{"gene":"SCN11A","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":1998,"finding":"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.","method":"Sequence analysis, Northern blot, in situ hybridization, axotomy model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — original cloning and characterization paper with multiple orthogonal methods; independently replicated across many subsequent studies","pmids":["9671787"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Yeast two-hybrid screen, in vitro pulldown, co-expression in mammalian cell lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding demonstrated by yeast two-hybrid and in vitro pulldown with domain-mapping mutagenesis in a single rigorous study","pmids":["11376006"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Co-immunoprecipitation from DRG tissue and transfected CHO cells, co-localization by immunofluorescence, surface expression assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP from native tissue and heterologous cells, functional consequence (surface expression) demonstrated, single lab","pmids":["11581273"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Western blot, enzymatic deglycosylation, whole-cell patch-clamp electrophysiology, neuraminidase treatment","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical deglycosylation combined with functional electrophysiology with pharmacological intervention, rigorous controls, single lab","pmids":["11739573"],"is_preprint":false},{"year":2000,"finding":"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.","method":"In vitro and in vivo GDNF treatment, whole-cell patch-clamp, RT-PCR, Western blot, genetic null mouse model","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods in vitro and in vivo, genetic confirmation with SNS-null mice, replicated across conditions","pmids":["11102483"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Whole-cell patch-clamp, RT-PCR, single-cell profiling, immunostaining","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology, molecular biology, immunostaining) in native tissue","pmids":["12684457"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Gene knockout, whole-cell patch-clamp, behavioral testing (von Frey, Hargreaves, formalin, CFA, nerve ligation models)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with electrophysiological and behavioral phenotyping; replicated by multiple subsequent KO studies","pmids":["15964986"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Whole-cell patch-clamp in Nav1.8-null and wild-type mouse DRG neurons, pertussis toxin and cholera toxin pharmacological dissection","journal":"Brain research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro electrophysiology with pharmacological pathway dissection using specific toxins, confirmed in two genetic backgrounds","pmids":["15374752"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Single-channel and whole-cell patch-clamp in ND7/23 cells stably expressing human Nav1.9, GTPγS intracellular dialysis","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-channel biophysical analysis with mechanistic GTPγS experiments establishing G-protein potentiation mechanism at single-channel level","pmids":["23359282"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Nav1.9 global knockout (exons 4-5 deletion), whole-cell patch-clamp, GTPγS intracellular dialysis, rescue by hNav1.9 transfection","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null with electrophysiological confirmation and rescue experiment; mechanistically definitive","pmids":["18096591"],"is_preprint":false},{"year":2008,"finding":"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).","method":"Nav1.9 gene targeting (knockout), whole-cell patch-clamp (CsCl and KCl pipettes), computer modeling, pharmacological inflammatory mediator application","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout combined with multiple electrophysiological paradigms and computational modeling; coincident detection mechanism demonstrated with orthogonal recording conditions","pmids":["18270172"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Single-channel and whole-cell patch-clamp from cultured DRG and myenteric neurons, comparison of CsCl vs. CsF pipette solutions","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-channel gating analysis with defined pharmacological manipulation, mechanistic detail at biophysical level","pmids":["15121184"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Exome sequencing, knock-in mouse model, whole-cell patch-clamp, behavioral testing","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics plus knock-in mouse model with electrophysiological characterization; mechanistic gain-of-function confirmed by multiple methods","pmids":["24036948"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Exome sequencing, Sanger sequencing, whole-cell patch-clamp in transfected mouse DRG neurons","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional expression in native DRG neurons with electrophysiological phenotyping, cosegregation in two independent families","pmids":["24207120"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Whole-exome sequencing, whole-cell patch-clamp electrophysiology, current-clamp of mouse sensory neurons","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — electrophysiological characterization of mutant channel and cellular hyperexcitability in native sensory neurons","pmids":["26645915"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Voltage-clamp in superior cervical ganglion neurons, current-clamp in DRG neurons, site-directed mutagenesis","journal":"Neuromolecular medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-function