Affinage

SCN11A

Sodium channel protein type 11 subunit alpha · UniProt Q9UI33

Length
1791 aa
Mass
204.9 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 30 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

SCN11A encodes Nav1.9 (originally NaN), a tetrodotoxin-resistant voltage-gated sodium channel alpha-subunit preferentially expressed in small-diameter nociceptive neurons of dorsal root and trigeminal ganglia, where it generates a persistent, low-threshold Na+ current (PMID:9671787, PMID:15964986). Because it activates near rest with long open times and high open probability, Nav1.9 acts as a subthreshold amplifier that produces regenerative depolarizations, plateau potentials, oscillatory bursting, and bistable membrane behaviors lost in null neurons (PMID:23359282, PMID:18270172). This persistent current is potentiated by coincident inflammatory mediator signaling: PGE2 and a combination of inflammatory mediators acting through Gi/o G-proteins hyperpolarize the channel's activation and availability and increase mean open time and open probability, providing a coincidence-detection mechanism for inflammatory pain (PMID:15374752, PMID:23359282, PMID:18270172). Channel behavior is further shaped by developmentally regulated glycosylation, which sets the steady-state inactivation of the persistent current (PMID:11739573), and by nitric oxide signaling under tonic PKA control, which drives CGRP secretion in dural nociceptors during medication-overuse headache (PMID:31534133). Functionally, Nav1.9 contributes to inflammatory thermal and mechanical hypersensitivity, acute heat and mechanical nociception, cold pain, and itch, established through knockout, knockdown, and gain-of-function mouse models (PMID:15964986, PMID:25959819, PMID:30395542, PMID:21857998, PMID:27780178). Nav1.9 surface targeting along nonmyelinated axons is facilitated by direct binding to the cell adhesion molecule contactin, which recruits tenascin and enhances surface expression (PMID:11581273), and its C-terminus binds FHF1B (PMID:11376006). Gain-of-function SCN11A mutations cause a spectrum of pain disorders—from familial episodic pain and cold-aggravated pain through hyperexcitability, to congenital insensitivity to pain through resting depolarization and action-potential failure—while loss-of-function mutations also impair pain sensation, explained by a U-shaped relationship between resting potential and action-potential threshold (PMID:24036948, PMID:24207120, PMID:26645915, PMID:28530638).

Mechanistic history

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

    Established the existence and identity of Nav1.9 as a distinct sensory-neuron sodium channel, answering whether a separate alpha-subunit underlies TTX-resistant currents in nociceptors.

    Evidence Cloning, sequence analysis, Northern blot and in situ hybridization in DRG/trigeminal ganglia, with axotomy model

    PMID:9671787

    Open questions at the time
    • Did not directly demonstrate which current the channel carries
    • Functional electrophysiology of the cloned channel not yet shown
  2. 2001 High

    Identified the first direct protein partners of Nav1.9, addressing how the channel is targeted to and stabilized at the axonal membrane.

    Evidence Yeast two-hybrid, in vitro pulldown for FHF1B C-terminal binding; reciprocal Co-IP from DRG and CHO cells plus surface-expression assay for contactin/tenascin

    PMID:11376006 PMID:11581273

    Open questions at the time
    • Functional consequence of FHF1B binding on gating not determined
    • Structural basis of contactin-Nav1.9 interaction unresolved
  3. 2001 High

    Showed that post-translational glycosylation tunes Nav1.9 gating, answering how the channel's inactivation properties change developmentally.

    Evidence Western blot with enzymatic deglycosylation and neuraminidase treatment coupled to whole-cell patch-clamp in neonatal vs adult DRG neurons

    PMID:11739573

    Open questions at the time
    • Specific glycosylation sites not mapped
    • Enzymes mediating developmental glycosylation change unknown
  4. 2004 High

    Genetically proved Nav1.9 carries the persistent TTX-resistant current and defined its in vivo role in inflammatory but not neuropathic pain, resolving conflicting early antisense data.

    Evidence Gene knockout with whole-cell patch-clamp and behavioral testing across inflammation and nerve-injury models; earlier antisense knockdown had reported no neuropathic phenotype

    PMID:10393873 PMID:15964986

    Open questions at the time
    • Modest baseline acute nociception phenotype left role in normal sensation uncertain
    • Antisense vs knockout discrepancies not fully reconciled
  5. 2008 High

    Defined the biophysical and signaling mechanism of Nav1.9 potentiation, answering how G-proteins and inflammatory mediators amplify the persistent current.

    Evidence Whole-cell and single-channel patch-clamp with PGE2, pertussis/cholera toxin dissection, GTPgammaS dialysis, and conjoint inflammatory mediator application in DRG and heterologous cells

    PMID:15374752 PMID:18096591 PMID:18270172 PMID:23359282

    Open questions at the time
    • Direct G-protein subunit contact site on the channel not mapped
    • Identity of all converging mediator receptors incomplete
  6. 2004 High

    Characterized resting-state gating control and pharmacological state-dependence, establishing the channel's bias toward opening and modulator binding determinants.

