Affinage

SCN3A

Sodium channel protein type 3 subunit alpha · UniProt Q9NY46

Length
2000 aa
Mass
226.3 kDa
Annotated
2026-06-10
75 papers in source corpus 34 papers cited in narrative 34 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

SCN3A encodes Nav1.3, a voltage-gated sodium channel α-subunit that generates rapidly activating, fast-inactivating currents with rapid repriming at negative potentials, slow closed-state inactivation, and large ramp currents in response to slow depolarizations (PMID:11487618, PMID:12220575). Channel behavior is shaped by auxiliary β-subunits: β1 and β3 shift steady-state inactivation negatively and slow repriming, with the β3 intracellular domain (a short amphipathic α-helix plus a disordered region) stabilizing fast inactivation, whereas β2 has little effect (PMID:12220575, PMID:20675377). Cell-surface current is amplified by the adhesion molecule contactin, which binds the Nav1.3 N- and C-termini and increases functional channel density at the membrane without altering biophysical properties (PMID:15317864), and channel gating is further modulated by calmodulin binding to the C-terminus and by PKC phosphorylation (PMID:16912065, PMID:21314936). Nav1.3 plays a central developmental role: it is most highly expressed in fetal cortical progenitors and migrating cortical neurons, and gain-of-function variants that increase persistent and ramp current cause polymicrogyria and infantile epileptic encephalopathy, with the most pathogenic variants clustering in transmembrane segments 4–6 of domains II–IV (PMID:29466837, PMID:30146301, PMID:32515017). This gain-of-function mechanism produces neuronal hyperexcitability that has been recapitulated in patient-derived and isogenic iPSC neurons and reversed by the Nav1.3-selective blocker ICA-121431 (PMID:37935051). After nerve or spinal cord injury Nav1.3 is re-expressed in sensory and dorsal horn/thalamic neurons, driving hyperexcitability and neuropathic pain; this re-expression is driven by TNF-α signaling through NF-κB and p38 MAPK/JNK and is controlled epigenetically, including by SIRT1-dependent histone H3 acetylation at the Scn3a promoter (PMID:14523090, PMID:16109750, PMID:20638792, PMID:20858468, PMID:22129822, PMID:38828629). Beyond the nervous system, Nav1.3 is the predominant sodium channel α-subunit in pancreatic α-cells where it is required for glucagon and insulin secretion, and it regulates neutrophil adhesion and transmigration (PMID:25172946, PMID:29509584).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2001 High

    Established the intrinsic biophysical signature of Nav1.3 — fast activation/inactivation, rapid repriming, slow closed-state inactivation and large ramp currents — and showed cellular background modulates these properties, defining the channel's baseline behavior.

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

    PMID:11487618

    Open questions at the time
    • β-subunit effects were small in this system
    • structural basis of slow closed-state inactivation not addressed
  2. 2002 High

    Confirmed and quantified that β1 and β3, but not β2, modulate Nav1.3 inactivation voltage dependence and repriming, defining which auxiliary subunits shape channel kinetics.

    Evidence Whole-cell patch clamp in stably transfected CHO cells with β1/β2/β3 coexpression

    PMID:12220575

    Open questions at the time
    • did not resolve structural mechanism of β-subunit action
    • native neuronal β-subunit composition not determined
  3. 2003 High

    Linked Nav1.3 upregulation in second-order dorsal horn neurons to central neuropathic pain, moving the channel from a biophysical entity to a disease driver after spinal cord injury.

    Evidence Intrathecal antisense ODN knockdown with electrophysiological, molecular and behavioral readouts plus reversal controls in rat SCI model

    PMID:14523090

    Open questions at the time
    • upstream signal driving Nav1.3 upregulation not identified
    • antisense specificity limits
  4. 2004 High

    Identified contactin as a Nav1.3 interactor that increases surface channel density, providing a mechanism for regulating functional channel abundance distinct from gating modulation.

    Evidence Reciprocal Co-IP from rat brain and HEK293 cells, GST pulldown of N/C termini, patch clamp, and enzymatic surface removal

    PMID:15317864

    Open questions at the time
    • intracellular trafficking pathway not mapped
    • physiological role of contactin–Nav1.3 in vivo not tested
  5. 2005 High

    Extended injury-driven Nav1.3 pathology to thalamic relay neurons, showing the channel alters supraspinal somatosensory processing after SCI.

    Evidence Antisense ODN knockdown with thalamic unit recordings and anatomical controls in rat SCI model

    PMID:16109750

    Open questions at the time
    • mechanism of remote thalamic upregulation unresolved
    • no direct human correlate
  6. 2006 Medium

    Demonstrated calmodulin binds the Nav1.3 C-terminus and modulates current and Ca2+-dependent activation, adding a calcium-sensing layer to channel regulation.

    Evidence GST C-terminal pulldown, Co-IP, and patch clamp with CaM inhibitors and Ca2+ manipulation in vasa recta pericytes

    PMID:16912065

    Open questions at the time
    • single lab, peripheral cell type
    • structural CaM-binding determinants not mapped
  7. 2010 High

    Established the canonical gain-of-function disease mechanism by showing an epilepsy-linked variant (K354Q) enhances persistent and ramp currents in native Nav1.3 and induces spontaneous neuronal firing.