analysis with mutagenesis, dual voltage- and current-clamp in defined cellular contexts","pmids":["25791876"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Nav1.9 knockout mice, antisense knockdown in rats, whole-cell patch-clamp, behavioral cold pain testing, oxaliplatin neuropathy model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and antisense KD with electrophysiological and behavioral confirmation across multiple models","pmids":["25959819"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Stable HEK-293 expression of human/mouse/rat Nav1.9, whole-cell patch-clamp, site-directed mutagenesis (K799N), pharmacological profiling","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis with functional electrophysiology in heterologous system, single lab, no structural validation","pmids":["27556810"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Chimeric channel construction, patch-clamp and two-electrode voltage-clamp, site-directed mutagenesis (S360Y, IFM motif)","journal":"Pflugers Archiv : European journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — chimera and mutagenesis strategy with functional electrophysiological characterization, mechanistically definitive for gating and TTX-resistance determinants","pmids":["25916202"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Voltage-clamp in transfected heterologous cells, current-clamp in transfected rat DRG neurons","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — dual voltage- and current-clamp with two mutations, mechanistic model with U-shaped relationship established","pmids":["28530638"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Scn11a knockout, electrophysiology of dural afferent neurons, behavioral testing, CGRP secretion assay, mast cell degranulation assay, signaling network analysis (PKA)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple functional readouts (electrophysiology, secretion assays, behavioral), signaling mechanism identified","pmids":["31534133"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Nav1.9 fluorescent knock-in mouse line, Nav1.9 knockout, gain-of-function knock-in (L799P), patch-clamp, behavioral scratching assays with pruritogens","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple genetic mouse models with electrophysiological and behavioral characterization, single lab","pmids":["30395542"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Nav1.9 knockout mice, antisense knockdown in rats, behavioral testing (von Frey, Hargreaves, dynamic weight bearing), immunohistochemistry","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent loss-of-function approaches (genetic KO and antisense KD) across multiple behavioral modalities","pmids":["21857998"],"is_preprint":false},{"year":2019,"finding":"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.","method":"CFA-induced arthritis rat model, PKC activator/inhibitor in vitro and in vivo, qPCR, Western blot, immunofluorescence","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological manipulation with in vitro and in vivo confirmation, multiple readouts, but no direct kinase-substrate interaction assay","pmids":["31385361"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Antisense oligodeoxynucleotide knockdown in rats, behavioral testing (hyperalgesia, allodynia)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — negative result from antisense KD with behavioral assays, single lab, no electrophysiological confirmation of knockdown efficacy reported","pmids":["10393873"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Single-fiber recordings from isolated skin, compound action potential recordings from sciatic nerve, Hargreaves test, CGRP release assay from KO vs WT mice","journal":"Pain","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal electrophysiological techniques plus neurochemical readout in genetic KO, mechanistically detailed","pmids":["27780178"],"is_preprint":false},{"year":2013,"finding":"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).","method":"Scn11a knockout, behavioral tests, dural afferent electrophysiology","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple functional mechanistic readouts; full mechanistic detail reported in PMID 31534133","pmids":["31534133"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Immunohistochemistry, whole-cell patch-clamp in cultured MSC, negative control for Nav1.8","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — immunohistochemistry plus electrophysiology in native cells, single lab, no genetic confirmation","pmids":["24424281"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Confocal immunofluorescence with double-labeling (Nav1.9 + calbindin), Western blot","journal":"Journal of pediatric surgery","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — immunohistochemistry and Western blot, single lab, no electrophysiological confirmation","pmids":["27297039"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Whole-cell patch-clamp from acutely isolated rat trigeminal ganglion neurons, concentration-response analysis","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro pharmacological characterization with state-dependence analysis, single lab, no mutagenesis to confirm binding site","pmids":["24228717"],"is_preprint":false}],"current_model":"Nav1.9 (SCN11A) is a tetrodotoxin-resistant, voltage-gated sodium channel alpha-subunit preferentially expressed in small-diameter nociceptive DRG, trigeminal, and myenteric sensory neurons, where it generates a persistent, low-threshold Na+ current that sets resting membrane potential and amplifies subthreshold depolarizations; its activity is potentiated by coincident inflammatory mediator signaling through Gi/o G-proteins (increasing channel open probability and mean open time), regulated by glycosylation (which shifts steady-state inactivation), and modulated by nitric oxide and PKCα, while its surface expression is facilitated by direct interaction with the cell adhesion molecule contactin; gain-of-function mutations cause a spectrum of pain disorders (from familial episodic pain to congenital pain insensitivity) by either depolarizing nociceptors to the point of action potential failure or by rendering them hyperexcitable, depending on the magnitude of the resting membrane potential shift."