    Evidence Single-channel and whole-cell analysis with fluoride manipulation; amitriptyline concentration-response; lysine K799 mutagenesis affecting local anesthetic potency

    PMID:15121184 PMID:24228717 PMID:27556810

    Open questions at the time
    • No structural validation of K799 in a binding pocket
    • Amitriptyline binding site not confirmed by mutagenesis
  7. 2015 High

    Solved the heterologous-expression barrier and mapped structural determinants of TTX resistance and slow inactivation, enabling mechanistic dissection of the channel.

    Evidence Nav1.4 C-terminal chimera plus IFM motif and S360Y mutagenesis with patch-clamp and two-electrode voltage-clamp; beta1/beta2 co-expression in HEK-293; S4-S5 linker mutation analysis

    PMID:25791876 PMID:25916202 PMID:27556810

    Open questions at the time
    • No high-resolution structure of native Nav1.9
    • Determinants limiting native trafficking incompletely defined
  8. 2017 High

    Extended Nav1.9 function to acute mechanical and thermal nociception at the C-fiber level, refining the view that it acts only in inflammation.

    Evidence Single-fiber and compound action potential recordings, Hargreaves testing, and CGRP-release assays in knockout vs WT mice

    PMID:27780178

    Open questions at the time
    • Contribution to specific fiber subtypes not fully resolved
    • Coupling to receptor potentials of individual transducers not dissected
  9. 2016 High

    Defined Nav1.9 as a subthreshold amplifier in cold-sensitive nociceptors, linking it to cold pain and chemotherapy-induced cold hypersensitivity.

    Evidence Knockout mice, antisense knockdown in rats, patch-clamp, cold-pain behavior, and oxaliplatin neuropathy model

    PMID:25959819

    Open questions at the time
    • Mechanism coupling cold transducers to Nav1.9 not detailed
    • Cold-specific regulation of channel activity unclear
  10. 2018 High

    Demonstrated a role for Nav1.9 in itch signaling, broadening its sensory function beyond pain.

    Evidence Fluorescent knock-in, knockout, and L799P gain-of-function knock-in mice with patch-clamp and pruritogen scratching assays

    PMID:30395542

    Open questions at the time
    • Pruritogen receptor coupling to Nav1.9 not defined
    • Distinction from pain pathways in shared neurons unclear
  11. 2013 High

    Established SCN11A as a human pain-disease gene with a bidirectional genotype-phenotype relationship, explaining how both gain and loss of function impair pain.

    Evidence Exome sequencing, knock-in mouse models, and dual voltage-/current-clamp characterizing mutations causing congenital pain insensitivity, familial episodic pain, cold-aggravated pain, and the U-shaped excitability relationship

    PMID:24036948 PMID:24207120 PMID:25791876 PMID:26645915 PMID:28530638

    Open questions at the time
    • Why specific mutations bias toward hyper- vs hypoexcitability not fully predictable
    • Therapeutic targeting of mutant channels not addressed
  12. 2019 High

    Identified nitric oxide and PKC-alpha as upstream regulators driving Nav1.9-dependent CGRP release in headache and arthritis, defining inflammatory signaling control of the channel.

    Evidence Scn11a knockout with dural afferent electrophysiology, CGRP/mast cell assays, PKA signaling analysis; PKC activator/inhibitor with qPCR, Western blot, immunofluorescence in arthritis model

    PMID:31385361 PMID:31534133

    Open questions at the time
    • Direct NO modification site on Nav1.9 not mapped
    • PKC-alpha-Nav1.9 regulation lacks a direct kinase-substrate assay
  13. 2014 Medium

    Detected Nav1.9 expression outside peripheral sensory neurons, raising the possibility of central and visceral roles.

    Evidence Immunohistochemistry and patch-clamp in supraoptic magnocellular neurosecretory cells; immunofluorescence and Western blot in human colon enteric neurons and Hirschsprung tissue

    PMID:24424281 PMID:27297039

    Open questions at the time
    • No genetic confirmation of functional role in these tissues
    • Physiological significance of central/visceral expression undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How upstream regulators (NO, PKC-alpha, G-proteins, glycosylation) physically and structurally converge on the Nav1.9 protein to set its open probability remains unresolved.
  • No high-resolution Nav1.9 structure available
  • Direct modification/binding sites for NO, PKC, and G-proteins not mapped
  • Mechanism integrating multiple regulatory inputs at the channel undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1643685 Disease 3 R-HSA-9709957 Sensory Perception 3
Partners
CNTN1FHF1BSCN1BSCN2BTNC

