Affinage

Showing SCN8A — NAV1.6 is a alias.

SCN8A

Sodium channel protein type 8 subunit alpha · UniProt Q9UQD0

Length
1980 aa
Mass
225.3 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 44 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

SCN8A encodes Nav1.6, a voltage-gated sodium channel alpha subunit expressed in CNS and PNS neurons but not cardiac or skeletal muscle, where loss of expression causes motor endplate disease, paralysis, and Purkinje cell degeneration (PMID:7670495). Nav1.6 localizes to axon initial segments, nodes of Ranvier, and dendrites (PMID:10745220), where its rapid recovery from inactivation, use-dependent potentiation, and resistance to slow inactivation enable sustained high-frequency firing (PMID:12843211, PMID:15465873). It is the principal source of resurgent and persistent sodium currents that drive pacemaking, fast spiking, and temporal precision of repetitive firing in central neurons, and its loss reduces sustained firing with compensatory upregulation of Nav1.1/Nav1.2 (PMID:16822974, PMID:18057213, PMID:20173079). In sensory and inflamed peripheral neurons Nav1.6 underlies spontaneous bursting, mechanically-evoked spike initiation, and pain behaviors (PMID:19657055, PMID:23622763, PMID:25652923). Channel function is set by an extensive regulatory network: calcium-independent and calcium-dependent calmodulin binding at the C-terminus controls current amplitude and inactivation (PMID:12967988); phosphorylation by p38 MAPK at Ser553, by CaMKII at Ser561 and Ser641/Thr642, and JAK2-dependent phosphorylation of FGF14-Y158 tune current density and gating (PMID:16014723, PMID:32611770, PMID:32599005); S-palmitoylation at Cys1169/Cys1170/Cys1978 modulates current and inactivation (PMID:32161114); and surface trafficking requires the N-terminal Map1b interaction, the beta1 subunit, and APP (PMID:20133873, PMID:22474336, PMID:25767117). RBFOX proteins direct inclusion of exon 18A required for functional full-length protein (PMID:22044765), and transcription is repressed by CDYL-recruited H3K27me3 and induced by TNF-alpha/STAT3-p300 acetylation or MAPK-ERK-CREB signaling (PMID:28842554, PMID:30736806, PMID:37453670). Gain-of-function mutations elevate persistent and/or resurgent currents to cause neuronal hyperexcitability and epileptic encephalopathy, acting critically through excitatory neurons but also via depolarization block and inhibitory failure of SST and PV interneurons, while loss-of-function variants reduce firing; this disease link is established by knock-in mouse models, patient iPSC neurons, and antisense rescue (PMID:25227913, PMID:30601941, PMID:30615093, PMID:32968789, PMID:34544834, PMID:39435659, PMID:31943325).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1995 High

    Established that SCN8A encodes a neuron-specific sodium channel whose loss is lethal, defining its identity and the consequence of deficiency.

    Evidence Positional cloning and transgene-induced deletion with tissue expression analysis in mice

    PMID:7670495

    Open questions at the time
    • Did not define subcellular localization or biophysical properties
    • Mechanism linking channel loss to Purkinje degeneration unresolved
  2. 2000 High

    Resolved where Nav1.6 acts by localizing it to nodes of Ranvier, axon initial segments, and dendrites, linking the channel to action potential initiation and propagation.

    Evidence Isoform-specific immunohistochemistry in rat nervous system

    PMID:10745220

    Open questions at the time
    • Localization mechanism not addressed
    • Functional consequence of dendritic localization untested
  3. 2003 High

    Provided the biophysical basis for Nav1.6-driven high-frequency firing through fast repriming and identified calmodulin as a direct C-terminal regulator of current and inactivation.

    Evidence Whole-cell patch clamp of recombinant channels in DRG neurons; GST pulldown, co-expression, and C-terminal mutagenesis

    PMID:12843211 PMID:12967988

    Open questions at the time
    • Calmodulin's structural binding mode not defined
    • In vivo relevance of CaM modulation not tested
  4. 2004 High

    Explained why Nav1.6 sustains rather than dampens repetitive firing by demonstrating use-dependent potentiation arising from fast activation and slow-inactivation resistance.

    Evidence Patch clamp of Nav1.6 vs Nav1.2 with fast-inactivation-removed mutants in Xenopus oocytes

    PMID:15465873

    Open questions at the time
    • Native neuron relevance addressed only later
    • Molecular determinants of slow-inactivation resistance not mapped
  5. 2005 High

    Opened post-translational regulation of Nav1.6 by identifying p38 MAPK phosphorylation at Ser553 that suppresses current without altering gating.

    Evidence In vitro kinase assay, S553A mutagenesis, patch clamp in p38-activated cells

    PMID:16014723

    Open questions at the time
    • Physiological trigger of p38 regulation unclear
    • Whether reduction reflects trafficking or open probability not resolved
  6. 2006 High

    Demonstrated in vivo that Nav1.6 is required for sustained high-frequency firing and that other isoforms partially compensate at AIS and nodes.

    Evidence Patch clamp and immunofluorescence in retinal ganglion cells from null vs wild-type mice

    PMID:16822974

    Open questions at the time
    • Compensation mechanism not defined
    • Persistent vs resurgent contributions not separated here
  7. 2007 High

    Attributed resurgent sodium current and pacemaking/fast-spiking to Nav1.6, defining its role in autonomous firing.

    Evidence Patch clamp in null GPe neurons plus computational modeling

    PMID:18057213

    Open questions at the time
    • Molecular basis of resurgent current not addressed
    • Beta4/FHF dependency identified only later
  8. 2008 High

    Linked activity-dependent increases in Nav1.6 and persistent current to seizure circuit facilitation, an early connection to epileptogenesis.

    Evidence Immunocytochemistry, in situ hybridization, patch clamp and kindling in wild-type vs Nav1.6+/- mice

    PMID:18637833

    Open questions at the time
    • Whether persistent current increase is cause or consequence of hyperactivity not separated
    • Cell-type specificity not resolved
  9. 2009 High

    Identified FGF14 splice variants and Nav1.6 mechanosensitivity, showing the channel is both a regulated complex member and a mechanically gated sodium leak.