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1998,"claim":"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","pmids":["9671787"],"confidence":"High","gaps":["Did not directly demonstrate which current the channel carries","Functional electrophysiology of the cloned channel not yet shown"]},{"year":2001,"claim":"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","pmids":["11376006","11581273"],"confidence":"High","gaps":["Functional consequence of FHF1B binding on gating not determined","Structural basis of contactin-Nav1.9 interaction unresolved"]},{"year":2001,"claim":"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","pmids":["11739573"],"confidence":"High","gaps":["Specific glycosylation sites not mapped","Enzymes mediating developmental glycosylation change unknown"]},{"year":2004,"claim":"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","pmids":["15964986","10393873"],"confidence":"High","gaps":["Modest baseline acute nociception phenotype left role in normal sensation uncertain","Antisense vs knockout discrepancies not fully reconciled"]},{"year":2008,"claim":"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","pmids":["15374752","23359282","18096591","18270172"],"confidence":"High","gaps":["Direct G-protein subunit contact site on the channel not mapped","Identity of all converging mediator receptors incomplete"]},{"year":2004,"claim":"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","pmids":["15121184","24228717","27556810"],"confidence":"High","gaps":["No structural validation of K799 in a binding pocket","Amitriptyline binding site not confirmed by mutagenesis"]},{"year":2015,"claim":"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","pmids":["25916202","27556810","25791876"],"confidence":"High","gaps":["No high-resolution structure of native Nav1.9","Determinants limiting native trafficking incompletely defined"]},{"year":2017,"claim":"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","pmids":["27780178"],"confidence":"High","gaps":["Contribution to specific fiber subtypes not fully resolved","Coupling to receptor potentials of individual transducers not dissected"]},{"year":2016,"claim":"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","pmids":["25959819"],"confidence":"High","gaps":["Mechanism coupling cold transducers to Nav1.9 not detailed","Cold-specific regulation of channel activity unclear"]},{"year":2018,"claim":"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","pmids":["30395542"],"confidence":"High","gaps":["Pruritogen receptor coupling to Nav1.9 not defined","Distinction from pain pathways in shared neurons unclear"]},{"year":2013,"claim":"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","pmids":["24036948","24207120","26645915","25791876","28530638"],"confidence":"High","gaps":["Why specific mutations bias toward hyper- vs hypoexcitability not fully predictable","Therapeutic targeting of mutant channels not addressed"]},{"year":2019,"claim":"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","pmids":["31534133","31385361"],"confidence":"High","gaps":["Direct NO modification site on Nav1.9 not mapped","PKC-alpha-Nav1.9 regulation lacks a direct kinase-substrate assay"]},{"year":2014,"claim":"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","pmids":["24424281","27297039"],"confidence":"Medium","gaps":["No genetic confirmation of functional role in these tissues","Physiological significance of central/visceral expression undefined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,6,8,10]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[10,16,25]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,17]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,10,25]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[16,21,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,13,19]}],"complexes":[],"partners":["CNTN1","FHF1B","TNC","SCN1B","SCN2B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UI33","full_name":"Sodium channel protein type 11 subunit alpha","aliases":["Peripheral nerve sodium channel 5","PN5","Sensory neuron sodium channel 2","Sodium channel protein type XI subunit alpha","Voltage-gated sodium channel subunit alpha Nav1.9","hNaN"],"length_aa":1791,"mass_kda":204.9,"function":"Sodium channel mediating the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which sodium ions may pass in accordance with their electrochemical gradient (PubMed:10580103, PubMed:12384689, PubMed:24036948, PubMed:24776970, PubMed:25791876, PubMed:26645915). Involved in membrane depolarization during action potential in nociceptors which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system (PubMed:24036948, PubMed:24776970, PubMed:25791876, PubMed:26645915). Also involved in rapid BDNF-evoked neuronal depolarization (PubMed:12384689)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UI33/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SCN11A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HMGA1","stoichiometry":0.2},{"gene":"HNRNPD","stoichiometry":0.2},{"gene":"LAMP1","stoichiometry":0.2},{"gene":"NUCKS1","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"RTN4","stoichiometry":0.2},{"gene":"SLC16A1","stoichiometry":0.2},{"gene":"TMED2","stoichiometry":0.2},{"gene":"VPS8","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SCN11A","total_profiled":1310},"omim":[{"mim_id":"615552","title":"EPISODIC