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 NaN (Nav1.9) is a novel voltage-gated sodium channel alpha-subunit predicted to be tetrodotoxin-resistant, preferentially expressed in peripheral sensory neurons of dorsal root ganglia and trigeminal ganglia; transcript levels are significantly reduced 7 days post-axotomy, consistent with reduction in TTX-R Na currents in DRG neurons. Sequence analysis, Northern blot, in situ hybridization, axotomy model Proceedings of the National Academy of Sciences of the United States of America High 9671787
2001 Fibroblast growth factor homologous factor 1B (FHF1B) directly binds the C-terminal region of Nav1.9 (rNav1.9a/NaN) but not the C-termini of Nav1.7 or Nav1.8; the N-terminal 5-77 residues of FHF1B are essential for this interaction. This was identified by yeast two-hybrid screen and confirmed by in vitro pulldown and co-expression in mammalian cell lines. Yeast two-hybrid screen, in vitro pulldown, co-expression in mammalian cell lines The Journal of biological chemistry High 11376006
2001 Cell adhesion molecule contactin binds directly to Nav1.9/NaN and recruits tenascin to the protein complex in vitro. Nav1.9 and contactin co-immunoprecipitate from DRG and co-transfected CHO cells; co-transfection with contactin enhances surface expression of Nav1.9 over Nav1.9 alone, indicating contactin participates in membrane targeting of Nav1.9 along nonmyelinated axons. Co-immunoprecipitation from DRG tissue and transfected CHO cells, co-localization by immunofluorescence, surface expression assay The Journal of biological chemistry High 11581273
2001 Glycosylation state of Nav1.9 is developmentally regulated: neonatal DRG neurons contain a higher-molecular-weight, more extensively glycosylated form of Nav1.9. Enzymatic deglycosylation collapses both forms to a single band. This developmental difference in glycosylation is paralleled by a 7 mV hyperpolarizing shift in steady-state inactivation of the persistent TTX-R current in neonatal versus adult DRG neurons; neuraminidase treatment of neonatal neurons reverses this shift. Western blot, enzymatic deglycosylation, whole-cell patch-clamp electrophysiology, neuraminidase treatment The Journal of neuroscience : the official journal of the Society for Neuroscience High 11739573
2000 GDNF upregulates both slowly inactivating (Nav1.8) and persistent (Nav1.9) TTX-resistant sodium currents and their mRNA and protein levels in axotomized DRG neurons in vitro and in vivo (intrathecal delivery). In SNS-null mice, GDNF still upregulates the persistent TTX-R current, demonstrating that this current is Nav1.9-dependent. In vitro and in vivo GDNF treatment, whole-cell patch-clamp, RT-PCR, Western blot, genetic null mouse model The Journal of neuroscience : the official journal of the Society for Neuroscience High 11102483
2003 Nav1.9 subunit generates the persistent TTX-resistant Na+ current in myenteric sensory (Dogiel type II) neurons of the enteric nervous system but not in interneurons or motor neurons. Expression confirmed by RT-PCR, single-cell profiling, and immunostaining; biophysical properties of the current are consistent with DRG Nav1.9. Whole-cell patch-clamp, RT-PCR, single-cell profiling, immunostaining The Journal of neuroscience : the official journal of the Society for Neuroscience High 12684457
2004 Nav1.9 underlies the persistent TTX-resistant Na+ current in small-diameter DRG neurons. Loss of SCN11A gene function (knockout mice) eliminates this persistent current and reveals that Nav1.9 contributes to persistent thermal hypersensitivity and spontaneous pain behavior after peripheral inflammation, but contributes little to mechanical/thermal responsiveness in the absence of injury or to mechanical hypersensitivity after nerve injury. Gene knockout, whole-cell patch-clamp, behavioral testing (von Frey, Hargreaves, formalin, CFA, nerve ligation models) Proceedings of the National Academy of Sciences of the United States of America High 15964986
2004 PGE2 increases Nav1.9 current approximately twofold in DRG neurons via Gi/o G-proteins (blocked by pertussis toxin but not cholera toxin), shifting steady-state activation by 6-8 mV and availability by 12 mV hyperpolarized, without affecting kinetics. Whole-cell patch-clamp in Nav1.8-null and wild-type mouse DRG neurons, pertussis toxin and cholera toxin pharmacological dissection Brain research High 15374752
2004 Nav1.9 channels exhibit long open times and high open probability generating persistent Na+ current. Single-channel recordings confirm that GTPγS (G-protein activation proxy) increases mean open time and open probability but does not change single-channel amplitude, explaining larger peak and persistent currents during inflammation. Single-channel and whole-cell patch-clamp in ND7/23 cells stably expressing human Nav1.9, GTPγS intracellular dialysis The Journal of general physiology High 23359282
2007 GTP (via GTPγS) upregulates the persistent TTX-resistant Na+ current and causes a negative shift in voltage threshold in small DRG neurons; this upregulation is absent in Nav1.9-null neurons, establishing that Nav1.9 is required for G-protein-regulated persistent current. Heterologous expression of human Nav1.9 in KO neurons restores the persistent current. Nav1.9 global knockout (exons 4-5 deletion), whole-cell patch-clamp, GTPγS intracellular dialysis, rescue by hNav1.9 transfection The Journal of physiology High 18096591