    Evidence Co-expression patch clamp with FGF14 deletion mutants; mechanical stretch/aspiration with Na+ dye fluorimetry in heterologous cells

    PMID:19465131 PMID:19657055

    Open questions at the time
    • Mechanotransduction structural mechanism unknown
    • In vivo significance of mechanosensitivity untested
  10. 2010 High

    Refined Nav1.6's firing role to persistent-current-dependent temporal precision and established beta1 as required for AIS localization and resurgent current.

    Evidence Conditional KO granule cell patch clamp; Scn1b-null AIS immunofluorescence, electrophysiology, and shRNA knockdown

    PMID:20133873 PMID:20173079

    Open questions at the time
    • Beta1 targeting mechanism not molecularly defined
    • Interplay of beta1 with other trafficking partners unresolved
  11. 2011 Medium

    Clarified beta-subunit modulation as comparatively weak for Nav1.6, distinguishing its regulation from other isoforms.

    Evidence Co-expression of beta1-beta4 and beta-subunit chimeras in Xenopus oocytes with patch clamp

    PMID:21562192

    Open questions at the time
    • Single heterologous system
    • Beta4 role in resurgent current not addressed here
  12. 2012 High

    Identified Map1b as an N-terminal trafficking partner essential for Nav1.6 surface current, mechanistically linking channel delivery to the cytoskeleton.

    Evidence Yeast two-hybrid, brain co-IP, alanine-scanning mutagenesis (residues 77-80), patch clamp

    PMID:22474336

    Open questions at the time
    • Step in trafficking pathway affected not defined
    • Whether Map1b acts with beta1 or independently unknown
  13. 2013 High

    Demonstrated a causal role for Nav1.6 in peripheral pathological pain and ectopic bursting following inflammation.

    Evidence In vivo DRG siRNA knockdown with behavioral, single-unit, qPCR and IHC readouts in rat

    PMID:23622763

    Open questions at the time
    • Whether effect is via persistent or resurgent current not separated
    • Upstream inflammatory regulation defined only later
  14. 2014 High

    Established gain-of-function as the disease mechanism in SCN8A epileptic encephalopathy via persistent-current and activation-shift mutations.

    Evidence N1768D knock-in mouse with EEG and dose-response; T767I mutagenesis with patch clamp in cells and neurons

    PMID:24874546 PMID:25227913

    Open questions at the time
    • Critical cell type not yet identified
    • Connection from channel biophysics to network seizures not resolved here
  15. 2015 High

    Expanded the trafficking and signaling network controlling Nav1.6 by identifying APP-Go-JNK surface regulation, kinase control of the FGF14:Nav1.6 complex, and a peripheral spike-initiation role.

    Evidence Reciprocal co-IP, Go/JNK mutants and T668 mutagenesis with biotinylation; split-luciferase kinase screen with neuronal electrophysiology; selective Nav1.6 toxins in colon-nerve preparation

    PMID:25652923 PMID:25659151 PMID:25767117

    Open questions at the time
    • GSK3/PI3K regulation acts indirectly through FGF14
    • In vivo significance of APP-Nav1.6 axis not tested at this stage
  16. 2016 High

    Connected gain-of-function mutations to elevated resurgent current, identified CDYL-H3K27me3 transcriptional repression, FHF2 isoform regulation of resurgent current, somatic nanocluster organization, and a pharmacological handle (cannabidiol).

    Evidence Mutant channel patch clamp with Navbeta4 peptide; ChIP and in vivo CDYL gain/loss-of-function; FHF2 chimeras and siRNA in DRG neurons; single-particle tracking/PALM imaging; M136V electrophysiology

    PMID:27267376 PMID:27496104 PMID:27653482 PMID:27999940 PMID:28842554

    Open questions at the time
    • Nanocluster scaffolding identity beyond ankyrin-independence unknown
    • Resurgent current's molecular partner in vivo not fully defined
  17. 2017 High

    Localized seizure mechanisms to specific neuron types, showing both excitatory persistent-current elevation (with reverse NCX) and reticular thalamic inhibitory failure can drive distinct seizure phenotypes.

    Evidence N1768D knock-in cell-type patch clamp with TTX/riluzole/SN-6 pharmacology; conditional RT-cell and adult thalamic KO with EEG

    PMID:28193882 PMID:28238546

    Open questions at the time
    • Relative contribution of excitatory vs inhibitory mechanisms to overall disease not weighed here
    • Reverse NCX role inferred pharmacologically
  18. 2019 High

    Pinpointed excitatory neurons as the critical pathogenic cell type for gain-of-function encephalopathy, distinguished gain- from loss-of-function and depolarization-block variants, and showed Nav1.6 promotes neuroinflammation after demyelination.

    Evidence Cell-type-specific Cre knock-in with EEG/survival; multi-variant patch clamp with computational modeling; AAV-Cre conditional deletion in EAE

    PMID:30601941 PMID:30615093 PMID:31722722

    Open questions at the time
    • Inhibitory neuron contributions revisited in later work
    • EAE neuroinflammation mechanism is correlative/conditional, single lab
  19. 2020 High

    Mapped the post-translational control surface of Nav1.6 (CaMKII, S-palmitoylation, JAK2-FGF14) and demonstrated therapeutic transcript reduction by antisense oligonucleotides in two epilepsy models.

    Evidence Mass spectrometry, mutagenesis and patch clamp for CaMKII sites; acyl-biotin exchange and mutagenesis for palmitoylation; HTS, MS and FGF14Y158A patch clamp for JAK2; ICV ASO in R1872W and Scn1a+/- mice; patient iPSC neuron electrophysiology

    PMID:31943325 PMID:32161114 PMID:32599005 PMID:32611770 PMID:32968789

    Open questions at the time
    • Integration of competing PTMs on the same channel pool not resolved
    • ASO long-term safety and cognitive effects not addressed
  20. 2021 High

    Demonstrated that gain-of-function in SST inhibitory interneurons paradoxically promotes seizures through depolarization block driven by persistent current.

    Evidence SST-Cre conditional knock-in with EEG, patch clamp, pharmacology, modeling and chemogenetics

    PMID:34544834

    Open questions at the time
    • Relative weight of SST vs excitatory contributions in patients unclear
    • Mechanism of selective audiogenic susceptibility unresolved
  21. 2022 Medium

    Linked Nav1.6 to Alzheimer's pathology by showing hippocampal knockdown rescues cognition and lowers amyloid via a reverse-NCX/calcium/NFAT1/BACE1 axis.