PAIN SYNDROME, FAMILIAL, 3; FEPS3","url":"https://www.omim.org/entry/615552"},{"mim_id":"615548","title":"NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE VII; HSAN7","url":"https://www.omim.org/entry/615548"},{"mim_id":"615040","title":"EPISODIC PAIN SYNDROME, FAMILIAL, 1; FEPS1","url":"https://www.omim.org/entry/615040"},{"mim_id":"613698","title":"SOLUTE CARRIER FAMILY 25 (CARNITINE/ACYLCARNITINE TRANSLOCASE), MEMBER 20; SLC25A20","url":"https://www.omim.org/entry/613698"},{"mim_id":"608065","title":"SOLUTE CARRIER FAMILY 38 (AMINO ACID TRANSPORTER), MEMBER 4; SLC38A4","url":"https://www.omim.org/entry/608065"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":2.8},{"tissue":"placenta","ntpm":1.8},{"tissue":"urinary bladder","ntpm":2.0}],"url":"https://www.proteinatlas.org/search/SCN11A"},"hgnc":{"alias_symbol":["Nav1.9","NaN","SNS-2"],"prev_symbol":["SCN12A"]},"alphafold":{"accession":"Q9UI33","domains":[{"cath_id":"1.20.120.350","chopping":"14-37_54-229","consensus_level":"medium","plddt":75.3595,"start":14,"end":229},{"cath_id":"1.20.120.350","chopping":"559-595_603-683","consensus_level":"high","plddt":81.6512,"start":559,"end":683},{"cath_id":"1.20.120.350","chopping":"1056-1160","consensus_level":"high","plddt":82.7652,"start":1056,"end":1160},{"cath_id":"1.10.287","chopping":"1167-1318","consensus_level":"medium","plddt":83.9864,"start":1167,"end":1318},{"cath_id":"1.20.120.350","chopping":"1348-1480","consensus_level":"high","plddt":82.9297,"start":1348,"end":1480},{"cath_id":"1.10.238.10","chopping":"1621-1739","consensus_level":"high","plddt":76.6858,"start":1621,"end":1739},{"cath_id":"1.10.287","chopping":"685-723_754-822","consensus_level":"medium","plddt":77.0463,"start":685,"end":822}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI33","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI33-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI33-F1-predicted_aligned_error_v6.png","plddt_mean":69.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SCN11A","jax_strain_url":"https://www.jax.org/strain/search?query=SCN11A"},"sequence":{"accession":"Q9UI33","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UI33.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UI33/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI33"}},"corpus_meta":[{"pmid":"9671787","id":"PMC_9671787","title":"NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9671787","citation_count":420,"is_preprint":false},{"pmid":"10393873","id":"PMC_10393873","title":"A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10393873","citation_count":259,"is_preprint":false},{"pmid":"24036948","id":"PMC_24036948","title":"A de novo gain-of-function mutation in SCN11A causes loss of pain perception.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24036948","citation_count":241,"is_preprint":false},{"pmid":"15964986","id":"PMC_15964986","title":"Contribution of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensory transmission and nociceptive behavior.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15964986","citation_count":222,"is_preprint":false},{"pmid":"16822986","id":"PMC_16822986","title":"Intense isolectin-B4 binding in rat dorsal root ganglion neurons distinguishes C-fiber nociceptors with broad action potentials and high Nav1.9 expression.","date":"2006","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16822986","citation_count":222,"is_preprint":false},{"pmid":"11972962","id":"PMC_11972962","title":"NaN/Nav1.9: a sodium channel with unique properties.","date":"2002","source":"Trends in neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/11972962","citation_count":207,"is_preprint":false},{"pmid":"10692601","id":"PMC_10692601","title":"Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states.","date":"2000","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/10692601","citation_count":175,"is_preprint":false},{"pmid":"24207120","id":"PMC_24207120","title":"Gain-of-function mutations in SCN11A cause familial episodic pain.","date":"2013","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24207120","citation_count":155,"is_preprint":false},{"pmid":"15374752","id":"PMC_15374752","title":"PGE2 increases the tetrodotoxin-resistant Nav1.9 sodium current in mouse DRG neurons via G-proteins.","date":"2004","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/15374752","citation_count":140,"is_preprint":false},{"pmid":"18270172","id":"PMC_18270172","title":"Inflammatory mediators increase Nav1.9 current and excitability in nociceptors through a coincident detection mechanism.","date":"2008","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18270172","citation_count":137,"is_preprint":false},{"pmid":"17190903","id":"PMC_17190903","title":"Pharmacological dissection and distribution of NaN/Nav1.9, T-type Ca2+ currents, and mechanically activated cation currents in different populations of DRG neurons.","date":"2007","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17190903","citation_count":125,"is_preprint":false},{"pmid":"17950013","id":"PMC_17950013","title":"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.","date":"2007","source":"European journal of pain (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17950013","citation_count":125,"is_preprint":false},{"pmid":"11487631","id":"PMC_11487631","title":"Developmental expression of the TTX-resistant voltage-gated sodium channels Nav1.8 (SNS) and Nav1.9 (SNS2) in primary sensory neurons.","date":"2001","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/11487631","citation_count":122,"is_preprint":false},{"pmid":"11376006","id":"PMC_11376006","title":"Fibroblast growth factor homologous factor 1B binds to the C terminus of the tetrodotoxin-resistant sodium channel rNav1.9a (NaN).","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11376006","citation_count":116,"is_preprint":false},{"pmid":"12684457","id":"PMC_12684457","title":"Selective expression of a persistent tetrodotoxin-resistant Na+ current and NaV1.9 subunit in myenteric sensory neurons.","date":"2003","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12684457","citation_count":114,"is_preprint":false},{"pmid":"11102483","id":"PMC_11102483","title":"Glial-derived neurotrophic factor upregulates expression of functional SNS and NaN sodium channels and their currents in axotomized dorsal root ganglion neurons.","date":"2000","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/11102483","citation_count":111,"is_preprint":false},{"pmid":"15121184","id":"PMC_15121184","title":"Gating and modulation of presumptive NaV1.9 channels in enteric and spinal sensory neurons.","date":"2004","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/15121184","citation_count":103,"is_preprint":false},{"pmid":"18096591","id":"PMC_18096591","title":"GTP up-regulated persistent Na+ current and enhanced nociceptor excitability require NaV1.9.","date":"2007","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18096591","citation_count":95,"is_preprint":false},{"pmid":"1535319","id":"PMC_1535319","title":"The putative 5-HT1A receptor antagonists NAN-190 and BMY 7378 are partial agonists in the rat dorsal raphe nucleus in vitro.","date":"1992","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/1535319","citation_count":94,"is_preprint":false},{"pmid":"21857998","id":"PMC_21857998","title":"Nav1.9 channel contributes to mechanical and heat pain hypersensitivity induced by subacute and chronic inflammation.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21857998","citation_count":87,"is_preprint":false},{"pmid":"11739573","id":"PMC_11739573","title":"Glycosylation alters steady-state inactivation of sodium channel Nav1.9/NaN in dorsal root ganglion neurons and is developmentally regulated.","date":"2001","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/11739573","citation_count":85,"is_preprint":false},{"pmid":"2282513","id":"PMC_2282513","title":"NAN-190: agonist and antagonist interactions with brain 5-HT1A receptors.","date":"1990","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/2282513","citation_count":83,"is_preprint":false},{"pmid":"14729231","id":"PMC_14729231","title":"Differential expression of tetrodotoxin-resistant sodium channels Nav1.8 and Nav1.9 in normal and inflamed rats.","date":"2004","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/14729231","citation_count":82,"is_preprint":false},{"pmid":"10082431","id":"PMC_10082431","title":"Distribution of HLA gene and haplotype frequencies in Taiwan: a comparative study among Min-nan, Hakka, Aborigines and Mainland Chinese.","date":"1999","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/10082431","citation_count":72,"is_preprint":false},{"pmid":"26645915","id":"PMC_26645915","title":"Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26645915","citation_count":70,"is_preprint":false},{"pmid":"28530638","id":"PMC_28530638","title":"Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability.","date":"2017","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/28530638","citation_count":70,"is_preprint":false},{"pmid":"17363266","id":"PMC_17363266","title":"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.","date":"2007","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/17363266","citation_count":70,"is_preprint":false},{"pmid":"34957388","id":"PMC_34957388","title":"Identifying infectiousness of SARS-CoV-2 by ultra-sensitive SnS2 SERS biosensors with capillary effect.","date":"2021","source":"Matter","url":"https://pubmed.ncbi.nlm.nih.gov/34957388","citation_count":68,"is_preprint":false},{"pmid":"11581273","id":"PMC_11581273","title":"Direct interaction with contactin targets voltage-gated sodium channel Na(v)1.9/NaN to the cell membrane.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11581273","citation_count":68,"is_preprint":false},{"pmid":"30226050","id":"PMC_30226050","title":"SnS2 Quantum Dots as New Emitters with Strong Electrochemiluminescence for Ultrasensitive Antibody Detection.","date":"2018","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30226050","citation_count":67,"is_preprint":false},{"pmid":"25791876","id":"PMC_25791876","title":"The Domain II S4-S5 Linker in Nav1.9: A Missense Mutation Enhances Activation, Impairs Fast Inactivation, and Produces Human Painful Neuropathy.","date":"2015","source":"Neuromolecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25791876","citation_count":66,"is_preprint":false},{"pmid":"25959819","id":"PMC_25959819","title":"The Nav1.9 channel is a key determinant of cold pain sensation and cold allodynia.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25959819","citation_count":65,"is_preprint":false},{"pmid":"20696915","id":"PMC_20696915","title":"Severe anemia in the Nan mutant mouse caused by sequence-selective disruption of erythroid Kruppel-like factor.