    Evidence Site-directed mutagenesis with patch clamp in HEK293 cells and hippocampal neurons

    PMID:20420834

    Open questions at the time
    • genotype–phenotype generalization beyond one variant not yet established
    • in vivo consequence not tested
  8. 2010 High

    Defined the inflammatory upstream pathway for injury-induced Nav1.3 re-expression, placing TNF-α (via TNFR1) and NF-κB as drivers in sensory neurons.

    Evidence In vivo/in vitro recombinant TNF-α, TNFR1 knockout mice, NF-κB inhibitor PDTC, with molecular and electrophysiological readouts

    PMID:20638792 PMID:20858468

    Open questions at the time
    • direct transcription factor binding to Scn3a promoter not shown
    • NF-κB epistasis was pharmacological
  9. 2010 High

    Resolved the structural basis of β3-mediated gating control, showing its amphipathic helix and disordered region stabilize fast inactivation of Nav1.3.

    Evidence Patch clamp plus CD/NMR of β3 intracellular domain and deletion mutagenesis in HEK293 cells

    PMID:20675377

    Open questions at the time
    • full channel–β3 complex structure not determined
    • in vivo relevance of biphasic inactivation unclear
  10. 2011 Medium

    Added kinase regulation (p38 MAPK/JNK downstream of TNF-α; PKC modulation of gating) to the network controlling Nav1.3 expression and function in neuropathic states.

    Evidence Pharmacological kinase inhibition in cultured DRG neurons and PKC inhibitors in stable CHO Nav1.3 cells with patch clamp

    PMID:21314936 PMID:22129822

    Open questions at the time
    • direct phosphorylation sites on Nav1.3 not mapped
    • pharmacological inhibitor specificity
  11. 2013 High

    Generalized the gain-of-function model by showing a panel of SCN3A epilepsy variants share increased ramp-current activation despite heterogeneous individual defects.

    Evidence Site-directed mutagenesis and patch clamp of multiple human Nav1.3 variants in HEK293/CHO cells

    PMID:24157691

    Open questions at the time
    • mechanistic basis for shared ramp current not resolved
    • no in vivo modeling of these variants
  12. 2014 Medium

    Revealed multilayered post-transcriptional and epigenetic control of Scn3a — CpG methylation/MBD2, GAPDH binding to the 3'UTR, and microRNA targeting — establishing how channel abundance is tuned in seizure and pain states.

    Evidence Reporter assays, MBD2/GAPDH knockdown, RNA-protein binding, mRNA stability assays, and miRNA delivery across seizure and CCI models

    PMID:24234845 PMID:25459751 PMID:27816501

    Open questions at the time
    • relative contribution of each regulatory layer in vivo unclear
    • single-lab findings for individual mechanisms
  13. 2014 High

    Identified a non-neuronal physiological role: Nav1.3 is the dominant α-cell sodium channel and is required for islet glucagon and insulin secretion.

    Evidence Single-cell PCR, Scn3a knockout mice, patch clamp of α/β cells, and hormone secretion assays

    PMID:25172946

    Open questions at the time
    • coupling between Nav1.3 current and secretory machinery not detailed
    • human islet relevance not addressed
  14. 2016 High

    Showed that loss-of-function Nav1.3 (trafficking-deficient L247P; hypomorphic mice) can also increase seizure susceptibility, revealing that both gain and loss of channel activity disrupt network excitability.

    Evidence Heterologous expression, surface biotinylation, and Scn3a hypomorphic mouse seizure-threshold and behavioral testing

    PMID:28235671

    Open questions at the time
    • mechanism reconciling gain- and loss-of-function phenotypes unresolved
    • trafficking defect not localized to a specific step
  15. 2018 High

    Established Nav1.3 as a developmental channel whose persistent-current gain-of-function variants cause polymicrogyria by disrupting cortical neuronal migration and folding.

    Evidence Patch clamp of variants, human fetal cortex expression mapping, and in utero ferret electroporation recapitulating cortical malformation

    PMID:29466837 PMID:30146301

    Open questions at the time
    • how sodium current influences migration mechanistically not defined
    • progenitor-cell function of the channel unresolved
  16. 2018 Medium

    Extended Nav1.3 function to innate immunity, implicating it in neutrophil adhesion, transmigration and chemotaxis during ischemic injury.

    Evidence Neutrophil expression profiling, mouse ischemia models, selective inhibitors, and in vitro migration assays with patch clamp

    PMID:29509584

    Open questions at the time
    • downstream signaling linking Nav1.3 to motility unknown
    • inhibitor selectivity caveats
  17. 2020 High

    Systematized genotype–phenotype correlation by showing nearly all cortical-malformation–associated variants are gain-of-function and localize to domain II–IV S4–S6 segments.

