-function variants less well characterized
  15. 2024 High

    SIRT1 was identified as an epigenetic repressor of Scn3a via histone H3 deacetylation at its promoter, and iPSC-derived neurons carrying the p.Ile875Thr variant recapitulated persistent current increase and bursting that was rescued by the Nav1.3 blocker ICA-121431, validating both an epigenetic control node and a patient-relevant disease model.

    Evidence ChIP-PCR for H3 acetylation, SIRT1 overexpression/knockdown in CaMKIIα-Cre mice with CCI model; CRISPR-edited iPSC-derived glutamatergic neurons with isogenic controls and pharmacological rescue

    PMID:37935051 PMID:38828629

    Open questions at the time
    • Whether SIRT1-mediated regulation interacts with MBD2/CpG methylation pathway not tested
    • Long-term effects of ICA-121431 in patient-derived neurons unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of Nav1.3 (alone and with auxiliary subunits/disease variants), the precise mechanism by which persistent current disrupts cortical progenitor migration, and whether therapeutic targeting of Nav1.3-specific persistent current can rescue cortical malformation in vivo.
  • No cryo-EM or X-ray structure of Nav1.3
  • Mechanism linking persistent current to cortical migration defect not resolved at cellular level
  • No clinical trial data for Nav1.3-selective blockers in SCN3A-related epilepsy

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0140299 molecular sensor activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3
Partners
CALM1CNTN1GAPDHMBD2SCN1BSCN3BSIRT1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Nav1.3 channels expressed in HEK293 cells generate fast-activating, fast-inactivating TTX-sensitive sodium currents with rapid repriming at negative potentials and slow closed-state inactivation kinetics, producing large ramp currents. Coexpression of β3 subunits had small but significant effects on kinetic and voltage-dependent properties, while β1 and β2 subunits had little or no effect. Repriming kinetics were twofold faster in SNS-null DRG neurons than in HEK293 cells, indicating cellular factors modulate Nav1.3 properties. Whole-cell patch-clamp electrophysiology in HEK293 cells and SNS-null DRG neurons via biolistics; mutagenesis to generate TTX-resistant construct The Journal of neuroscience High 11487618
2002 Human Nav1.3 expressed in CHO cells forms rapidly inactivating sodium channels. Coexpression of β1 or β3 subunits shifts the inactivation curve ~10 mV negative and slows repriming rate ~3-fold, while β2 subunit had no effect either alone or in combination with β1 or β3. Stable transfection in CHO cells; whole-cell electrophysiological recording Neuroscience High 12220575
2003 Nav1.3 is upregulated in dorsal horn nociceptive neurons after spinal cord injury (SCI), and antisense knockdown of Nav1.3 reduces neuronal hyperexcitability and attenuates mechanical allodynia and thermal hyperalgesia. Expression of Nav1.3 and pain behaviors returned after cessation of antisense delivery, demonstrating a functional link between Nav1.3 expression and central neuropathic pain. Quantitative RT-PCR, in situ hybridization, immunocytochemistry, extracellular recording, intrathecal antisense oligodeoxynucleotide administration in rat SCI model The Journal of neuroscience High 14523090
2003 Lidocaine reversibly inhibits Nav1.3n (neonatal isoform) peak current, shifts steady-state inactivation to hyperpolarized potentials, and delays recovery from inactivation in Xenopus oocytes. These effects are attenuated by co-expression of β1 (greater effect) or β3 subunits, demonstrating differential pharmacological modulation by beta subunits. Two-electrode voltage clamp in Xenopus oocytes expressing Nav1.3 with or without β1/β3 subunits European journal of pharmacology Medium 12706451
2004 Contactin/F3 coimmunoprecipitates with Nav1.3 from postnatal rat brain and from HEK293 cells stably expressing Nav1.3. GST fusion proteins of Nav1.3 N- and C-termini pull down contactin from HEK293 cell lysates. Transfection of contactin into HEK-Nav1.3 cells increases current amplitude threefold without changing biophysical properties, and enzymatic removal of surface contactin does not reduce elevated Nav1.3 current, suggesting contactin increases channel density at the cell surface. Co-immunoprecipitation from native tissue and transfected HEK293 cells; GST pulldown; whole-cell patch clamp; enzymatic removal of surface contactin The Journal of neuroscience High 15317864