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20696915","citation_count":65,"is_preprint":false},{"pmid":"31595739","id":"PMC_31595739","title":"Synthesis and Application of CeO2/SnS2 Heterostructures as a Highly Efficient Coreaction Accelerator in the Luminol-Dissolved O2 System for Ultrasensitive Biomarkers Immunoassay.","date":"2019","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31595739","citation_count":63,"is_preprint":false},{"pmid":"9300624","id":"PMC_9300624","title":"Influence of 5-HT1A receptor antagonism on plus-maze behaviour in mice. II. WAY 100635, SDZ 216-525 and NAN-190.","date":"1997","source":"Pharmacology, biochemistry, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/9300624","citation_count":59,"is_preprint":false},{"pmid":"2143565","id":"PMC_2143565","title":"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.","date":"1990","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/2143565","citation_count":54,"is_preprint":false},{"pmid":"10444332","id":"PMC_10444332","title":"Coding sequence, genomic organization, and conserved chromosomal localization of the mouse gene Scn11a encoding the sodium channel NaN.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10444332","citation_count":51,"is_preprint":false},{"pmid":"23359282","id":"PMC_23359282","title":"Mechanism of sodium channel NaV1.9 potentiation by G-protein signaling.","date":"2013","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23359282","citation_count":49,"is_preprint":false},{"pmid":"32601768","id":"PMC_32601768","title":"Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels.","date":"2020","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32601768","citation_count":46,"is_preprint":false},{"pmid":"27327156","id":"PMC_27327156","title":"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.","date":"2016","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/27327156","citation_count":46,"is_preprint":false},{"pmid":"26746779","id":"PMC_26746779","title":"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.","date":"2015","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/26746779","citation_count":45,"is_preprint":false},{"pmid":"27556810","id":"PMC_27556810","title":"Biophysical and Pharmacological Characterization of Nav1.9 Voltage Dependent Sodium Channels Stably Expressed in HEK-293 Cells.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27556810","citation_count":45,"is_preprint":false},{"pmid":"30395542","id":"PMC_30395542","title":"A disease mutation reveals a role for NaV1.9 in acute itch.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30395542","citation_count":45,"is_preprint":false},{"pmid":"10675548","id":"PMC_10675548","title":"SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves.","date":"2000","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10675548","citation_count":45,"is_preprint":false},{"pmid":"24099150","id":"PMC_24099150","title":"Epidemiology and clinical features of rotavirus and norovirus infection among children in Ji'nan, China.","date":"2013","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/24099150","citation_count":43,"is_preprint":false},{"pmid":"27224030","id":"PMC_27224030","title":"Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27224030","citation_count":41,"is_preprint":false},{"pmid":"30928738","id":"PMC_30928738","title":"Quench-type electrochemiluminescence immunosensor for detection of amyloid β-protein based on resonance energy transfer from luminol@SnS2-Pd to Cu doped WO3 nanoparticles.","date":"2019","source":"Biosensors & bioelectronics","url":"https://pubmed.ncbi.nlm.nih.gov/30928738","citation_count":41,"is_preprint":false},{"pmid":"12410816","id":"PMC_12410816","title":"NAN fusions: a synthetic sialidase reporter gene as a sensitive and versatile partner for GUS.","date":"2002","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12410816","citation_count":38,"is_preprint":false},{"pmid":"21956110","id":"PMC_21956110","title":"Cooperative regulation of the Vibrio vulnificus nan gene cluster by NanR protein, cAMP receptor protein, and N-acetylmannosamine 6-phosphate.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21956110","citation_count":38,"is_preprint":false},{"pmid":"20691777","id":"PMC_20691777","title":"Mutation in erythroid specific transcription factor KLF1 causes Hereditary Spherocytosis in the Nan hemolytic anemia mouse model.","date":"2010","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/20691777","citation_count":38,"is_preprint":false},{"pmid":"12560118","id":"PMC_12560118","title":"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.","date":"2003","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/12560118","citation_count":37,"is_preprint":false},{"pmid":"30142477","id":"PMC_30142477","title":"Ultrasensitive photoelectrochemical immunosensor for the detection of amyloid β-protein based on SnO2/SnS2/Ag2S nanocomposites.","date":"2018","source":"Biosensors & bioelectronics","url":"https://pubmed.ncbi.nlm.nih.gov/30142477","citation_count":36,"is_preprint":false},{"pmid":"26607325","id":"PMC_26607325","title":"The role of Nav1.9 channel in the development of neuropathic orofacial pain associated with trigeminal neuralgia.","date":"2015","source":"Molecular pain","url":"https://pubmed.ncbi.nlm.nih.gov/26607325","citation_count":36,"is_preprint":false},{"pmid":"10623608","id":"PMC_10623608","title":"Identification of a novel human voltage-gated sodium channel alpha subunit gene, SCN12A.