2008 Nav1.9 subunits carry the TTX-resistant 'persistent' NaN current in DRG neurons. Nav1.9-null nociceptors lose the ability to generate subthreshold regenerative depolarizations, plateau potentials, active hyperpolarizing responses, oscillatory bursting, and bistable membrane behaviors. A soup of multiple inflammatory mediators (bradykinin, ATP, histamine, PGE2, norepinephrine) applied conjointly—but not individually—potentiates Nav1.9 channel activity, generating subthreshold amplification and increased excitability (coincident detection mechanism). Nav1.9 gene targeting (knockout), whole-cell patch-clamp (CsCl and KCl pipettes), computer modeling, pharmacological inflammatory mediator application The Journal of general physiology High 18270172
2004 Internal fluoride in the recording pipette promotes entry of Nav1.9 channels into a preopen closed state, causing a strong bias toward opening and a large negative shift in activation and inactivation gates; this modulation of resting-closed states strongly influences nociceptor excitability. Single-channel analysis confirms this gating shift is specific to Nav1.9 and not Nav1.8. Single-channel and whole-cell patch-clamp from cultured DRG and myenteric neurons, comparison of CsCl vs. CsF pipette solutions Molecular and cellular neurosciences High 15121184
2013 A de novo gain-of-function missense mutation in SCN11A causes congenital inability to experience pain. Mutant Nav1.9 channels show excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired action potential generation, and aberrant synaptic transmission. Heterozygous knock-in mice carrying the orthologous mutation recapitulate reduced pain sensitivity and self-inflicted tissue lesions. Exome sequencing, knock-in mouse model, whole-cell patch-clamp, behavioral testing Nature genetics High 24036948
2013 Two gain-of-function missense mutations in SCN11A (p.Arg225Cys, p.Ala808Gly) enhance Nav1.9 channel electrical activity and induce hyperexcitability of DRG neurons when expressed in mouse DRG neurons, causing familial episodic pain disorder. Exome sequencing, Sanger sequencing, whole-cell patch-clamp in transfected mouse DRG neurons American journal of human genetics High 24207120
2015 A gain-of-function Nav1.9 mutation (p.V1184A) shifts voltage dependence of channel opening to hyperpolarized potentials, diminishes resting membrane potential of mouse primary sensory neurons, and causes cold-resistant hyperexcitability of nociceptors, providing a mechanistic basis for cold-aggravated pain. Whole-exome sequencing, whole-cell patch-clamp electrophysiology, current-clamp of mouse sensory neurons Nature communications High 26645915
2015 Nav1.9 mutation G699R in the domain II S4-S5 linker hyperpolarizes activation by -10.1 mV, depolarizes steady-state fast inactivation by +6.3 mV, slows deactivation, and enhances ramp responses. Current-clamp demonstrates DRG neuron hyperexcitability. This identifies the S4-S5 linker as a key structural determinant of Nav1.9 gating. Voltage-clamp in superior cervical ganglion neurons, current-clamp in DRG neurons, site-directed mutagenesis Neuromolecular medicine High 25791876
2015 Nav1.9 activity is upregulated in a subpopulation of cold-sensitive nociceptors, amplifying subthreshold depolarizations generated by cold transducers. Nav1.9-null mice and knockdown rats show increased cold pain thresholds; disrupting Nav1.9 also alleviates oxaliplatin-induced cold pain hypersensitivity. Nav1.9 functions as a subthreshold amplifier in cold-sensitive nociceptive neurons. Nav1.9 knockout mice, antisense knockdown in rats, whole-cell patch-clamp, behavioral cold pain testing, oxaliplatin neuropathy model Cell reports High 25959819
2016 Nav1.9 functional expression requires co-expression with β1/β2 subunits for optimal activity in HEK-293 cells. A unique lysine residue (K799) in domain 2 S6 pore domain influences interaction of inhibitors with the Nav1.9 pore (K799N mutation increases tetracaine potency but decreases TC-N 1752 potency), suggesting this residue modulates local anesthetic binding site. Stable HEK-293 expression of human/mouse/rat Nav1.9, whole-cell patch-clamp, site-directed mutagenesis (K799N), pharmacological profiling PloS one Medium 27556810
2015 The C-terminal structure of Nav1.9 limits its heterologous expression. A chimera of Nav1.9 harboring the C terminus of Nav1.4 enables functional expression in non-excitable cells (HEK 293T, Xenopus oocytes) and neuronal cells. The IFM inactivation motif mediates the unusual slow open-state inactivation of Nav1.9. Mutation S360Y renders Nav1.9 sensitive to tetrodotoxin and saxitoxin. Chimeric channel construction, patch-clamp and two-electrode voltage-clamp, site-directed mutagenesis (S360Y, IFM motif) Pflugers Archiv : European journal of physiology High 25916202
2017 Nav1.9 loss-of-function mutations (L1302F, L811P) associated with insensitivity to pain cause large hyperpolarizing shifts in activation voltage-dependence in heterologous cells and large depolarizations of resting membrane potential with impaired action potential generation in small DRG neurons, demonstrating cellular loss-of-function as the basis for impaired pain sensation. A U-shaped relationship between resting potential and action potential threshold explains why small Nav1.9 gain-of-function causes hyperexcitability while large gain-of-function causes hypoexcitability. Voltage-clamp in transfected heterologous cells, current-clamp in transfected rat DRG neurons The Journal of clinical investigation High 28530638