2005 Following spinal cord injury, Nav1.3 protein is upregulated in thalamic VPL and VPM neurons, correlating with increased spontaneous discharge, afterdischarge, and hyperresponsiveness to peripheral stimuli. Intrathecal antisense ODNs targeting Nav1.3 reduced Nav1.3 expression in thalamic neurons and reversed electrophysiological alterations. Immunocytochemistry, extracellular unit recordings, intrathecal antisense ODN knockdown in rat SCI model Brain High 16109750
2006 Nav1.3 is expressed in descending vasa recta (DVR) smooth muscle pericytes. Calmodulin (CaM) binds to the C-terminal domain of Nav1.3 as shown by pull-down and immunoprecipitation. Inhibition of CaM binding with calmodulin inhibitory peptide (CIP) or W7 suppresses Nav1.3 currents in pericytes. Raising intracellular Ca2+ produces a depolarizing shift in activation voltage dependence. RT-PCR in isolated DVR; immunoblot; immunochemistry; GST pull-down and co-immunoprecipitation; whole-cell patch clamp with CaM inhibitors American journal of physiology. Renal physiology High 16912065
2008 A novel SCN3A coding variant K354Q, found in a pediatric patient with cryptogenic partial epilepsy, introduces an increase in persistent current when analyzed functionally, similar in magnitude to epileptogenic mutations in SCN1A and SCN2A. This is the first identified potentially pathogenic mutation of SCN3A. Patient genetic screening; functional analysis by heterologous expression (in SCN5A backbone due to technical constraints at the time) Neuroscience letters Medium 18242854
2010 The SCN3A epilepsy-associated K354Q mutation, expressed in its native Nav1.3 channel, enhances persistent and ramp currents. When expressed in hippocampal neurons, mutant Nav1.3-K354Q reduces current threshold and produces spontaneous firing and paroxysmal depolarizing shift-like complexes. Whole-cell patch clamp of Nav1.3 expressed in HEK293 cells; current-clamp recording in hippocampal neurons expressing mutant Nav1.3 Experimental neurology High 20420834
2010 β3 subunit coexpression with Nav1.3 in HEK293 cells depolarizes the voltage sensitivity of activation and inactivation, induces biphasic inactivation (fast and a novel slower component), and increases the fraction of channels inactivating via the slower component. NMR and CD spectroscopy of the β3 intracellular domain identified a short amphipathic α-helix and disordered region, both of which contribute to selective stabilization of fast inactivation. Whole-cell patch clamp in HEK293 cells; CD spectroscopy and NMR spectroscopy of β3 intracellular domain; mutagenesis The Journal of biological chemistry High 20675377
2010 TNF-α mediates upregulation of Nav1.3 in uninjured DRG neurons following motor fiber injury (L5 ventral root transection). Peri-sciatic recombinant TNF-α upregulates Nav1.3 in vivo and in cultured DRG neurons in a dose-dependent manner. TNF receptor 1 knockout mice show significantly reduced Nav1.3 upregulation, confirming TNF-α acts via TNFR1 to regulate Nav1.3 expression. RT-PCR, immunohistochemistry, Western blot, recombinant TNF-α administration in vivo and in vitro, TNFR1 knockout mice Pain High 20638792
2011 TNF-α-induced re-expression of Nav1.3 in adult rat DRG neurons is mediated through p38 MAPK and JNK signaling pathways, as pharmacological inhibition of either kinase dose-dependently blocks Nav1.3 re-expression. Primary DRG neuron cultures, rrTNF-α administration, p38 MAPK inhibitor (SB203580) and JNK inhibitor (SP600125) pretreatment, Nav1.3 immunoreactivity quantification The Chinese journal of physiology Medium 22129822
2011 NF-κB activation is required for TNF-α-induced re-expression of Nav1.3 in DRG neurons. Intrathecal injection of PDTC (NF-κB inhibitor) prevents Nav1.3 re-expression induced by L5 ventral root transection when applied early but not after established allodynia. PDTC also dose-dependently blocks rrTNF-α-induced Nav1.3 upregulation in cultured DRG neurons. In vivo nerve injury model, intrathecal PDTC administration, immunoreactivity quantification, primary DRG neuron culture Brain research Medium 20858468
2011 In neuropathic DRG neurons after spinal nerve ligation, PKC modulates Nav1.3 channel function: PKC inhibition causes a depolarizing shift in voltage dependence and decreases current amplitude in CHO cells stably expressing Nav1.3. P2X3 receptor-mediated currents activate TTX-sensitive VGSCs (including Nav1.3) in neuropathic nociceptors, a sensitization prevented by PKC blockers. Whole-cell patch clamp, spinal nerve ligation model, PKC inhibitors (staurosporine, calphostin C), in situ hybridization, CHO cell stable expression of Nav1.3 Molecular pain Medium 21314936