    Evidence Whole-cell voltage clamp of 11 variants coexpressed with β1/β2 in HEK-293T cells across a 22-patient cohort

    PMID:32515017

    Open questions at the time
    • mechanistic link between channel locus and phenotype severity not fully explained
    • loss-of-function variants underrepresented
  18. 2024 High

    Provided human-cell validation that a recurrent variant drives pathological hyperexcitability via persistent current, with pharmacological rescue confirming Nav1.3 causality.

    Evidence CRISPR isogenic and patient-derived iPSC glutamatergic neurons, patch clamp, and ICA-121431 rescue

    PMID:37935051

    Open questions at the time
    • network/circuit-level consequences in human tissue not tested
    • single variant studied
  19. 2024 High

    Identified a specific epigenetic switch (SIRT1-dependent histone H3 acetylation at the Scn3a promoter) controlling injury-induced Nav1.3 upregulation in defined spinal neuron populations.

    Evidence ChIP-PCR, SIRT1 knockout/overexpression, Co-IP, chemogenetics in CaMKIIα+ neurons, and behavioral pain assays in CCI model

    PMID:38828629

    Open questions at the time
    • direct SIRT1 substrate at the promoter not defined
    • integration with TNF-α/NF-κB axis not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the same channel produces opposing gain- and loss-of-function disease phenotypes and how Nav1.3 sodium influx mechanistically controls non-electrical processes such as cortical progenitor behavior, neutrophil migration, and islet hormone secretion.
  • no unifying mechanism for gain- vs loss-of-function epilepsy outcomes
  • molecular coupling of Na+ current to migration/secretion/motility undefined
  • no high-resolution structure of Nav1.3 with auxiliary partners in the timeline

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 1
Partners
CALM1CNTN1SCN1BSCN2BSCN3B