    Evidence AAV-shRNA knockdown in APP/PS1 mice with behavioral, biochemical and calcium imaging readouts

    PMID:35353937

    Open questions at the time
    • NFAT1-BACE1 pathway partially inferred, single lab
    • Direct demonstration of reverse NCX in vivo limited
  22. 2023 Medium

    Identified MAPK-ERK-CREB transcriptional induction of Nav1.6 as a driver of chemotherapy-induced neuropathic pain.

    Evidence ChIP for CREB at Scn8a promoter, kinase inhibitor pharmacology, qPCR and behavior in rats

    PMID:37453670

    Open questions at the time
    • Single lab, single pain model
    • Crosstalk with other Scn8a transcriptional regulators not examined
  23. 2024 High

    Showed that PV interneuron gain-of-function alone causes spontaneous lethal seizures and that splice-isoform and TTX-resistance context shape variant phenotypes, refining genotype-phenotype interpretation.

    Evidence PV-Cre conditional knock-in with EEG and synaptic/intrinsic electrophysiology; automated patch clamp of 15 variants across two isoforms in engineered low-Nav cells

    PMID:38771640 PMID:39435659

    Open questions at the time
    • Combined effect of excitatory and multiple interneuron classes in patients not modeled
    • Physiological role of neonatal vs adult isoform switch not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many parallel regulatory inputs (phosphorylation, palmitoylation, accessory subunits, trafficking partners, and transcriptional/epigenetic control) are coordinated on a single Nav1.6 channel pool to set excitability in specific neuron types remains unresolved.
  • No integrated model of competing PTMs and partners on the same channel
  • Structural basis of resurgent current and nanocluster scaffolding undefined
  • Cell-type-specific therapeutic targeting not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1643685 Disease 6 R-HSA-112316 Neuronal System 4 R-HSA-74160 Gene expression (Transcription) 4
Partners
APPCALMFGF14FHF2MAP1BSCN1BSCN4B