2019 Abnormal activation of Nav1.9 channels by nitric oxide (NO) is responsible for triptan-induced medication overuse headache (MOH). Deletion of Scn11a abolishes NO-mediated symptoms including cephalic/extracephalic allodynia, photophobia, and phonophobia. NO strongly activates Nav1.9 in dural afferent neurons from MOH mice; this triggers CGRP secretion, causing artery dilation and mast cell degranulation, whose mediators further potentiate Nav1.9. PKA is downregulated in trigeminal neurons from MOH mice, relieving its inhibitory action on NO-Nav1.9 coupling. Scn11a knockout, electrophysiology of dural afferent neurons, behavioral testing, CGRP secretion assay, mast cell degranulation assay, signaling network analysis (PKA) Nature communications High 31534133
2018 Nav1.9 is expressed in a subset of nonmyelinated, nonpeptidergic small-diameter DRG neurons. In WT DRG neurons but not Nav1.9-null neurons, pruritogens alter action potential parameters and Na channel gating properties. Nav1.9-null mice show strongly reduced acute scratching behavior to pruritogens; Nav1.9-gain-of-function knock-in mice (L799P) show increased spontaneous scratching, demonstrating Nav1.9 contributes to itch signaling. Nav1.9 fluorescent knock-in mouse line, Nav1.9 knockout, gain-of-function knock-in (L799P), patch-clamp, behavioral scratching assays with pruritogens The Journal of clinical investigation High 30395542
2011 Nav1.9 plays an important role in heat pain hypersensitivity induced by carrageenan (subacute) and CFA-induced monoarthritis (chronic), and also contributes to mechanical hypersensitivity in both models, as assessed in Nav1.9-null mice and Nav1.9 antisense knockdown rats. Increased Nav1.9 immunoreactivity was observed in ipsilateral DRGs and nerve fibers 24 h after carrageenan, consistent with increased axonal transport. Nav1.9 knockout mice, antisense knockdown in rats, behavioral testing (von Frey, Hargreaves, dynamic weight bearing), immunohistochemistry PloS one High 21857998
2019 Protein kinase C-α (PKCα) upregulates Nav1.9 expression in DRG neurons in an inflammatory arthritis model. PKC activator (PMA) increases Nav1.9 expression in cultured DRG neurons and naïve rats; PKC inhibitor (GF-109203X) prevents this upregulation. PKCα and Nav1.9 co-localize in IB4+ DRG neurons in rheumatoid arthritis model. CFA-induced arthritis rat model, PKC activator/inhibitor in vitro and in vivo, qPCR, Western blot, immunofluorescence Journal of cellular biochemistry Medium 31385361
1999 Antisense oligodeoxynucleotide knockdown of NaN/SNS2 protein in DRG has no effect on nerve injury-induced behavioral responses (hyperalgesia and allodynia), in contrast to knockdown of PN3/SNS (Nav1.8), suggesting Nav1.9 does not contribute to neuropathic pain behaviors in these models. Antisense oligodeoxynucleotide knockdown in rats, behavioral testing (hyperalgesia, allodynia) Proceedings of the National Academy of Sciences of the United States of America Medium 10393873
2017 Nav1.9-null C fibers have elevated electrical thresholds (55% higher), reduced prevalence of C mechano-heat-sensitive fibers (25.6% vs 75.8% in WT), elevated heat thresholds, reduced activity-dependent slowing of conduction upon noxious heat stimulation, and reduced heat-induced CGRP release, demonstrating Nav1.9 contributes to acute mechanical and thermal nociception by increasing excitability and amplifying receptor potentials. Single-fiber recordings from isolated skin, compound action potential recordings from sciatic nerve, Hargreaves test, CGRP release assay from KO vs WT mice Pain High 27780178
2013 Nav1.9 activation by nitric oxide and inflammatory mediators in dural nociceptors triggers CGRP secretion. Deletion of Scn11a abolishes NO-mediated cephalic allodynia in MOH, and PKA downregulation in trigeminal neurons from MOH mice relieves inhibitory control of NO-Nav1.9 coupling (replicated in the Bonnet 2019 paper with more detail). Scn11a knockout, behavioral tests, dural afferent electrophysiology Nature communications High 31534133
2014 Nav1.9 is expressed in vasopressin- and oxytocin-producing magnocellular neurosecretory cells (MSC) of the rat supraoptic nucleus, extending its known distribution beyond peripheral neurons. Cultured MSC exhibit sodium currents with characteristics of Nav1.9 channels. Nav1.8 is not detectable in the SON. Immunohistochemistry, whole-cell patch-clamp in cultured MSC, negative control for Nav1.8 Experimental neurology Medium 24424281
2016 Nav1.9 is expressed in Nav1.9-immunoreactive neurons of the submucosal and myenteric plexus of the human colon, co-localizing with the IPAN marker calbindin, and also on smooth muscle cells. Nav1.9 protein expression is markedly decreased in Hirschsprung's disease aganglionic tissue compared to normal controls. Confocal immunofluorescence with double-labeling (Nav1.9 + calbindin), Western blot Journal of pediatric surgery Medium 27297039
2013 Amitriptyline inhibits Nav1.9 currents in rat trigeminal DRG neurons in a concentration-dependent manner (IC50 ~15 μM), shifting steady-state inactivation in the hyperpolarizing direction without affecting voltage-dependent activation, and without use-dependent block, identifying amitriptyline as a state-selective blocker of Nav1.9. Whole-cell patch-clamp from acutely isolated rat trigeminal ganglion neurons, concentration-response analysis Molecular pain Medium 24228717