Evidence

Reading pass · 34 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 and fast-inactivating currents with rapid repriming at negative potentials, slow closed-state inactivation, and large ramp currents in response to slow depolarizations. 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 when Nav1.3 was expressed in SNS-null DRG neurons compared to HEK293 cells, demonstrating that cellular background modulates channel properties. Whole-cell patch clamp electrophysiology in HEK293 cells and SNS-null DRG neurons (via biolistics); TTX-resistant Nav1.3 mutant construct; coexpression of β subunits The Journal of neuroscience High 11487618
2002 Human Nav1.3 expressed in CHO cells forms rapidly inactivating channels. Coexpression of β1 or β3 subunits shifted the inactivation curve ~10 mV negative and slowed repriming ~3-fold, whereas β2 had no effect alone or in combination with β1 or β3. Whole-cell patch clamp electrophysiology in stably transfected CHO cells; coexpression of β1, β2, and β3 subunits Neuroscience High 12220575
2003 Intrathecal antisense oligodeoxynucleotides targeting Nav1.3 reduced Nav1.3 mRNA and protein in dorsal horn neurons, decreased hyperexcitability of multireceptive nociceptive neurons, and attenuated mechanical allodynia and thermal hyperalgesia after spinal cord injury (SCI) in rats. Effects reversed after cessation of antisense delivery, establishing a functional link between Nav1.3 upregulation in second-order dorsal horn neurons and central neuropathic pain after SCI. Intrathecal antisense ODN knockdown; extracellular electrophysiological recordings of dorsal horn neurons; quantitative RT-PCR, in situ hybridization, immunocytochemistry; behavioral pain assays in rat SCI model The Journal of neuroscience High 14523090
2003 Lidocaine inhibited peak Nav1.3 current, shifted steady-state inactivation to hyperpolarized potentials, and delayed recovery from inactivation in Xenopus oocytes. These effects were attenuated by coexpression of β1 or β3, with β1 producing greater attenuation including reduced use-dependent block. Two-electrode voltage clamp in Xenopus oocytes; coexpression of β1 and β3 subunits; use-dependent block protocol European journal of pharmacology Medium 12706451
2004 Contactin coimmunoprecipitates with Nav1.3 from postnatal rat brain and from HEK293 cells stably expressing Nav1.3. GST fusion proteins of the N and C termini of Nav1.3 pull down contactin from HEK293 cell lysates. Cotransfection of contactin increases Nav1.3 current amplitude ~3-fold without changing biophysical channel properties. Enzymatic removal of contactin from the cell surface did not reduce elevated Nav1.3 current, suggesting contactin increases intracellular channel density at the surface rather than acting as a direct extracellular modulator. Co-immunoprecipitation from rat brain and HEK293 cells; GST pulldown; whole-cell patch clamp; enzymatic contactin removal; immunocytochemistry The Journal of neuroscience High 15317864
2005 After spinal cord contusion injury in rats, Nav1.3 protein is upregulated in thalamic VPL and VPM neurons, and these neurons show increased spontaneous discharge, afterdischarge, hyperresponsiveness to peripheral stimuli, and expanded receptive fields. Intrathecal antisense ODNs targeting Nav1.3 reduced Nav1.3 expression in thalamic neurons and reversed these electrophysiological alterations, linking Nav1.3 upregulation to altered thalamic somatosensory processing after SCI. Intrathecal antisense ODN knockdown; extracellular unit recordings in thalamic VPL neurons; immunocytochemistry; spinal cord transection control experiment in rats Brain : a journal of neurology High 16109750
2006 Nav1.3 vasa recta (descending vasa recta) pericyte currents are regulated by calmodulin (CaM): CaM binds to the C-terminal domain of Nav1.3 via pulldown and co-immunoprecipitation assays. Calmodulin inhibitory peptide (CIP) and the CaM inhibitor W7 suppressed Nav1.3 currents in patch clamp. Raising intracellular Ca2+ from 20 to ~2000 nM produced a depolarizing shift in Nav1.3 activation. RT-PCR identification of Nav1.3 in DVR; immunoblot and immunofluorescence; GST-Nav1.3 C-terminal pulldown; co-immunoprecipitation; patch-clamp electrophysiology with CaM inhibitors and Ca2+ manipulation American journal of physiology. Renal physiology Medium 16912065
2008 The novel SCN3A variant K354Q (K345Q in Nav1.3 DI/S5-6 linker) was identified in a pediatric epilepsy patient. Functional analysis in the Nav1.5 backbone demonstrated increased persistent current of a magnitude similar to epileptogenic SCN1A/SCN2A mutations, suggesting pathogenicity. Patient sequencing; heterologous functional expression and whole-cell patch clamp (in Nav1.5 backbone as surrogate) Neuroscience letters Low 18242854