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Scn8a encodes a voltage-gated sodium channel alpha subunit (Nav1.6) expressed in brain and spinal cord but not skeletal muscle or heart; an intragenic deletion at the transgene insertion site results in loss of expression, causing motor endplate disease (med) phenotype including progressive paralysis, muscle atrophy, Purkinje cell degeneration, and juvenile lethality in mice. Positional cloning, transgene-induced deletion, expression analysis (tissue Northern blot) Nature genetics High 7670495
2000 Nav1.6 (NaCh6) protein localizes to nodes of Ranvier in peripheral nerve and spinal cord, axon initial segments, dendrites of pyramidal cells, and motor neuron axons; it is the first sodium channel isoform localized to both nodes of Ranvier and dendrites. Immunohistochemistry with isoform-specific antibodies in rat nervous system sections The Journal of comparative neurology High 10745220
2003 Recombinant Nav1.6 channels exhibit approximately 5-fold faster recovery from inactivation (repriming) and faster development of closed-state inactivation compared to Nav1.7, providing a molecular basis for high-frequency firing in large myelinated DRG neurons. Whole-cell patch clamp of recombinant Nav1.6 and Nav1.7 expressed in mouse DRG neurons The Journal of physiology High 12843211
2003 Calmodulin (CaM) binds to the C-terminal domain of Nav1.6 in a calcium-independent manner; disrupting this interaction reduced Nav1.6 current amplitude by 62%, and CaM also modulates Nav1.6 inactivation kinetics in a calcium-dependent manner. GST-fusion protein pulldown, co-expression with CaM in transfected cells, whole-cell patch clamp, C-terminal mutagenesis The Journal of neuroscience High 12967988
2003 In EAE (experimental autoimmune encephalomyelitis), Nav1.6 co-localizes with the Na+/Ca2+ exchanger (NCX) along demyelinated axons; 73.5% of injured (beta-APP positive) axons co-express Nav1.6 and NCX, suggesting that Nav1.6-mediated sodium influx drives reverse NCX operation and calcium-mediated axonal degeneration. Triple-label fluorescent immunohistochemistry in mouse EAE spinal cord Brain : a journal of neurology Medium 14662515
2004 Nav1.6 channels exhibit use-dependent potentiation (increased current) during rapid repetitive depolarizations, in contrast to Nav1.2 which shows use-dependent decrease; this results from faster channel activation and resistance to slow inactivation in Nav1.6. Whole-cell patch clamp of Nav1.6 and Nav1.2 co-expressed with beta1 in Xenopus oocytes; fast inactivation-removed mutant channels used to dissect mechanism Biophysical journal High 15465873
2005 p38 MAP kinase (p38alpha) phosphorylates Nav1.6 specifically at serine 553 within cytoplasmic loop L1 (joining domains 1 and 2); activation of p38 in neuronal cells significantly reduces Nav1.6 peak current amplitude without affecting gating; S553A substitution prevents this p38-mediated reduction. In vitro kinase assay with GST-fusion fragments of Nav1.6, site-directed mutagenesis (S553A), whole-cell patch clamp in p38-activated ND7/23 cells transfected with Nav1.6 The Journal of neuroscience High 16014723
2006 Nav1.6 is required for repetitive high-frequency firing in retinal ganglion cells (RGCs); in Nav1.6-null (med) mice, maximal sustained and instantaneous firing rates are reduced by postnatal day 18. Compensatory upregulation of Nav1.2 and Nav1.1 at axon initial segments and nodes occurs in a cell-type-specific manner. Whole-cell patch clamp recordings from RGCs during postnatal development in med vs. wild-type mice; immunofluorescence for sodium channel isoforms at AIS and nodes The Journal of neuroscience High 16822974
2007 Nav1.6 channels underlie resurgent sodium current in globus pallidus (GPe) neurons; Nav1.6-null GPe neurons show significantly reduced resurgent current, impaired pacemaking and fast spiking, and inability to follow high-frequency stimulation. Whole-cell patch clamp in acutely isolated GPe neurons from Nav1.6-null mice; computational modeling The Journal of neuroscience High 18057213
2008 Nav1.6 expression and persistent sodium current increase selectively in hippocampal CA3 neurons following kindling; heterozygous Nav1.6-deficient mice (Nav1.6+/-) resist initiation and development of kindling, identifying Nav1.6 as a participant in activity-dependent facilitation in hippocampal circuits. Immunocytochemistry, in situ hybridization, patch clamp recordings, kindling behavioral analysis in wild-type vs. Nav1.6+/- mice Epilepsia High 18637833
2009 FGF14 N-terminal splice variants (FGF14-1a and FGF14-1b) differentially regulate Nav1.6 currents: FGF14-1b (but not FGF14-1a) attenuates Nav1.6 current density; an FGF14 mutant lacking the N-terminus increases Nav1.6 current density; the N-terminus is required for axon initial segment targeting of FGF14. Co-expression in neurons with patch clamp, immunofluorescence localization in neurons, deletion mutagenesis Molecular and cellular neurosciences High 19465131
2009 Mechanical membrane trauma (bleb-inducing aspiration or uniaxial stretch) causes Nav1.6 channels to exhibit irreversible hyperpolarizing shifts in steady-state inactivation and activation, expanding window current; stretch of Nav1.6-expressing HEK cells causes tetrodotoxin-sensitive cytoplasmic Na+ increase, demonstrating Nav1.6 acts as a mechanosensitive sodium leak channel. Patch clamp of recombinant Nav1.6 in oocyte patches (cell-attached aspiration) and HEK cells (substrate stretch); Na+-dye fluorimetry American journal of physiology. Cell physiology High 19657055
2010 Nav1.6 at axon initial segments contributes to persistent (but not transient or resurgent) sodium current in cerebellar granule cells; loss of Nav1.6 at AIS leads to faster action potential repolarization, larger post-spike hyperpolarization, and increased interspike-interval variability, demonstrating a role in temporal precision of repetitive firing. Whole-cell patch clamp of acute cerebellar slices and acutely dissociated granule cells from granule cell-specific Scn8a conditional KO mice; immunofluorescence for Nav subunits The Journal of physiology High 20173079
2010 Beta1 (Scn1b) subunit is required for normal Nav1.6 localization at the axon initial segment during postnatal development; in Scn1b-null cerebellar granule neurons, Nav1.6 at AIS is reduced and Nav1.1 substitutes; beta1-mediated neurite outgrowth requires Nav1.6-mediated sodium current, and Nav1.6 resurgent current is reduced in Scn1b-null neurons. Immunofluorescence of AIS in Scn1b-null cerebellar neurons, whole-cell patch clamp recording of resurgent current, shRNA knockdown of Nav1.6 Proceedings of the National Academy of Sciences of the United States of America High 20133873
2011 Rbfox proteins (Fox-1 and Fox-2) regulate alternative splicing of SCN8A by promoting inclusion of exon 18A over exon 18N; exon 18A selection is dependent on a Fox consensus binding site 28 bp downstream of exon 18A; exon 18A is required for production of functional full-length Nav1.6 protein. Scn8a minigene co-transfection with Fox-1 or Fox-2; mutagenesis of Fox binding site; RT-PCR of purified cell populations (neurons vs. glia) Molecular and cellular neurosciences High 22044765