2012 BmK AS (a site 4-specific sodium channel modulator from Buthus martensi Karsch scorpion) acts on Nav1.3 expressed in Xenopus oocytes to hyperpolarize voltage dependence of activation and inactivation, preferentially inhibit slow inactivation, and accelerate recovery from inactivation, suggesting it stabilizes both closed and open channel states by binding to two receptor sites. Two-electrode voltage clamp in Xenopus oocytes expressing Nav1.3; concentration-response analysis Neuroscience bulletin Medium 22622820
2013 Four novel SCN3A missense variants (R357Q, D766N, E1111K, M1323V) identified in pediatric focal epilepsy patients show heterogeneous functional defects: R357Q has reduced current density, slower activation, and depolarized voltage dependences; E1111K shows greater persistent current; all variants share increased ramp current activation, suggesting a common biophysical mechanism of neuronal hyperexcitability. Heterologous expression of human Nav1.3 variants; whole-cell patch clamp electrophysiology Neurobiology of disease High 24157691
2014 In mouse pancreatic α-cells, Nav1.3 (Scn3a) is the predominant Na+ channel α subunit. Genetic ablation of Scn3a reduces the Na+ current in α-cells by 80%. In β-cells, Scn3a deletion reveals a small Nav1.3-dependent component. Glucagon and insulin secretion are inhibited in Scn3a−/− islets. Nav1.3 is thus the functionally important Na+ channel subunit in both α- and β-cells. Single-cell PCR, Scn3a knockout mice, whole-cell patch clamp, glucagon/insulin secretion assays The Journal of physiology High 25172946
2014 CpG methylation of the Scn3a promoter at the -39C site (mediated by MBD2) represses Scn3a expression. During postnatal development, increased methylation at -39C reduces Nav1.3 expression. In seizure conditions, MBD2 expression increases, the -39C site becomes demethylated, and Nav1.3 expression rises. MBD2 knockdown increases Scn3a expression by reducing promoter activity. Luciferase reporter assay, CpG methylation analysis, MBD2 knockdown in N1E-115 cells, ChIP, mouse seizure model (KA treatment), immunohistochemistry Biochimica et biophysica acta High 25459751
2014 miR-96 directly targets Nav1.3 mRNA and suppresses its expression in DRG neurons in vitro. Intrathecal administration of miR-96 suppresses CCI-induced Nav1.3 upregulation and alleviates neuropathic pain. In vitro DRG neuron cultures, intrathecal miR-96 delivery, RT-PCR, Western blot in CCI rat model Neurochemical research Medium 24234845
2016 Valproate (but not carbamazepine or lamotrigine) epigenetically downregulates Scn3a expression through FTO-mediated upregulation of FTO protein, which downregulates MBD2 at the posttranscriptional level. Knockdown of MBD2 increases Scn3a expression. VPA induces CpG methylation at the -39C site in the Scn3a promoter, decreasing promoter activity. Luciferase reporter assay, CpG methylation analysis, FTO/MBD2 knockdown in Neuro-2a cells, mouse seizure model Molecular neurobiology Medium 27013471
2016 GAPDH binds to a conserved region in the 3' UTR of SCN3A mRNA, increasing Scn3a mRNA stability and upregulating expression. Phosphorylation of GAPDH in seizure conditions enhances binding to the 3' UTR and upregulates Scn3a. Administration of ketogenic diet generates β-hydroxybutyric acid that weakens GAPDH binding to the 3' UTR element, rescuing abnormal Scn3a expression. RNA-protein binding assays, GAPDH phosphorylation analysis, seizure mouse model, ketogenic diet experiments, luciferase reporters Neuropharmacology Medium 27816501
2017 miR-30b directly targets SCN3A (as identified by TargetScan). miR-30b overexpression (agomir) in spinal nerve ligation (SNL) rats decreases Nav1.3 mRNA and protein in DRG neurons and spinal cord, attenuating neuropathic pain. miR-30b antagomir increases Nav1.3 expression and exacerbates pain. TargetScan bioinformatics, miR-30b agomir/antagomir transfection in primary DRG neurons, SNL rat model, qPCR, Western blot, behavioral testing Frontiers in molecular neuroscience Medium 28529474
2018 Pathogenic Nav1.3 variants (p.Ile875Thr in 2 cases, p.Pro1333Leu, p.Val1769Ala) identified in patients with epileptic encephalopathy show prominent gain of channel function: markedly increased slowly inactivating (persistent) current amplitude; p.Ile875Thr and p.Pro1333Leu also show leftward shift in voltage dependence of activation. Phenytoin and lacosamide selectively block slowly inactivating over transient current in wild-type and mutant Nav1.3. p.Ile875Thr is associated with diffuse polymicrogyria. Whole-cell voltage clamp electrophysiology of mutant channels; pharmacological testing with antiseizure medications; patient genetic analysis Annals of neurology High 29466837