2010 The K354Q epilepsy-linked mutation directly assessed in Nav1.3 enhances both persistent and ramp currents of Nav1.3, reduces current threshold, and produces spontaneous firing and paroxysmal depolarizing shift-like complexes when Nav1.3/K354Q is expressed in hippocampal neurons. Site-directed mutagenesis; heterologous expression in HEK293 cells; whole-cell patch clamp; expression in hippocampal neurons by transfection Experimental neurology High 20420834
2010 TNF-α upregulates Nav1.3 in DRG neurons: peri-sciatic administration of recombinant TNF-α without nerve injury upregulated Nav1.3 mRNA and protein and increased TTX-sensitive current densities in DRG neurons in vivo. TNF-α also dose-dependently enhanced Nav1.3 expression in cultured adult DRG neurons in vitro. Upregulation after L5 ventral root transection was significantly reduced in TNF receptor 1 knockout mice. In vivo recombinant TNF-α administration; in vitro DRG neuron culture with TNF-α; quantitative RT-PCR; immunocytochemistry; patch clamp; TNF receptor 1 knockout mice Pain High 20638792
2010 Inhibition of NF-κB (via PDTC) prevented the re-expression of Nav1.3 induced by L5 ventral root transection and blocked the Nav1.3 upregulation caused by TNF-α in cultured DRG neurons, placing NF-κB downstream of TNF-α in the signaling pathway that drives Nav1.3 re-expression in sensory neurons after nerve injury. Intrathecal PDTC injection in rat VRT model; cultured adult DRG neurons treated with recombinant TNF-α ± PDTC; immunocytochemistry for Nav1.3; behavioral allodynia assays Brain research Medium 20858468
2010 The β3 subunit depolarizes voltage sensitivity of Nav1.3 activation and inactivation, induces biphasic inactivation with a novel slower component, and increases the fraction of channels inactivating by the slower pathway. NMR/CD structural analysis of the β3 intracellular domain revealed a short amphipathic α-helix followed by a disordered region; both regions selectively stabilize fast inactivation of Nav1.3. Whole-cell patch clamp in HEK293 cells; CD and NMR spectroscopy of β3 intracellular domain; deletion mutagenesis of β3 intracellular regions The Journal of biological chemistry High 20675377
2011 PKC inhibition (staurosporine or calphostin C) in Nav1.3-expressing CHO cells caused a depolarizing shift in voltage dependence and decreased current amplitude, demonstrating that Nav1.3 channel function is regulated by PKC. In neuropathic DRG neurons, PKC inhibition reduced P2X-evoked TTX-sensitive sodium channel activity and reversed hyperexcitability. Whole-cell patch clamp in CHO cells stably expressing Nav1.3; PKC inhibitors (staurosporine, calphostin C); patch clamp of DRG neurons from spinal nerve ligation model; in situ hybridization for Nav1.3 Molecular pain Medium 21314936
2011 TNF-α-induced re-expression of Nav1.3 in cultured adult DRG neurons requires activation of both p38 MAPK and JNK: pharmacological inhibition of p38 MAPK (SB203580) or JNK (SP600125) dose-dependently blocked Nav1.3 re-expression triggered by recombinant TNF-α. Cultured adult rat DRG neurons; recombinant TNF-α treatment; p38 MAPK inhibitor SB203580 and JNK inhibitor SP600125; immunocytochemistry for Nav1.3 The Chinese journal of physiology Medium 22129822
2012 The Nav1.3 pharmacological modulator BmK AS (scorpion toxin, site 4-specific) hyperpolarized voltage dependence of steady-state activation and inactivation, accelerated recovery from inactivation, and preferentially inhibited slow inactivation over fast inactivation, suggesting BmK AS stabilizes both closed and open states of Nav1.3. Two-electrode voltage clamp in Xenopus oocytes expressing Nav1.3; concentration-response analysis of BmK AS Neuroscience bulletin Medium 22622820
2013 Four novel SCN3A missense variants (R357Q, D766N, E1111K, M1323V) and the previously reported K354Q variant, expressed as human Nav1.3 in heterologous cells, showed heterogeneous but overlapping functional defects. All variants shared increased current activation in response to depolarizing ramp voltages. R357Q had reduced current density and slower activation; E1111K produced increased persistent sodium current. This common ramp-current gain of function is consistent with neuronal hyperexcitability. Site-directed mutagenesis; heterologous expression of human Nav1.3 variants; whole-cell patch clamp in HEK293 or CHO cells Neurobiology of disease High 24157691
2014 In mouse pancreatic α-cells, Nav1.3 (Scn3a) is the predominant voltage-gated sodium channel α-subunit; genetic ablation of Scn3a reduces the α-cell Na+ current by 80%. In β-cells, knockout of Scn3a reveals a small Scn3a-dependent Na+ current component. Glucagon and insulin secretion are inhibited in Scn3a-/- islets, establishing Nav1.3 as functionally important for islet hormone secretion. Single-cell PCR; Scn3a knockout mice; patch clamp of isolated α- and β-cells; glucagon/insulin secretion assays from isolated islets The Journal of physiology High 25172946