2012 The N-terminal domain of Nav1.6 (residues 1-153) interacts with the light chain of microtubule-associated protein Map1b; residues 77-80 (VAVP) contribute to this interaction; Map1b co-immunoprecipitates with endogenous Nav1.6 from mouse brain; co-expression of Map1b with Nav1.6 increases current density ~50%; mutation of the Map1b binding site prevents sodium current generation, establishing Map1b as a trafficking partner for Nav1.6. Yeast two-hybrid screen, co-immunoprecipitation from mouse brain, alanine-scanning mutagenesis, whole-cell patch clamp in ND7/23 cells The Journal of biological chemistry High 22474336
2013 In vivo knockdown of Nav1.6 in rat lumbar DRG via siRNA completely blocked development of mechanical pain behaviors and abnormal spontaneous bursting activity following local DRG inflammation; cells capable of repetitive firing had higher Nav1.6 expression, and spontaneously active bursting cells in inflamed DRG expressed high Nav1.6 immunoreactivity. In vivo siRNA knockdown, behavioral pain testing (paw withdrawal threshold), single-unit electrophysiology, qPCR and immunohistochemistry Pain High 23622763
2014 The de novo SCN8A mutation p.Asn1768Asp (N1768D) results in increased persistent sodium current and neuronal hyperactivity; knock-in mice carrying this mutation exhibit seizures, SUDEP, and EEG-confirmed ictal discharges; severity scales with mutant protein dose (heterozygous < hemizygous < homozygous). Knock-in mouse model, video/EEG analysis, behavioral testing, transfected cell electrophysiology Human molecular genetics High 25227913
2014 The de novo SCN8A mutation p.Thr767Ile causes enhanced channel activation with a 10 mV depolarizing shift in voltage dependence, increased ramp current, and increased spontaneous firing with paroxysmal depolarizing shift-like complexes in hippocampal neurons, establishing a gain-of-function mechanism for epilepsy. Site-directed mutagenesis, whole-cell patch clamp in transfected neuronal cells and hippocampal pyramidal neurons Neurobiology of disease High 24874546
2015 Amyloid precursor protein (APP) co-localizes and interacts with Nav1.6 in mouse cortical neurons; APP knockdown decreases Nav1.6 currents and cell surface expression; APP increases Nav1.6 surface expression through a Go protein-dependent, JNK-mediated pathway; phosphorylation of APP at Thr668 by JNK enhances APP-Nav1.6 interaction and Nav1.6 surface expression. Co-immunoprecipitation, siRNA knockdown, dominant-active/negative Go mutants, JNK inhibitors, T668E/T668A mutagenesis, whole-cell patch clamp, surface biotinylation The Journal of biological chemistry High 25767117
2015 The PI3K/Akt pathway, Wee1 kinase, and protein kinase C (PKC) regulate the FGF14:Nav1.6 protein-protein interaction complex; inhibition of GSK3 (a convergence point of these pathways) impairs excitability of hippocampal neurons. Split-luciferase complementation assay in live cells screening 12 kinase inhibitor pathways; dose-response validation; hippocampal neuron electrophysiology PloS one Medium 25659151
2015 Nav1.6 is required for spike initiation at stretch-sensitive colorectal afferent endings; selective Nav1.6 antagonists (mu-conotoxin GIIIa and PIIIa) significantly reduced afferent responses to colorectal stretch, while Nav1.7 or Nav1.8 antagonists did not; computational modeling confirmed Nav1.6 is necessary for tonic spiking at sensory endings. In vitro colon-nerve preparation with selective toxin pharmacology, immunohistochemistry/Western blot, computational modeling Journal of neurophysiology High 25652923
2016 Epilepsy-associated Nav1.6 mutations N1768D and L1331V dramatically increase resurgent sodium currents; cannabidiol preferentially inhibits resurgent and persistent sodium currents from wild-type and mutant Nav1.6 over peak transient currents; this inhibition reduces action potential firing in striatal neurons. Whole-cell patch clamp in HEK293T cells with Navβ4 peptide to induce resurgent current; Nav1.6 mutant channels; current clamp in striatal neurons Brain : a journal of neurology High 27267376
2016 The SCN8A gain-of-function mutation p.Met136Val increases peak current density (~1.5-fold) and resurgent current (~1.6-fold) without altering gating properties; it increases the fraction of high-firing neurons, lowers current threshold, and increases action potential frequency in trigeminal ganglion neurons. Whole-cell voltage clamp in transfected cells, current clamp in trigeminal ganglion neurons Molecular medicine (Cambridge, Mass.) High 27496104
2016 CDYL (Chromodomain Y-like) epigenetic factor binds a regulatory element in the intron of SCN8A and recruits H3K27me3 activity to repress Nav1.6 transcription; CDYL knockdown in hippocampal neurons augments Nav1.6 currents and lowers seizure threshold; CDYL overexpression raises neuronal threshold and reduces epileptogenesis. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation, siRNA knockdown, transgenic overexpression, patch clamp recordings, seizure susceptibility testing in mice Nature communications High 28842554
2016 Nav1.6 somatic nanoclusters (~230 nm diameter) exist on the surface of hippocampal neuron soma that are stable for >30 minutes via an ankyrin-independent mechanism; non-clustered Nav1.6 channels show anomalous diffusion and can be transiently trapped in nanoclusters. Single-particle tracking, photoactivation localization microscopy (PALM), mean-square displacement analysis, Bayesian inference analysis Biophysical journal High 27653482
2017 Loss of Scn8a in reticular thalamic (RT) neurons alters intrinsic RT cell excitability and causes failure in recurrent RT-RT synaptic inhibition, leading to enhanced thalamocortical network synchrony and absence epilepsy (spike-wave discharges); deletion of Scn8a in adult thalamus alone is sufficient to generate spike-wave discharges. Conditional KO (Cre-dependent deletion in RT cells), EEG recording, patch clamp in thalamic slices, adult-specific deletion Neuron High 28238546
2017 Gain-of-function SCN8A mutation p.Asn1768Asp (N1768D) increases persistent sodium current density selectively in hippocampal CA1 pyramidal neurons (not bipolar neurons) and CA3 pyramidal and bipolar neurons; CA1 pyramidal neurons show early afterdepolarization-like action potential waveforms blocked by TTX, riluzole, and reverse Na/Ca exchange inhibitor SN-6, implicating elevated persistent INa and reverse NCX in hyperexcitability. Patch clamp of acutely dissociated neurons and brain slices from Scn8a N1768D knock-in mice; pharmacological dissection with TTX, riluzole, SN-6 Proceedings of the National Academy of Sciences of the United States of America High 28193882
2019 Restricting expression of the gain-of-function SCN8A mutation p.Arg1872Trp to excitatory neurons (via Emx1-Cre) recapitulates seizures and juvenile lethality; expression in inhibitory neurons (Gad2-Cre or Dlx5/6-Cre) does not induce seizures, establishing excitatory neurons as the critical cell type for SCN8A encephalopathy pathogenesis. Conditional knock-in mouse model with neuron-type-specific Cre drivers (Emx1-Cre, Gad2-Cre, Dlx5/6-Cre); EEG monitoring; survival analysis Brain : a journal of neurology High 30601941
2019 Multiple SCN8A epilepsy mutations (E1483K, R1872W) increase neuronal firing in primary neuronal cultures; loss-of-function mutations (R1620L) reduce neuronal firing; A1622D dramatically slows fast inactivation and induces depolarization block reducing neuronal firing despite epileptic presentation, confirming distinct genotype-phenotype correlations. Whole-cell patch clamp in neuroblastoma cells and primary cultured neurons; current clamp in neurons; computational modeling Brain : a journal of neurology High 30615093