2018 Pathogenic SCN3A variants causing polymicrogyria and neurodevelopmental disorder (including p.Ile875Thr) show increased persistent current (gain of function). SCN3A is highly expressed in fetal cortical progenitor cells of the outer subventricular zone and cortical plate neurons and decreases postnatally. Mutant Nav1.3 channels cause disrupted cerebral cortical folding and neuronal migration, recapitulated in ferret models. Biophysical characterization by patch clamp; developmental expression analysis; ferret in vivo model with mutant channel expression; patient clinical/genetic analysis Neuron High 30146301
2018 Nav1.3 is expressed in neutrophils recruited to ischemic mouse heart and kidney in vivo, and regulates neutrophil adhesion to endothelium, transmigration through endothelial cells, and chemotactic migration in vitro. These effects are blocked by Nav1.3-preferential inhibitors ICA121431 and Pterinotoxin-2, and by lidocaine. Sodium currents were confirmed by whole-cell patch clamp in neutrophils. PCR, flow cytometry, immunofluorescence in ischemia mouse models; inhibitor studies (tetrodotoxin, ICA121431, Pterinotoxin-2, lidocaine); adhesion, transmigration, and chemotaxis assays; whole-cell patch clamp Anesthesiology Medium 29509584
2018 Nav1.1 and Nav1.3 both show a depolarizing shift in voltage dependence of activation during extracellular acidosis and a moderate reduction in current density; voltage dependence of fast inactivation and recovery from fast inactivation are unchanged. Nav1.3 has similar pH sensitivity to Nav1.1. Whole-cell patch clamp electrophysiology at varying extracellular pH Channels Medium 30362397
2020 Systematic analysis of 22 patients with pathogenic SCN3A variants shows most pathogenic missense variants (10/11) exhibit gain of channel function, with increased persistent current and/or leftward shift in voltage dependence of activation. Pathogenic variants cluster in transmembrane segments 4–6 of domains II–IV. All variants associated with malformation of cortical development show gain of channel function. Rare variants show loss of function. Whole-cell voltage clamp in HEK-293T cells coexpressing Nav1.3 with β1 and β2 subunits; systematic genotype-phenotype correlation in 22 patients Annals of neurology High 32515017
2016 The SCN3A loss-of-function variant L247P is a trafficking-deficient mutant: cell surface biotinylation shows reduced Nav1.3-L247P at the plasma membrane. Heterozygous Scn3a hypomorphic mice show no spontaneous seizures but increased susceptibility to electroconvulsive, flurothyl, and kainic acid-induced seizures, and deficits in locomotor activity and motor learning. Voltage clamp in heterologous expression; cell surface biotinylation; Scn3a hypomorphic (gene-trap) mouse behavioral testing Neurobiology of disease High 28235671
2016 Mutant SOD1 (A4V) increases Nav1.3 total Na+ conductance and produces a hyperpolarizing shift in voltage dependence of Nav1.3 activation in Xenopus oocytes, leading to hyperexcitability modeled in NEURON simulations as increased spontaneous firing frequency. Two-electrode voltage clamp in Xenopus oocytes expressing Nav1.3 with wild-type or A4V mutant SOD1; computational neuron modeling Journal of biological physics Medium 27072680
2024 SIRT1 epigenetically regulates Nav1.3 expression in spinal CaMKIIα+ neurons: SIRT1 knockdown increases histone H3 acetylation at the Scn3a promoter (measured by ChIP-PCR), increasing Nav1.3 expression. SIRT1 overexpression reverses CCI-induced Nav1.3 increase and alleviates neuropathic pain. Co-immunoprecipitation revealed binding relationship of involved proteins. ChIP-PCR for histone H3 acetylation at Scn3a promoter; co-immunoprecipitation; SIRT1 overexpression/knockdown; chemogenetics in CaMKIIα-Cre/Sirt1loxP/loxP mice; CCI pain model CNS neuroscience & therapeutics High 38828629
2024 iPSC-derived glutamatergic neurons (iNeurons) expressing the SCN3A p.Ile875Thr variant show markedly increased slowly-inactivating/persistent Na+ current, abnormal firing with paroxysmal bursting and plateau-like potentials, and hyperpolarized action potential threshold compared to controls. The Nav1.3-selective blocker ICA-121431 normalizes action potential threshold and aberrant firing in variant iNeurons. CRISPR/Cas9 gene editing of iPSCs; Ngn2-based rapid induction of glutamatergic neurons; whole-cell patch clamp electrophysiology; isogenic control lines from patient iPSCs; pharmacological rescue with ICA-121431 Brain High 37935051