2014 CpG methylation of a specific site (-39C) in the Scn3a promoter represses promoter activity. MBD2 binds to the methylated -39C motif; knockdown of MBD2 in mouse cells led to -39C methylation and downregulation of Scn3a transcription. In seizure mice, demethylation of -39C and upregulation of Scn3a co-occur with decreased MBD2 binding, establishing an epigenetic CpG methylation/MBD2 mechanism for Scn3a expression control. Luciferase reporter assays; CpG methylation analysis; MBD2 knockdown in N1E-115 cells; chromatin pulldown/MBD2 binding assay; kainate seizure mouse model Biochimica et biophysica acta Medium 25459751
2014 miR-96 directly inhibits Nav1.3 mRNA expression in embryonic DRG neurons in vitro and reduces Nav1.3 protein in DRG after CCI injury in vivo following intrathecal miR-96 administration. Intrathecal miR-96 delivery in CCI rat model; in vitro DRG neuron transfection; qRT-PCR and western blot for Nav1.3 Neurochemical research Medium 24234845
2014 Comparison of equivalent pore-region mutations in Nav1.1 (N301S) and Nav1.3 (N302S): SCN1A-N301S produced complete loss of function (no measurable sodium current), while SCN3A-N302S only slightly reduced channel activity, demonstrating that identical pore mutations have isoform-dependent electrophysiological consequences. Site-directed mutagenesis; heterologous expression; whole-cell patch clamp Molecular neurobiology Medium 24990319
2016 Valproate (but not carbamazepine or lamotrigine) epigenetically downregulates Scn3a expression by inducing methylation at the -39C site in the Scn3a promoter, decreasing promoter activity. VPA downregulates MBD2 at the posttranscriptional level, and MBD2 knockdown increases Scn3a expression. VPA also upregulates FTO protein; FTO knockdown abolishes VPA's repressive effects on MBD2 and Nav1.3. Luciferase reporter assays; CpG methylation analysis; MBD2 and FTO knockdown in Neuro-2a cells; western blot; real-time PCR; seizure mouse model Molecular neurobiology Medium 27013471
2016 A loss-of-function SCN3A variant (L247P) traffics deficiently to the cell surface (demonstrated by cell surface biotinylation), producing no detectable sodium current in heterologous expression. Heterozygous Scn3a hypomorphic (Scn3a+/Hyp) mice showed increased susceptibility to electroconvulsive and chemiconvulsive seizures and deficits in locomotor activity and motor learning, establishing that reduced Nav1.3 activity can increase seizure susceptibility. Whole-exome sequencing; heterologous expression + whole-cell patch clamp; cell surface biotinylation; Scn3a hypomorphic mouse line (gene trap); seizure threshold assays (6Hz, flurothyl, kainic acid); behavioral testing Neurobiology of disease High 28235671
2016 GAPDH binds to a conserved element in the 3' UTR of SCN3A mRNA, increasing Scn3a mRNA stability and expression. In seizure mice, upregulated and phosphorylated GAPDH enhances binding to the Scn3a 3' UTR, upregulating Scn3a. β-hydroxybutyric acid (produced by ketogenic diet) weakens GAPDH binding and rescues abnormal Scn3a expression. RNA-protein binding assays; mRNA stability assays; GAPDH knockdown; phosphorylation analysis; seizure and ketogenic diet mouse models; qRT-PCR Neuropharmacology Medium 27816501
2017 miR-30b overexpression attenuated Nav1.3 mRNA and protein expression in DRG neurons and spinal cord in a spinal nerve ligation neuropathic pain model. miR-30b agomir transfection down-regulated Nav1.3 stimulated by TNF-α in primary DRG neurons; miR-30b antagomir activated Nav1.3 expression. miR-30b agomir/antagomir transfection in primary DRG neurons; in vivo SNL model with intrathecal miR-30b delivery; western blot and qRT-PCR for Nav1.3; behavioral pain assays Frontiers in molecular neuroscience Medium 28529474
2018 De novo pathogenic Nav1.3 variants (p.Ile875Thr, p.Pro1333Leu, p.Val1769Ala) associated with infantile epileptic encephalopathy showed prominent gain of channel function with markedly increased slowly inactivating persistent current and, for two variants, leftward shift in voltage dependence of activation. Antiseizure drugs phenytoin and lacosamide selectively blocked slowly inactivating over transient current in both wild-type and mutant Nav1.3. Whole-cell patch clamp electrophysiology of heterologously expressed mutant Nav1.3; pharmacological testing with phenytoin and lacosamide Annals of neurology High 29466837