2019 TNF-α/STAT3 signaling upregulates Nav1.6 in DRG neurons: STAT3 binds the Scn8a promoter, interacts with p300, and promotes histone H4 hyperacetylation at the Scn8a promoter region, leading to increased Nav1.6 transcription following L5 ventral root transection; TNF-α inhibition reduces STAT3 recruitment and Nav1.6 upregulation. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (STAT3-p300), qPCR, Western blot, in vivo pharmacology Journal of neuroinflammation High 30736806
2020 Scn8a antisense oligonucleotide (ASO) treatment reducing Scn8a transcript by 25-50% delays seizure onset and lethality in the Scn8a-R1872W mouse model in a dose-dependent manner; a single Scn8a ASO treatment also extends survival of Dravet syndrome (Scn1a+/-) mice from 3 weeks to >5 months. Intracerebroventricular ASO injection in conditional Scn8a-R1872W knock-in mice and Scn1a+/- mice; EEG recording; survival analysis; open field and wheel running assays Annals of neurology High 31943325
2020 CaMKII phosphorylates Nav1.6 at Ser-561 and Ser-641/Thr-642 within the first intracellular loop; CaMKII inhibition reduces Nav1.6 transient and persistent currents by ~72% and causes a 5.8 mV depolarizing shift in activation; S561A and S641A/T642A substitutions recapitulate these effects, demonstrating CaMKII modulates Nav1.6 channel activity. CaMKII-specific inhibitor CN21, whole-cell voltage clamp in Purkinje neurons and ND7/23/HEK293 cells, immobilized peptide arrays, LC-MS/MS phosphoproteomics, site-directed mutagenesis, computational modeling The Journal of biological chemistry High 32611770
2020 Nav1.6 undergoes S-palmitoylation in mouse brain at three sites (Cys1169, Cys1170, Cys1978); enhancing palmitoylation increases Nav1.6 current while blocking it reduces current and shifts steady-state inactivation; Cys1978 is exclusive to Nav1.6 among all Nav isoforms and its palmitoylation specifically regulates current amplitude; loss of S-palmitoylation at specific sites alters neuronal excitability in DRG neurons. Acyl-biotin exchange assay in mouse brain and HEK cells, whole-cell voltage clamp with palmitic acid and 2-bromopalmitate, site-directed mutagenesis, current clamp in DRG neurons The Journal of biological chemistry High 32161114
2020 JAK2 phosphorylates FGF14 at Y158, a site that mediates both FGF14 homodimerization and FGF14:Nav1.6 complex formation; JAK2 inhibition increases FGF14 homodimerization while decreasing FGF14:Nav1.6 interaction; through Y158, JAK2 controls FGF14-dependent modulation of Nav1.6 channels; JAK2 inhibitor Fedratinib reduces hippocampal CA1 firing in a FGF14-dependent manner. High-throughput screening (split-luciferase), in vitro phosphorylation, mass spectrometry, FGF14Y158A mutagenesis, patch clamp electrophysiology in hippocampal neurons Biochimica et biophysica acta. Molecular cell research High 32599005
2020 Patient iPSC-derived neurons from SCN8A-related epilepsy exhibit variant-specific alterations: mutations p.R1872L and p.V1592L show elevated persistent current, while p.N1759S shows increased resurgent current; all three patient neuron lines have shorter axon initial segment lengths and prolonged action potential repolarization compared to controls. Patient iPSC-derived excitatory neurons, whole-cell patch clamp, immunofluorescence for AIS length (ankyrin-G staining), MEA network activity Brain : a journal of neurology High 32968789
2021 Selective expression of gain-of-function SCN8A mutation R1872W in somatostatin (SST) interneurons confers audiogenic seizure susceptibility; SST interneurons from mutant mice are hyperexcitable but hypersensitive to depolarization block; aberrantly large persistent sodium currents contribute directly to SST dysfunction; GqDREADD activation of WT SST interneurons also produces prolonged electrographic seizures. Cre-dependent conditional knock-in (SST-Cre), EEG, patch clamp electrophysiology, pharmacology, computational modeling, chemogenetics (GqDREADD) The Journal of neuroscience High 34544834
2022 Reducing Nav1.6 expression in hippocampus (via shRNA AAV) rescues cognitive impairments and attenuates synaptic deficits in APP/PS1 Alzheimer's model mice; Nav1.6 knockdown reduces Aβ levels by suppressing BACE1 transcription through a mechanism involving reduced intracellular calcium overload (via suppressed reverse NCX), increased inactive NFAT1, and thereby decreased BACE1 transcription. AAV-shRNA hippocampal injection, behavioral tests (Morris water maze), amyloid plaque quantification, ELISA, Western blot, calcium imaging Aging cell Medium 35353937
2023 The MAPK-ERK-CREB signaling pathway upregulates Nav1.6 (Scn8a) transcription in DRG during oxaliplatin-induced neuropathic pain; activated p-CREB directly binds the Scn8a promoter region as demonstrated by ChIP; inhibition of CREB reduces Nav1.6 mRNA and protein and alleviates pain. Western blot, RT-qPCR, ChIP, immunofluorescence, in vivo kinase inhibitor pharmacology in rats Toxicology letters Medium 37453670
2024 Selective expression of gain-of-function SCN8A variant R1872W in parvalbumin (PV) interneurons is sufficient to cause spontaneous seizures and seizure-induced death; PV interneurons from mutant mice show increased persistent sodium current, susceptibility to depolarization block, and reduced inhibitory synaptic transmission onto pyramidal cells. PV-Cre conditional knock-in, EEG, patch clamp electrophysiology (persistent current, evoked firing, IPSCs in pyramidal cells) JCI insight High 39435659
2024 SCN8A alternative splicing isoforms (neonatally expressed NaV1.6N vs. adult NaV1.6A) show small but significant differences in voltage dependence; many disease-associated variants exhibit isoform-dependent functional effects; TTX-resistant versions of both isoforms show significant functional differences from WT channels, highlighting the importance of molecular context in variant characterization. Automated patch clamp in ND7/LoNav cells (engineered low-endogenous-Nav cell line), comparison of 15 variants in two splice isoforms with and without TTX-resistance mutations JCI insight High 38771640
2011 Beta-subunit regulation of Nav1.6 is weak compared to Nav1.8; the beta4-subunit induces a hyperpolarizing shift in Nav1.6 activation (-7.6 mV) but does not alter inactivation or current density; the intracellular C-terminal domain of the beta1-subunit is essential for strong regulation of Nav1.8 but not Nav1.6. Co-expression of Nav1.6 with beta1-beta4 subunits in Xenopus oocytes, whole-cell patch clamp, beta-subunit chimera analysis Journal of neurophysiology Medium 21562192
2016 FHF2 isoforms differentially regulate Nav1.6-mediated resurgent currents in DRG neurons: FHF2A enhances long-term inactivation and negatively regulates fast resurgent current; FHF2B lacks this long-term inactivation enhancement and positively regulates resurgent current; FHF2A and FHF2B expression are differentially regulated in a radicular pain model. Patch clamp electrophysiology in DRG neurons and cell lines; FHF2A/Navβ4 chimeric constructs; FHF2 isoform-specific siRNA knockdown Pflugers Archiv : European journal of physiology Medium 27999940
2019 Nav1.6 deletion from retinal ganglion cells (via AAV-Cre in Scn8a-floxed mice) during EAE reduces pro-inflammatory cytokines (IL-6, IFN-γ) and reactive gliosis marker (GFAP) expression, reduces macrophage infiltration in targeted optic nerves, and improves axonal health, demonstrating Nav1.6 promotes neuroinflammation and axonal degeneration following demyelination. AAV-Cre conditional deletion in floxed Scn8a mice during EAE, gene expression analysis, immunohistochemistry, contralateral eye controls Journal of neuroinflammation Medium 31722722