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy. Proceedings of the National Academy of Sciences of the United States of America 420 9671787
1999 A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain. Proceedings of the National Academy of Sciences of the United States of America 259 10393873
2013 A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nature genetics 241 24036948
2006 Intense isolectin-B4 binding in rat dorsal root ganglion neurons distinguishes C-fiber nociceptors with broad action potentials and high Nav1.9 expression. The Journal of neuroscience : the official journal of the Society for Neuroscience 222 16822986
2005 Contribution of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensory transmission and nociceptive behavior. Proceedings of the National Academy of Sciences of the United States of America 222 15964986
2002 NaN/Nav1.9: a sodium channel with unique properties. Trends in neurosciences 207 11972962
2000 Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states. Pain 175 10692601
2013 Gain-of-function mutations in SCN11A cause familial episodic pain. American journal of human genetics 155 24207120
2004 PGE2 increases the tetrodotoxin-resistant Nav1.9 sodium current in mouse DRG neurons via G-proteins. Brain research 140 15374752
2008 Inflammatory mediators increase Nav1.9 current and excitability in nociceptors through a coincident detection mechanism. The Journal of general physiology 137 18270172
2007 Pharmacological dissection and distribution of NaN/Nav1.9, T-type Ca2+ currents, and mechanically activated cation currents in different populations of DRG neurons. The Journal of general physiology 125 17190903
2007 Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. European journal of pain (London, England) 125 17950013
2001 Developmental expression of the TTX-resistant voltage-gated sodium channels Nav1.8 (SNS) and Nav1.9 (SNS2) in primary sensory neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 122 11487631
2001 Fibroblast growth factor homologous factor 1B binds to the C terminus of the tetrodotoxin-resistant sodium channel rNav1.9a (NaN). The Journal of biological chemistry 116 11376006
2003 Selective expression of a persistent tetrodotoxin-resistant Na+ current and NaV1.9 subunit in myenteric sensory neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 114 12684457
2000 Glial-derived neurotrophic factor upregulates expression of functional SNS and NaN sodium channels and their currents in axotomized dorsal root ganglion neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 111 11102483
2004 Gating and modulation of presumptive NaV1.9 channels in enteric and spinal sensory neurons. Molecular and cellular neurosciences 103 15121184
2007 GTP up-regulated persistent Na+ current and enhanced nociceptor excitability require NaV1.9. The Journal of physiology 95 18096591
1992 The putative 5-HT1A receptor antagonists NAN-190 and BMY 7378 are partial agonists in the rat dorsal raphe nucleus in vitro. European journal of pharmacology 94 1535319
2011 Nav1.9 channel contributes to mechanical and heat pain hypersensitivity induced by subacute and chronic inflammation. PloS one 87 21857998
2001 Glycosylation alters steady-state inactivation of sodium channel Nav1.9/NaN in dorsal root ganglion neurons and is developmentally regulated. The Journal of neuroscience : the official journal of the Society for Neuroscience 85 11739573
1990 NAN-190: agonist and antagonist interactions with brain 5-HT1A receptors. Brain research 83 2282513
2004 Differential expression of tetrodotoxin-resistant sodium channels Nav1.8 and Nav1.9 in normal and inflamed rats. Neuroscience letters 82 14729231
1999 Distribution of HLA gene and haplotype frequencies in Taiwan: a comparative study among Min-nan, Hakka, Aborigines and Mainland Chinese. Tissue antigens 72 10082431
2017 Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability. The Journal of clinical investigation 70 28530638
2015 Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant. Nature communications 70 26645915
2007 Expression and localization of the Nav1.9 sodium channel in enteric neurons and in trigeminal sensory endings: implication for intestinal reflex function and orofacial pain. Molecular and cellular neurosciences 70 17363266
2021 Identifying infectiousness of SARS-CoV-2 by ultra-sensitive SnS2 SERS biosensors with capillary effect. Matter 68 34957388
2001 Direct interaction with contactin targets voltage-gated sodium channel Na(v)1.9/NaN to the cell membrane. The Journal of biological chemistry 68 11581273
2018 SnS2 Quantum Dots as New Emitters with Strong Electrochemiluminescence for Ultrasensitive Antibody Detection. Analytical chemistry 67 30226050
2015 The Domain II S4-S5 Linker in Nav1.9: A Missense Mutation Enhances Activation, Impairs Fast Inactivation, and Produces Human Painful Neuropathy. Neuromolecular medicine 66 25791876
2015 The Nav1.9 channel is a key determinant of cold pain sensation and cold allodynia. Cell reports 65 25959819
2010 Severe anemia in the Nan mutant mouse caused by sequence-selective disruption of erythroid Kruppel-like factor. Proceedings of the National Academy of Sciences of the United States of America 65 20696915