2018 Pathogenic Nav1.3 variants causing polymicrogyria of the perisylvian cortex exhibited increased persistent current in heterologous expression. SCN3A expression is highest in fetal cortical progenitor cells of the outer subventricular zone and cortical plate neurons and decreases postnatally. Expression of a mutant Nav1.3 channel in ferrets recapitulated disrupted cortical folding and neuronal migration, establishing a developmental role for Nav1.3 in progenitor cells and migrating neurons. Whole-cell patch clamp of mutant Nav1.3 in heterologous cells; immunostaining and in situ hybridization of human fetal cortex; in utero ferret electroporation of mutant channel; cortical histology Neuron High 30146301
2018 Nav1.3 is expressed in neutrophils recruited to ischemic mouse heart and kidney in vivo. Nav1.3-preferring inhibitors (ICA121431, Pterinotoxin-2) reduced endothelial adhesion, transmigration through endothelium, and chemotaxis of neutrophils in vitro, placing Nav1.3 as a regulator of neutrophil extravasation. PCR and flow cytometry of neutrophil Nav1.3 expression; mouse ischemia models; inhibitor treatment (TTX, ICA121431, Pterinotoxin-2, lidocaine); in vitro adhesion, transmigration, chemotaxis assays; whole-cell patch clamp of sodium currents Anesthesiology Medium 29509584
2018 Extracellular acidosis produces a depolarizing shift in the voltage dependence of activation and moderate reduction in current density of Nav1.3, while voltage dependence of steady-state fast inactivation and recovery from fast inactivation are unchanged. Whole-cell patch clamp electrophysiology of Nav1.3 at varying extracellular pH Channels (Austin, Tex.) Medium 30362397
2020 Among 22 patients with pathogenic SCN3A variants, 10 of 11 tested pathogenic missense variants displayed gain of channel function (increased persistent current and/or leftward shift in voltage dependence of activation) when coexpressed with β1 and β2 subunits in HEK-293T cells. All variants associated with malformation of cortical development showed gain of function; variants clustering in transmembrane segments 4–6 of domains II–IV were most pathogenic. Whole-cell voltage clamp in HEK-293T cells coexpressing Nav1.3 with β1 and β2 subunits; systematic analysis of 11 pathogenic variants; patient cohort genotyping Annals of neurology High 32515017
2020 miR-384-5p directly targets SCN3A as validated by dual-luciferase reporter assay. miR-384-5p agomir decreased Nav1.3 expression and alleviated mechanical allodynia and heat hyperalgesia in CCI rats. Dual-luciferase reporter assay; miR-384-5p agomir delivery in CCI rat model; western blot and qPCR for Nav1.3; behavioral pain assays Neurological research Medium 32098588
2021 miR-214-3p targets Nav1.3 and TLR4 as validated by dual-luciferase reporter assay. Overexpression of miR-214-3p in STZ-induced diabetic neuropathy rats reduced Nav1.3 expression, reversed thermal hyperalgesia, and improved nerve conduction velocity. Dual-luciferase reporter assay; lentiviral miR-214-3p delivery; western blot; neurophysiological measurements; behavioral assays Cell biology international Medium 34296787
2024 SIRT1 epigenetically regulates Nav1.3 in spinal CaMKIIα+ neurons: knockdown of spinal SIRT1 increased acetylation of histone H3 at the Scn3a promoter, increasing Nav1.3 expression and activating CaMKIIα+ neurons to cause neuropathic pain. Overexpression of SIRT1 reversed Nav1.3 upregulation and alleviated pain after CCI. ChIP-PCR for histone H3 acetylation at Scn3a promoter; co-immunoprecipitation; SIRT1 knockout (Sirt1loxP/loxP) and overexpression; chemogenetic activation/inhibition of CaMKIIα+ neurons; transcriptome sequencing; western blot; qRT-PCR; behavioral pain assays CNS neuroscience & therapeutics High 38828629
2024 SCN3A-p.Ile875Thr iPSC-derived glutamatergic neurons (iNeurons) exhibit markedly increased slowly inactivating/persistent Na+ current, abnormal firing with paroxysmal bursting and plateau potentials, and a hyperpolarized voltage threshold for action potential generation compared to isogenic controls. The Nav1.3-selective blocker ICA-121431 normalized action potential threshold and aberrant firing in variant iNeurons, validating Nav1.3 as the mediator of pathological hyperexcitability. CRISPR/Cas9 gene editing of iPSCs; Ngn2-directed differentiation to iNeurons; whole-cell patch clamp electrophysiology; pharmacological blockade with ICA-121431; patient-derived iPSC isogenic control comparison Brain : a journal of neurology High 37935051
2025 Three novel SCN3A variants (p.L209P, p.N52H, p.E1809K) show distinct biophysical mechanisms: p.N52H reduced current density and hyperpolarized activation (mixed gain- and loss-of-function); p.L209P selectively hyperpolarized activation curve; p.E1809K altered fast inactivation and accelerated recovery kinetics. All were expressed in CHO cells with β1 subunits. Whole-cell patch clamp electrophysiology in CHO cells cotransfected with mutant Nav1.3 and β1 subunits; whole-exome sequencing; clinical phenotyping Channels (Austin, Tex.) Medium 41165134