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10623608","citation_count":35,"is_preprint":false},{"pmid":"22342308","id":"PMC_22342308","title":"Increased expression of tetrodotoxin-resistant sodium channels Nav1.8 and Nav1.9 within dorsal root ganglia in a rat model of bone cancer pain.","date":"2012","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/22342308","citation_count":35,"is_preprint":false},{"pmid":"10585205","id":"PMC_10585205","title":"On the bioactive conformation of NAN-190 (1) and MP3022 (2), 5-HT(1A) receptor antagonists.","date":"1999","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10585205","citation_count":35,"is_preprint":false},{"pmid":"28298626","id":"PMC_28298626","title":"Gain-of-function mutation p.Arg225Cys in SCN11A causes familial episodic pain and contributes to essential tremor.","date":"2017","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28298626","citation_count":33,"is_preprint":false},{"pmid":"17889684","id":"PMC_17889684","title":"Expression of Nav1.9 channels in human dental pulp and trigeminal ganglion.","date":"2007","source":"Journal of endodontics","url":"https://pubmed.ncbi.nlm.nih.gov/17889684","citation_count":33,"is_preprint":false},{"pmid":"24144460","id":"PMC_24144460","title":"Correlation of Nav1.8 and Nav1.9 sodium channel expression with neuropathic pain in human subjects with lingual nerve neuromas.","date":"2013","source":"Molecular pain","url":"https://pubmed.ncbi.nlm.nih.gov/24144460","citation_count":33,"is_preprint":false},{"pmid":"33047953","id":"PMC_33047953","title":"Ultrasensitive Photoelectrochemical Assay for DNA Detection Based on a Novel SnS2/Co3O4 Sensitized Structure.","date":"2020","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33047953","citation_count":33,"is_preprint":false},{"pmid":"19190523","id":"PMC_19190523","title":"5-HT antagonists NAN-190 and SB 269970 block alpha2-adrenoceptors in the guinea pig.","date":"2009","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/19190523","citation_count":33,"is_preprint":false},{"pmid":"11805657","id":"PMC_11805657","title":"Nerve fibers in lumbar spine structures and injured spinal roots express the sensory neuron-specific sodium channels SNS/PN3 and NaN/SNS2.","date":"2002","source":"Spine","url":"https://pubmed.ncbi.nlm.nih.gov/11805657","citation_count":32,"is_preprint":false},{"pmid":"31534133","id":"PMC_31534133","title":"Maladaptive activation of Nav1.9 channels by nitric oxide causes triptan-induced medication overuse headache.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31534133","citation_count":31,"is_preprint":false},{"pmid":"23573123","id":"PMC_23573123","title":"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.","date":"2013","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/23573123","citation_count":31,"is_preprint":false},{"pmid":"30152599","id":"PMC_30152599","title":"SnS2 Nanosheets Coating on Nanohollow Cubic CoS2 /C for Ultralong Life and High Rate Capability Half/Full Sodium-Ion Batteries.","date":"2018","source":"Small (Weinheim an der Bergstrasse, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/30152599","citation_count":30,"is_preprint":false},{"pmid":"25916202","id":"PMC_25916202","title":"Heterologous expression of NaV1.9 chimeras in various cell systems.","date":"2015","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25916202","citation_count":29,"is_preprint":false},{"pmid":"29076723","id":"PMC_29076723","title":"Rapidly Synthesized, Few-Layered Pseudocapacitive SnS2 Anode for High-Power Sodium Ion Batteries.","date":"2017","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/29076723","citation_count":29,"is_preprint":false},{"pmid":"34137992","id":"PMC_34137992","title":"SnS2@C Hollow Nanospheres with Robust Structural Stability as High-Performance Anodes for Sodium Ion Batteries.","date":"2019","source":"Nano-micro letters","url":"https://pubmed.ncbi.nlm.nih.gov/34137992","citation_count":28,"is_preprint":false},{"pmid":"36127351","id":"PMC_36127351","title":"Apatinib plus vinorelbine versus vinorelbine for metastatic triple-negative breast cancer who failed first/second-line treatment: the NAN trial.","date":"2022","source":"NPJ breast cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36127351","citation_count":28,"is_preprint":false},{"pmid":"1425937","id":"PMC_1425937","title":"Discriminative stimulus effects of 8-OH-DPAT in pigeons: antagonism studies with the putative 5-HT1A receptor antagonists BMY 7378 and NAN-190.","date":"1992","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/1425937","citation_count":28,"is_preprint":false},{"pmid":"18197135","id":"PMC_18197135","title":"Increased nerve fiber expression of sensory sodium channels Nav1.7, Nav1.8, And Nav1.9 in rhinitis.","date":"2008","source":"The Laryngoscope","url":"https://pubmed.ncbi.nlm.nih.gov/18197135","citation_count":26,"is_preprint":false},{"pmid":"18347287","id":"PMC_18347287","title":"Primary erythermalgia as a sodium channelopathy: screening for SCN9A mutations: exclusion of a causal role of SCN10A and SCN11A.","date":"2008","source":"Archives of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/18347287","citation_count":25,"is_preprint":false},{"pmid":"30758946","id":"PMC_30758946","title":"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.","date":"2019","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30758946","citation_count":25,"is_preprint":false},{"pmid":"31551682","id":"PMC_31551682","title":"A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain.","date":"2019","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31551682","citation_count":24,"is_preprint":false},{"pmid":"38041500","id":"PMC_38041500","title":"Fast Energy Storage of SnS2 Anode Nanoconfined in Hollow Porous Carbon Nanofibers for Lithium-Ion Batteries.