2019 Synthesis and Application of CeO2/SnS2 Heterostructures as a Highly Efficient Coreaction Accelerator in the Luminol-Dissolved O2 System for Ultrasensitive Biomarkers Immunoassay. Analytical chemistry 63 31595739
1997 Influence of 5-HT1A receptor antagonism on plus-maze behaviour in mice. II. WAY 100635, SDZ 216-525 and NAN-190. Pharmacology, biochemistry, and behavior 59 9300624
1990 The behavioural, but not the hypothermic or corticosterone, response to 8-hydroxy-2-(DI-n-propylamino)-tetralin, is antagonized by NAN-190 in the rat. Neuropharmacology 54 2143565
1999 Coding sequence, genomic organization, and conserved chromosomal localization of the mouse gene Scn11a encoding the sodium channel NaN. Genomics 51 10444332
2013 Mechanism of sodium channel NaV1.9 potentiation by G-protein signaling. The Journal of general physiology 49 23359282
2020 Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels. Pflugers Archiv : European journal of physiology 46 32601768
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
2018 A disease mutation reveals a role for NaV1.9 in acute itch. The Journal of clinical investigation 45 30395542
2016 Biophysical and Pharmacological Characterization of Nav1.9 Voltage Dependent Sodium Channels Stably Expressed in HEK-293 Cells. PloS one 45 27556810
2015 Congenital insensitivity to pain: Fracturing without apparent skeletal pathobiology caused by an autosomal dominant, second mutation in SCN11A encoding voltage-gated sodium channel 1.9. Bone 45 26746779
2000 SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS letters 45 10675548
2013 Epidemiology and clinical features of rotavirus and norovirus infection among children in Ji'nan, China. Virology journal 43 24099150
2019 Quench-type electrochemiluminescence immunosensor for detection of amyloid β-protein based on resonance energy transfer from luminol@SnS2-Pd to Cu doped WO3 nanoparticles. Biosensors & bioelectronics 41 30928738
2016 Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families. PloS one 41 27224030
2011 Cooperative regulation of the Vibrio vulnificus nan gene cluster by NanR protein, cAMP receptor protein, and N-acetylmannosamine 6-phosphate. The Journal of biological chemistry 38 21956110
2010 Mutation in erythroid specific transcription factor KLF1 causes Hereditary Spherocytosis in the Nan hemolytic anemia mouse model. Genomics 38 20691777
2002 NAN fusions: a synthetic sialidase reporter gene as a sensitive and versatile partner for GUS. The Plant journal : for cell and molecular biology 38 12410816
2003 Tetrodotoxin-resistant sodium channels Na(v)1.8/SNS and Na(v)1.9/NaN in afferent neurons innervating urinary bladder in control and spinal cord injured rats. Brain research 37 12560118
2018 Ultrasensitive photoelectrochemical immunosensor for the detection of amyloid β-protein based on SnO2/SnS2/Ag2S nanocomposites. Biosensors & bioelectronics 36 30142477
2015 The role of Nav1.9 channel in the development of neuropathic orofacial pain associated with trigeminal neuralgia. Molecular pain 36 26607325
2012 Increased expression of tetrodotoxin-resistant sodium channels Nav1.8 and Nav1.9 within dorsal root ganglia in a rat model of bone cancer pain. Neuroscience letters 35 22342308
2000 Identification of a novel human voltage-gated sodium channel alpha subunit gene, SCN12A. Biochemical and biophysical research communications 35 10623608
1999 On the bioactive conformation of NAN-190 (1) and MP3022 (2), 5-HT(1A) receptor antagonists. Journal of medicinal chemistry 35 10585205
2020 Ultrasensitive Photoelectrochemical Assay for DNA Detection Based on a Novel SnS2/Co3O4 Sensitized Structure. Analytical chemistry 33 33047953
2017 Gain-of-function mutation p.Arg225Cys in SCN11A causes familial episodic pain and contributes to essential tremor. Journal of human genetics 33 28298626
2013 Correlation of Nav1.8 and Nav1.9 sodium channel expression with neuropathic pain in human subjects with lingual nerve neuromas. Molecular pain 33 24144460
2009 5-HT antagonists NAN-190 and SB 269970 block alpha2-adrenoceptors in the guinea pig. Neuroreport 33 19190523
2007 Expression of Nav1.9 channels in human dental pulp and trigeminal ganglion. Journal of endodontics 33 17889684
2002 Nerve fibers in lumbar spine structures and injured spinal roots express the sensory neuron-specific sodium channels SNS/PN3 and NaN/SNS2. Spine 32 11805657
2019 Maladaptive activation of Nav1.9 channels by nitric oxide causes triptan-induced medication overuse headache. Nature communications 31 31534133
2013 Electroacupuncture Reduces Carrageenan- and CFA-Induced Inflammatory Pain Accompanied by Changing the Expression of Nav1.7 and Nav1.8, rather than Nav1.9, in Mice Dorsal Root Ganglia. Evidence-based complementary and alternative medicine : eCAM 31 23573123
2018 SnS2 Nanosheets Coating on Nanohollow Cubic CoS2 /C for Ultralong Life and High Rate Capability Half/Full Sodium-Ion Batteries. Small (Weinheim an der Bergstrasse, Germany) 30 30152599
2017 Rapidly Synthesized, Few-Layered Pseudocapacitive SnS2 Anode for High-Power Sodium Ion Batteries. ACS applied materials & interfaces 29 29076723
2015 Heterologous expression of NaV1.9 chimeras in various cell systems. Pflugers Archiv : European journal of physiology 29 25916202
2022 Apatinib plus vinorelbine versus vinorelbine for metastatic triple-negative breast cancer who failed first/second-line treatment: the NAN trial. NPJ breast cancer 28 36127351