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 280 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 229 12610651
2010 TNF-α contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury. Pain 151 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 121 30146301
2014 Intrathecal miR-96 inhibits Nav1.3 expression and alleviates neuropathic pain in rat following chronic construction injury. Neurochemical research 106 24234845
2009 Abnormal expression of voltage-gated sodium channels Nav1.7, Nav1.3 and Nav1.8 in trigeminal neuralgia. Neuroscience 102 19699781
2018 Mutations in SCN3A cause early infantile epileptic encephalopathy. Annals of neurology 83 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 80 18784617
2017 MiR-30b Attenuates Neuropathic Pain by Regulating Voltage-Gated Sodium Channel Nav1.3 in Rats. Frontiers in molecular neuroscience 78 28529474
2014 Na+ current properties in islet α- and β-cells reflect cell-specific Scn3a and Scn9a expression. The Journal of physiology 77 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 65 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
2016 Epigenetic Downregulation of Scn3a Expression by Valproate: a Possible Role in Its Anticonvulsant Activity. Molecular neurobiology 44 27013471
2007 Voltage-gated sodium channel Nav1.1, Nav1.3 and beta1 subunit were up-regulated in the hippocampus of spontaneously epileptic rat. Brain research bulletin 42 18158113
2017 Electro-acupuncture-modulated miR-214 prevents neuronal apoptosis by targeting Bax and inhibits sodium channel Nav1.3 expression in rats after spinal cord injury. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 36 28298073
2001 Genomic structures of SCN2A and SCN3A - candidate genes for deafness at the DFNA16 locus. Gene 36 11245985
2003 L-type calcium channel activation up-regulates the mRNAs for two different sodium channel alpha subunits (Nav1.2 and Nav1.3) in rat pituitary GH3 cells. Brain research. Molecular brain research 35 12941467
2010 The sodium channel {beta}3-subunit induces multiphasic gating in NaV1.3 and affects fast inactivation via distinct intracellular regions. The Journal of biological chemistry 34 20675377
2019 Long noncoding RNA HOXA-AS2 regulates the expression of SCN3A by sponging miR-106a in breast cancer. Journal of cellular biochemistry 33 30993766
1994 Targeted gene walking by low stringency polymerase chain reaction: assignment of a putative human brain sodium channel gene (SCN3A) to chromosome 2q24-31. Proceedings of the National Academy of Sciences of the United States of America 32 8159690
2013 Case-control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy. Human genetics 31 24337656
2003 Lidocaine block of neonatal Nav1.3 is differentially modulated by co-expression of beta1 and beta3 subunits. European journal of pharmacology 30 12706451
2014 Electrophysiological Differences between the Same Pore Region Mutation in SCN1A and SCN3A. Molecular neurobiology 26 24990319
2020 miR-384-5p ameliorates neuropathic pain by targeting SCN3A in a rat model of chronic constriction injury. Neurological research 25 32098588
2018 Bulleyaconitine A attenuates hyperexcitability of dorsal root ganglion neurons induced by spared nerve injury: The role of preferably blocking Nav1.7 and Nav1.3 channels. Molecular pain 25 29783906
2007 Characterization of 5' untranslated regions of the voltage-gated sodium channels SCN1A, SCN2A, and SCN3A and identification of cis-conserved noncoding sequences. Genomics 25 17544618
2011 Intrathecal lidocaine pretreatment attenuates immediate neuropathic pain by modulating Nav1.3 expression and decreasing spinal microglial activation. BMC neurology 23 21676267
2014 Alteration of Scn3a expression is mediated via CpG methylation and MBD2 in mouse hippocampus during postnatal development and seizure condition. Biochimica et biophysica acta 22 25459751
2011 Neuropathic Nav1.3-mediated sensitization to P2X activation is regulated by protein kinase C. Molecular pain 21 21314936
2021 MiR-214-3p plays a protective role in diabetic neuropathic rats by regulating Nav1.3 and TLR4. Cell biology international 20 34296787
2018 Effects of acidosis on neuronal voltage-gated sodium channels: Nav1.1 and Nav1.3. Channels (Austin, Tex.) 20 30362397
2011 Infantile epilepsy associated with mosaic 2q24 duplication including SCN2A and SCN3A. Seizure 20 21893419
2006 Vasa recta voltage-gated Na+ channel Nav1.3 is regulated by calmodulin. American journal of physiology. Renal physiology 19 16912065
2012 Expression of voltage-gated sodium channel Nav1.3 is associated with severity of traumatic brain injury in adult rats. Journal of neurotrauma 18 22928478
2022 Structure and Function of Sodium Channel Nav1.3 in Neurological Disorders. Cellular and molecular neurobiology 17 35332400
2019 Neurodevelopmental disorder associated with de novo SCN3A pathogenic variants: two new cases and review of the literature. Brain & development 16 31677917
2018 Sodium Channel Nav1.3 Is Expressed by Polymorphonuclear Neutrophils during Mouse Heart and Kidney Ischemia In Vivo and Regulates Adhesion, Transmigration, and Chemotaxis of Human and Mouse Neutrophils In Vitro. Anesthesiology 16 29509584
2011 Upregulation of Nav1.3 Channel Induced by rrTNF in Cultured Adult Rat DRG Neurons via p38 MAPK and JNK Pathways. The Chinese journal of physiology 16 22129822
2013 Blockage of the upregulation of voltage-gated sodium channel nav1.3 improves outcomes after experimental traumatic brain injury. Journal of neurotrauma 14 24313291
1996 A new sodium channel alpha-subunit gene (Scn9a) from Schwann cells maps to the Scn1a, Scn2a, Scn3a cluster of mouse chromosome 2. Genomics 14 8812438
2018 Swimming Exercise Induced Reversed Expression of miR-96 and Its Target Gene NaV1.3 in Diabetic Peripheral Neuropathy in Rats. The Chinese journal of physiology 13 29689688
2016 Whole gene duplication of SCN2A and SCN3A is associated with neonatal seizures and a normal intellectual development. Clinical genetics 13 27153334
2012 Pharmacological kinetics of BmK AS, a sodium channel site 4-specific modulator on Nav1.3. Neuroscience bulletin 13 22622820
2024 SIRT1 mediates the excitability of spinal CaMKIIα-positive neurons and participates in neuropathic pain by controlling Nav1.3. CNS neuroscience & therapeutics 12 38828629
2021 Mutations in the sodium channel genes SCN1A, SCN3A, and SCN9A in children with epilepsy with febrile seizures plus(EFS+). Seizure 12 33895391
2016 GAPDH-mediated posttranscriptional regulations of sodium channel Scn1a and Scn3a genes under seizure and ketogenic diet conditions. Neuropharmacology 12 27816501
2013 Interstitial 2q24.3 deletion including SCN2A and SCN3A genes in a patient with autistic features, psychomotor delay, microcephaly and no history of seizures. Gene 12 24080482
2018 Deletions of SCN2A and SCN3A genes in a patient with West syndrome and autistic spectrum disorder. Seizure 11 29929112
2024 Targeted blockade of aberrant sodium current in a stem cell-derived neuron model of SCN3A encephalopathy. Brain : a journal of neurology 10 37935051
2021 Knockdown of rno_circRNA_009194 Improves Outcomes in Traumatic Brain Injury Rats through Inhibiting Voltage-Gated Sodium Channel Nav1.3. Journal of neurotrauma 10 34726508
2016 Mutant SOD1 protein increases Nav1.3 channel excitability. Journal of biological physics 10 27072680
2012 Upregulated expression of voltage-gated sodium channel Nav1.3 in cortical lesions of patients with focal cortical dysplasia type IIb. Neuroreport 10 22494998
2021 Slow recovery from the inactivation of voltage-gated sodium channel Nav1.3 in mouse taste receptor cells. Pflugers Archiv : European journal of physiology 9 33881614
2011 Promoter analysis of mouse Scn3a gene and regulation of the promoter activity by GC box and CpG methylation. Journal of molecular neuroscience : MN 9 21271300
2024 Exploring the mechanism of Nav1.3 in the ION-CCI rat model based on the TLR4/TRAF6/NF-κB pathway. Neuroscience letters 6 38714229
2018 Re-expression of voltage-gated sodium channel subtype Nav1.3 in the substantia nigra after dopamine depletion. Neuroscience letters 5 30267849
2016 Mapping of a FEB3 homologous febrile seizure locus on mouse chromosome 2 containing candidate genes Scn1a and Scn3a. The European journal of neuroscience 3 27690330
2021 Identification of a novel variant p.Ser606Gly in SCN3A associated with childhood absence epilepsy. Epilepsy research 2 34102392
2025 MiR-30b-5p alleviates trigeminal neuralgia induced by chronic constriction injury of the infraorbital nerve by regulating the voltage-gated sodium channel Nav1.3 in rats. Neuroscience letters 1 40180210
2025 SCN3A-related neurodevelopmental disorder: Clinical case reports and biophysical characterization. Channels (Austin, Tex.) 1 41165134
2026 Toward precision medicine in SCN3A variants-associated encephalopathies and epilepsy: optimizing genetic diagnosis and molecular subregional effects. Frontiers in neurology 0 41725720
2024 Fasting regulates expression of voltage-gated Na+ channel Nav1.3 in subfornical organ. Biochemical and biophysical research communications 0 39612642

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