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Mutation of a new sodium channel gene, Scn8a, in the mouse mutant 'motor endplate disease'. Nature genetics 267 7670495
2003 Distinct repriming and closed-state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons. The Journal of physiology 258 12843211
2015 The phenotypic spectrum of SCN8A encephalopathy. Neurology 238 25568300
2003 Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE. Brain : a journal of neurology 180 14662515
2016 Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Annals of neurology 147 26677014
2013 Sodium channel SCN8A (Nav1.6): properties and de novo mutations in epileptic encephalopathy and intellectual disability. Frontiers in genetics 138 24194747
2014 Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy. Human molecular genetics 127 25227913
2020 Scn8a Antisense Oligonucleotide Is Protective in Mouse Models of SCN8A Encephalopathy and Dravet Syndrome. Annals of neurology 117 31943325
2015 De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. Journal of medical genetics 115 25725044
2003 Calmodulin binds to the C terminus of sodium channels Nav1.4 and Nav1.6 and differentially modulates their functional properties. The Journal of neuroscience : the official journal of the Society for Neuroscience 115 12967988
2016 SCN8A encephalopathy: Research progress and prospects. Epilepsia 114 27270488
2006 Impaired firing and cell-specific compensation in neurons lacking nav1.6 sodium channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 114 16822974
2009 FGF14 N-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodium channels. Molecular and cellular neurosciences 113 19465131
2010 Functional reciprocity between Na+ channel Nav1.6 and beta1 subunits in the coordinated regulation of excitability and neurite outgrowth. Proceedings of the National Academy of Sciences of the United States of America 111 20133873
2016 Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol. Brain : a journal of neurology 106 27267376
2015 Recurrent and Non-Recurrent Mutations of SCN8A in Epileptic Encephalopathy. Frontiers in neurology 104 26029160
2005 Voltage-gated sodium channel Nav1.6 is modulated by p38 mitogen-activated protein kinase. The Journal of neuroscience : the official journal of the Society for Neuroscience 100 16014723
2017 Regulation of Thalamic and Cortical Network Synchrony by Scn8a. Neuron 99 28238546
2019 Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability. Brain : a journal of neurology 96 30615093
2008 Role of hippocampal sodium channel Nav1.6 in kindling epileptogenesis. Epilepsia 94 18637833
2000 Immunolocalization of sodium channel isoform NaCh6 in the nervous system. The Journal of comparative neurology 92 10745220
2016 A gain-of-function mutation in Nav1.6 in a case of trigeminal neuralgia. Molecular medicine (Cambridge, Mass.) 91 27496104
2019 Prominent role of forebrain excitatory neurons in SCN8A encephalopathy. Brain : a journal of neurology 89 30601941
2014 A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy. Neurobiology of disease 88 24874546
2007 Nav1.6 sodium channels are critical to pacemaking and fast spiking in globus pallidus neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 88 18057213
2000 Developmental and regional expression of sodium channel isoform NaCh6 in the rat central nervous system. The Journal of comparative neurology 86 10745221
2012 Genomic basis of broad host range and environmental adaptability of Rhizobium tropici CIAT 899 and Rhizobium sp. PRF 81 which are used in inoculants for common bean (Phaseolus vulgaris L.). BMC genomics 84 23270491
2013 Knockdown of sodium channel NaV1.6 blocks mechanical pain and abnormal bursting activity of afferent neurons in inflamed sensory ganglia. Pain 80 23622763
2017 Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy. Proceedings of the National Academy of Sciences of the United States of America 77 28193882
2017 Loss-of-function variants of SCN8A in intellectual disability without seizures. Neurology. Genetics 77 28702509
2009 Membrane trauma and Na+ leak from Nav1.6 channels. American journal of physiology. Cell physiology 69 19657055
2020 Variant-specific changes in persistent or resurgent sodium current in SCN8A-related epilepsy patient-derived neurons. Brain : a journal of neurology 62 32968789
2019 TNF-α/STAT3 pathway epigenetically upregulates Nav1.6 expression in DRG and contributes to neuropathic pain induced by L5-VRT. Journal of neuroinflammation 62 30736806
2010 Persistent Nav1.6 current at axon initial segments tunes spike timing of cerebellar granule cells. The Journal of physiology 62 20173079
2001 Sodium channels and neurological disease: insights from Scn8a mutations in the mouse. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 61 11496924
2015 SCN8A mutations in Chinese children with early onset epilepsy and intellectual disability. Epilepsia 60 25785782
2004 Allelic mutations of the sodium channel SCN8A reveal multiple cellular and physiological functions. Genetica 56 15619959
2021 SCN8A Epilepsy, Developmental Encephalopathy, and Related Disorders. Pediatric neurology 54 34353676
2019 SCN8A encephalopathy: Mechanisms and models. Epilepsia 52 31904118
2015 Identifying a kinase network regulating FGF14:Nav1.6 complex assembly using split-luciferase complementation. PloS one 51 25659151
2017 CDYL suppresses epileptogenesis in mice through repression of axonal Nav1.6 sodium channel expression. Nature communications 49 28842554
2011 Regulation of Nav1.6 and Nav1.8 peripheral nerve Na+ channels by auxiliary β-subunits. Journal of neurophysiology 49 21562192
2019 Distinct functional alterations in SCN8A epilepsy mutant channels. The Journal of physiology 47 31715021
2004 Use-dependent potentiation of the Nav1.6 sodium channel. Biophysical journal 47 15465873
2015 Experimental and computational evidence for an essential role of NaV1.6 in spike initiation at stretch-sensitive colorectal afferent endings. Journal of neurophysiology 46 25652923
2008 Exaggerated emotional behavior in mice heterozygous null for the sodium channel Scn8a (Nav1.6). Genes, brain, and behavior 46 18363861
2007 Sodium channel Nav1.6 accumulates at the site of infraorbital nerve injury. BMC neuroscience 43 17662136
2016 The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin. Epilepsia 42 27375106
2016 Single-Molecule Imaging of Nav1.6 on the Surface of Hippocampal Neurons Reveals Somatic Nanoclusters. Biophysical journal 42 27653482
2014 Role of the hippocampus in Nav1.6 (Scn8a) mediated seizure resistance. Neurobiology of disease 42 24704313
2011 Rbfox proteins regulate alternative splicing of neuronal sodium channel SCN8A. Molecular and cellular neurosciences 42 22044765
2004 Floxed allele for conditional inactivation of the voltage-gated sodium channel Scn8a (NaV1.6). Genesis (New York, N.Y. : 2000) 40 15286995