2011 Scn3a promoter activity is regulated by a GC box element (at nt -254 to -258) and by CpG methylation. Deletion of the GC box decreases promoter activity. CpG methylation of the F1.2 promoter region without the GC box completely represses promoter activity, indicating the GC box is critical for activity of the CpG-methylated Scn3a promoter. Luciferase reporter assays with stepwise 5' truncation constructs and GC box deletion; CpG methylation of promoter constructs; transfection in PC12, SH-SY5Y, and HEK293 cells Journal of molecular neuroscience Medium 21271300

Source papers

Stage 0 corpus · 75 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 279 14523090
2001 Nav1.3 sodium channels: rapid repriming and slow closed-state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 249 11487618
2003 Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Molecular psychiatry 227 12610651
2010 TNF-α contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury. Pain 149 20638792
2005 Changes in electrophysiological properties and sodium channel Nav1.3 expression in thalamic neurons after spinal cord injury. Brain : a journal of neurology 147 16109750
2005 Relationship between sodium channel NaV1.3 expression and neuropathic pain behavior in rats. Pain 143 16061326
2006 Nerve injury induces robust allodynia and ectopic discharges in Nav1.3 null mutant mice. Molecular pain 134 17052333
2008 Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy. Neuroscience letters 122 18242854
2018 Sodium Channel SCN3A (NaV1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development. Neuron 120 30146301
2014 Intrathecal miR-96 inhibits Nav1.3 expression and alleviates neuropathic pain in rat following chronic construction injury. Neurochemical research 105 24234845
2009 Abnormal expression of voltage-gated sodium channels Nav1.7, Nav1.3 and Nav1.8 in trigeminal neuralgia. Neuroscience 100 19699781
2018 Mutations in SCN3A cause early infantile epileptic encephalopathy. Annals of neurology 82 29466837
2010 A sodium channel mutation linked to epilepsy increases ramp and persistent current of Nav1.3 and induces hyperexcitability in hippocampal neurons. Experimental neurology 81 20420834
2008 Multidrug resistance in epilepsy and polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A: correlation among phenotype, genotype, and mRNA expression. Pharmacogenetics and genomics 79 18784617
2017 MiR-30b Attenuates Neuropathic Pain by Regulating Voltage-Gated Sodium Channel Nav1.3 in Rats. Frontiers in molecular neuroscience 77 28529474
2014 Na+ current properties in islet α- and β-cells reflect cell-specific Scn3a and Scn9a expression. The Journal of physiology 76 25172946
2002 Functional modulation of human brain Nav1.3 sodium channels, expressed in mammalian cells, by auxiliary beta 1, beta 2 and beta 3 subunits. Neuroscience 76 12220575
2013 Novel SCN3A variants associated with focal epilepsy in children. Neurobiology of disease 75 24157691
2020 SCN3A-Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation. Annals of neurology 64 32515017
2015 Virus-Mediated Knockdown of Nav1.3 in Dorsal Root Ganglia of STZ-Induced Diabetic Rats Alleviates Tactile Allodynia. Molecular medicine (Cambridge, Mass.) 62 26101954
2017 SCN3A deficiency associated with increased seizure susceptibility. Neurobiology of disease 57 28235671
2013 SCN1A, SCN2A and SCN3A gene polymorphisms and responsiveness to antiepileptic drugs: a multicenter cohort study and meta-analysis. Pharmacogenomics 52 23859570
2004 Contactin associates with sodium channel Nav1.3 in native tissues and increases channel density at the cell surface. The Journal of neuroscience : the official journal of the Society for Neuroscience 48 15317864
2016 Changes in the expression of voltage-gated sodium channels Nav1.3, Nav1.7, Nav1.8, and Nav1.9 in rat trigeminal ganglia following chronic constriction injury. Neuroreport 46 27327156
2010 Inhibition of NF-kappaB prevents mechanical allodynia induced by spinal ventral root transection and suppresses the re-expression of Nav1.3 in DRG neurons in vivo and in vitro. Brain research 45 20858468
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2013 Blockage of the upregulation of voltage-gated sodium channel nav1.3 improves outcomes after experimental traumatic brain injury. Journal of neurotrauma 14 24313291
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