2019 SnS2@C Hollow Nanospheres with Robust Structural Stability as High-Performance Anodes for Sodium Ion Batteries. Nano-micro letters 28 34137992
1992 Discriminative stimulus effects of 8-OH-DPAT in pigeons: antagonism studies with the putative 5-HT1A receptor antagonists BMY 7378 and NAN-190. European journal of pharmacology 28 1425937
2008 Increased nerve fiber expression of sensory sodium channels Nav1.7, Nav1.8, And Nav1.9 in rhinitis. The Laryngoscope 26 18197135
2019 Characterization of 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(indole-7-carboxamido)morphinan (NAN) as a Novel Opioid Receptor Modulator for Opioid Use Disorder Treatment. ACS chemical neuroscience 25 30758946
2008 Primary erythermalgia as a sodium channelopathy: screening for SCN9A mutations: exclusion of a causal role of SCN10A and SCN11A. Archives of dermatology 25 18347287
2023 Fast Energy Storage of SnS2 Anode Nanoconfined in Hollow Porous Carbon Nanofibers for Lithium-Ion Batteries. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 24 38041500
2019 A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain. Frontiers in neuroscience 24 31551682
1991 Is NAN-190 an effective antagonist of the hypothermia and hyperglycemia induced by the 5-HT1A receptor agonist, 8-OH-DPAT? European journal of pharmacology 24 1828770
2018 Improved Electrochemical Performance Based on Nanostructured SnS2@CoS2-rGO Composite Anode for Sodium-Ion Batteries. Nano-micro letters 23 30393695
1996 Sleep and EEG power spectrum effects of the 5-HT1A antagonist NAN-190 alone and in combination with citalopram. Behavioural brain research 23 8800653
2013 Effect of amitriptyline on tetrodotoxin-resistant Nav1.9 currents in nociceptive trigeminal neurons. Molecular pain 22 24228717
2023 Effects of konjac glucan-nan/low-acyl gellan edible coatings loaded thymol-β-cyclodextrin microcapsules on postharvest blueberry. Food chemistry 21 37549621
2019 A Plasma-Triggered O-S Bond and P-N Junction Near the Surface of a SnS2 Nanosheet Array to Enable Efficient Solar Water Oxidation. Angewandte Chemie (International ed. in English) 21 31507028
2017 Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development. Development (Cambridge, England) 21 28143845
2021 Ag functionalized SnS2 with enhanced photothermal activity for safe and efficient wound disinfection. Biomaterials science 20 34032227
2017 Reduced excitability and impaired nociception in peripheral unmyelinated fibers from Nav1.9-null mice. Pain 20 27780178
2022 Unveiling Targets for Treating Postoperative Pain: The Role of the TNF-α/p38 MAPK/NF-κB/Nav1.8 and Nav1.9 Pathways in the Mouse Model of Incisional Pain. International journal of molecular sciences 19 36232927
2021 Catalytic decontamination of organic/inorganic pollutants in water and green H2 generation using nanoporous SnS2 micro-flower structured film. Journal of hazardous materials 19 34229394
2018 A Simple One-Pot Strategy for Synthesizing Ultrafine SnS2 Nanoparticle/Graphene Composites as Anodes for Lithium/Sodium-Ion Batteries. ChemSusChem 19 29516664
2010 Ethanolic cofermentation with glucose and xylose by the recombinant industrial strain Saccharomyces cerevisiae NAN-127 and the effect of furfural on xylitol production. Bioresource technology 19 20456950
1996 The role of 5-HT1A autoreceptors and alpha 1-adrenoceptors in the inhibition of 5-HT release--II NAN-190 and SDZ 216-525. Neuropharmacology 19 8887982
2018 Familial episodic limb pain in kindreds with novel Nav1.9 mutations. PloS one 18 30557356
2016 Development of SnS2/RGO nanosheet composite for cost-effective aqueous hybrid supercapacitors. Nanotechnology 18 27924781
2014 Nav1.9 expression in magnocellular neurosecretory cells of supraoptic nucleus. Experimental neurology 18 24424281
2012 Activation of tetrodotoxin-resistant sodium channel NaV1.9 in rat primary sensory neurons contributes to melittin-induced pain behavior. Neuromolecular medicine 18 23264124
2009 Hematologic characterization and chromosomal localization of the novel dominantly inherited mouse hemolytic anemia, neonatal anemia (Nan). Blood cells, molecules & diseases 18 19409822
1992 Effects of the putative 5-HT1A receptor antagonist NAN-190 on free feeding and on feeding induced by the 5-HT1A receptor agonist 8-OH-DPAT in the rat. European journal of pharmacology 18 1397037
2016 Decreased Nav1.9 channel expression in Hirschsprung's disease. Journal of pediatric surgery 17 27297039
1992 Antagonism studies with BMY-7378 and NAN-190: effects on 8-hydroxy-2-(di-n-propylamino)tetralin-induced increases in punished responding of pigeons. The Journal of pharmacology and experimental therapeutics 17 1531359
2020 Insights into the photocatalysis mechanism of the novel 2D/3D Z-Scheme g-C3N4/SnS2 heterojunction photocatalysts with excellent photocatalytic performances. Journal of hazardous materials 16 33254755
2019 Protein kinase C-α upregulates sodium channel Nav1.9 in nociceptive dorsal root ganglion neurons in an inflammatory arthritis pain model of rat. Journal of cellular biochemistry 16 31385361
2018 SCN11A Arg225Cys mutation causes nociceptive pain without detectable peripheral nerve pathology. Neurology. Genetics 16 30046661

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