2006 Expression of sodium channels Nav1.2 and Nav1.6 during postnatal development of the retina. Neuroscience letters 38 16753259
2015 Regulatory nodD1 and nodD2 genes of Rhizobium tropici strain CIAT 899 and their roles in the early stages of molecular signaling and host-legume nodulation. BMC genomics 36 25880529
2016 RNA-seq analysis of the Rhizobium tropici CIAT 899 transcriptome shows similarities in the activation patterns of symbiotic genes in the presence of apigenin and salt. BMC genomics 35 26951045
2016 Autosomal dominant SCN8A mutation with an unusually mild phenotype. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 35 27210545
2022 Reducing Nav1.6 expression attenuates the pathogenesis of Alzheimer's disease by suppressing BACE1 transcription. Aging cell 34 35353937
2019 Nav1.6 promotes inflammation and neuronal degeneration in a mouse model of multiple sclerosis. Journal of neuroinflammation 34 31722722
2021 Soluble tumor necrosis factor-alpha-induced hyperexcitability contributes to retinal ganglion cell apoptosis by enhancing Nav1.6 in experimental glaucoma. Journal of neuroinflammation 33 34419081
2018 Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus. Human mutation 33 29726066
2015 Amyloid precursor protein enhances Nav1.6 sodium channel cell surface expression. The Journal of biological chemistry 33 25767117
2020 CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability. The Journal of biological chemistry 32 32611770
2019 A multi-disciplinary clinic for SCN8A-related epilepsy. Epilepsy research 32 31887642
2016 Indole-3-acetic acid production via the indole-3-pyruvate pathway by plant growth promoter Rhizobium tropici CIAT 899 is strongly inhibited by ammonium. Research in microbiology 32 27845247
2012 Interaction of voltage-gated sodium channel Nav1.6 (SCN8A) with microtubule-associated protein Map1b. The Journal of biological chemistry 32 22474336
2018 Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy. Scientific reports 30 29317669
2016 Remarkable alterations of Nav1.6 in reactive astrogliosis during epileptogenesis. Scientific reports 30 27905510
2015 Opening the "black box" of nodD3, nodD4 and nodD5 genes of Rhizobium tropici strain CIAT 899. BMC genomics 30 26502986
2021 Somatostatin-Positive Interneurons Contribute to Seizures in SCN8A Epileptic Encephalopathy. The Journal of neuroscience : the official journal of the Society for Neuroscience 29 34544834
2016 De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis. Epilepsy research 29 27875746
2016 FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons. Pflugers Archiv : European journal of physiology 29 27999940
2023 Distinguishing Loss-of-Function and Gain-of-Function SCN8A Variants Using a Random Forest Classification Model Trained on Clinical Features. Neurology. Genetics 28 37152443
2015 Human Nav1.6 Channels Generate Larger Resurgent Currents than Human Nav1.1 Channels, but the Navβ4 Peptide Does Not Protect Either Isoform from Use-Dependent Reduction. PloS one 27 26182346
2021 Autistic-like behavior, spontaneous seizures, and increased neuronal excitability in a Scn8a mouse model. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 26 33658654
2005 Multiple transcripts of sodium channel SCN8A (Na(V)1.6) with alternative 5'- and 3'-untranslated regions and initial characterization of the SCN8A promoter. Genomics 26 15676283
2020 JAK2 regulates Nav1.6 channel function via FGF14Y158 phosphorylation. Biochimica et biophysica acta. Molecular cell research 25 32599005
2016 Amyloid precursor protein modulates Nav1.6 sodium channel currents through a Go-coupled JNK pathway. Scientific reports 25 28008944
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
2020 S-Palmitoylation of the sodium channel Nav1.6 regulates its activity and neuronal excitability. The Journal of biological chemistry 23 32161114
2019 Modified age-dependent expression of NaV1.6 in an ALS model correlates with motor cortex excitability alterations. Neurobiology of disease 23 31302244
2023 MAPK-ERK-CREB signaling pathway upregulates Nav1.6 in oxaliplatin-induced neuropathic pain in the rat. Toxicology letters 20 37453670
2020 Gabra2 is a genetic modifier of Scn8a encephalopathy in the mouse. Epilepsia 20 33140451
2017 The Rhizobium tropici CIAT 899 NodD2 protein regulates the production of Nod factors under salt stress in a flavonoid-independent manner. Scientific reports 20 28488698
1999 Immunocytochemical localization of NaCh6 in cultured spinal cord astrocytes. Glia 20 10088676
2022 Genetic interaction between Scn8a and potassium channel genes Kcna1 and Kcnq2. Epilepsia 19 35892317
2019 Osmotic stress activates nif and fix genes and induces the Rhizobium tropici CIAT 899 Nod factor production via NodD2 by up-regulation of the nodA2 operon and the nodA3 gene. PloS one 19 30917160
2019 Over-expression of Nav1.6 channels is associated with lymph node metastases in colorectal cancer. World journal of surgical oncology 19 31672162
2015 Selective blocking effects of 4,9-anhydrotetrodotoxin, purified from a crude mixture of tetrodotoxin analogues, on NaV1.6 channels and its chemical aspects. Marine drugs 19 25686275
2015 An Scn1a epilepsy mutation in Scn8a alters seizure susceptibility and behavior. Experimental neurology 19 26410685
2024 Molecular and cellular context influences SCN8A variant function. JCI insight 18 38771640
2006 Expression of Nav1.6 sodium channels by Schwann cells at neuromuscular junctions: role in the motor endplate disease phenotype. Glia 18 16078241
2020 Variable patterns of mutation density among NaV1.1, NaV1.2 and NaV1.6 point to channel-specific functional differences associated with childhood epilepsy. PloS one 17 32845893
2019 Biallelic inherited SCN8A variants, a rare cause of SCN8A-related developmental and epileptic encephalopathy. Epilepsia 17 31625145
2022 Cannabidiol Increases Seizure Resistance and Improves Behavior in an Scn8a Mouse Model. Frontiers in pharmacology 16 35153788
2019 NaV1.6 and NaV1.7 channels are major endogenous voltage-gated sodium channels in ND7/23 cells. PloS one 16 31419255
2018 Dissecting the Acid Stress Response of Rhizobium tropici CIAT 899. Frontiers in microbiology 16 29760688
2015 Complex SCN8A DNA-abnormalities in an individual with therapy resistant absence epilepsy. Epilepsy research 16 26220391
2024 Long-Term Downregulation of the Sodium Channel Gene Scn8a Is Therapeutic in Mouse Models of SCN8A Epilepsy. Annals of neurology 15 38113311
2024 Parvalbumin interneuron impairment causes synaptic transmission deficits and seizures in SCN8A developmental and epileptic encephalopathy. JCI insight 15 39435659
2009 Cerebellum-related characteristics of Scn8a-mutant mice. Cerebellum (London, England) 15 19424768

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