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38041500","citation_count":24,"is_preprint":false},{"pmid":"1828770","id":"PMC_1828770","title":"Is NAN-190 an effective antagonist of the hypothermia and hyperglycemia induced by the 5-HT1A receptor agonist, 8-OH-DPAT?","date":"1991","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/1828770","citation_count":24,"is_preprint":false},{"pmid":"30393695","id":"PMC_30393695","title":"Improved Electrochemical Performance Based on Nanostructured SnS2@CoS2-rGO Composite Anode for Sodium-Ion Batteries.","date":"2018","source":"Nano-micro letters","url":"https://pubmed.ncbi.nlm.nih.gov/30393695","citation_count":23,"is_preprint":false},{"pmid":"8800653","id":"PMC_8800653","title":"Sleep and EEG power spectrum effects of the 5-HT1A antagonist NAN-190 alone and in combination with citalopram.","date":"1996","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/8800653","citation_count":23,"is_preprint":false},{"pmid":"24228717","id":"PMC_24228717","title":"Effect of amitriptyline on tetrodotoxin-resistant Nav1.9 currents in nociceptive trigeminal neurons.","date":"2013","source":"Molecular pain","url":"https://pubmed.ncbi.nlm.nih.gov/24228717","citation_count":22,"is_preprint":false},{"pmid":"37549621","id":"PMC_37549621","title":"Effects of konjac glucan-nan/low-acyl gellan edible coatings loaded thymol-β-cyclodextrin microcapsules on postharvest blueberry.","date":"2023","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37549621","citation_count":21,"is_preprint":false},{"pmid":"31507028","id":"PMC_31507028","title":"A Plasma-Triggered O-S Bond and P-N Junction Near the Surface of a SnS2 Nanosheet Array to Enable Efficient Solar Water Oxidation.","date":"2019","source":"Angewandte Chemie (International ed. in English)","url":"https://pubmed.ncbi.nlm.nih.gov/31507028","citation_count":21,"is_preprint":false},{"pmid":"28143845","id":"PMC_28143845","title":"Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development.","date":"2017","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28143845","citation_count":21,"is_preprint":false},{"pmid":"34032227","id":"PMC_34032227","title":"Ag functionalized SnS2 with enhanced photothermal activity for safe and efficient wound disinfection.","date":"2021","source":"Biomaterials science","url":"https://pubmed.ncbi.nlm.nih.gov/34032227","citation_count":20,"is_preprint":false},{"pmid":"27780178","id":"PMC_27780178","title":"Reduced excitability and impaired nociception in peripheral unmyelinated fibers from Nav1.9-null mice.","date":"2017","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/27780178","citation_count":20,"is_preprint":false},{"pmid":"36232927","id":"PMC_36232927","title":"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.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36232927","citation_count":19,"is_preprint":false},{"pmid":"34229394","id":"PMC_34229394","title":"Catalytic decontamination of organic/inorganic pollutants in water and green H2 generation using nanoporous SnS2 micro-flower structured film.","date":"2021","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/34229394","citation_count":19,"is_preprint":false},{"pmid":"8887982","id":"PMC_8887982","title":"The role of 5-HT1A autoreceptors and alpha 1-adrenoceptors in the inhibition of 5-HT release--II NAN-190 and SDZ 216-525.","date":"1996","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/8887982","citation_count":19,"is_preprint":false},{"pmid":"29516664","id":"PMC_29516664","title":"A Simple One-Pot Strategy for Synthesizing Ultrafine SnS2 Nanoparticle/Graphene Composites as Anodes for Lithium/Sodium-Ion Batteries.","date":"2018","source":"ChemSusChem","url":"https://pubmed.ncbi.nlm.nih.gov/29516664","citation_count":19,"is_preprint":false},{"pmid":"20456950","id":"PMC_20456950","title":"Ethanolic cofermentation with glucose and xylose by the recombinant industrial strain Saccharomyces cerevisiae NAN-127 and the effect of furfural on xylitol production.","date":"2010","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/20456950","citation_count":19,"is_preprint":false},{"pmid":"24424281","id":"PMC_24424281","title":"Nav1.9 expression in magnocellular neurosecretory cells of supraoptic nucleus.","date":"2014","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24424281","citation_count":18,"is_preprint":false},{"pmid":"30557356","id":"PMC_30557356","title":"Familial episodic limb pain in kindreds with novel Nav1.9 mutations.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30557356","citation_count":18,"is_preprint":false},{"pmid":"27924781","id":"PMC_27924781","title":"Development of SnS2/RGO nanosheet composite for cost-effective aqueous hybrid supercapacitors.","date":"2016","source":"Nanotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/27924781","citation_count":18,"is_preprint":false},{"pmid":"23264124","id":"PMC_23264124","title":"Activation of tetrodotoxin-resistant sodium channel NaV1.9 in rat primary sensory neurons contributes to melittin-induced pain behavior.","date":"2012","source":"Neuromolecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23264124","citation_count":18,"is_preprint":false},{"pmid":"1397037","id":"PMC_1397037","title":"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.","date":"1992","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/1397037","citation_count":18,"is_preprint":false},{"pmid":"19409822","id":"PMC_19409822","title":"Hematologic characterization and chromosomal localization of the novel dominantly inherited mouse hemolytic anemia, neonatal anemia (Nan).","date":"2009","source":"Blood cells, molecules & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19409822","citation_count":18,"is_preprint":false},{"pmid":"27297039","id":"PMC_27297039","title":"Decreased Nav1.9 channel expression in Hirschsprung's disease.","date":"2016","source":"Journal of pediatric surgery","url":"https://pubmed.ncbi.nlm.nih.gov/27297039","citation_count":17,"is_preprint":false},{"pmid":"1531359","id":"PMC_1531359","title":"Antagonism studies with BMY-7378 and NAN-190: effects on 8-hydroxy-2-(di-n-propylamino)tetralin-induced increases in punished responding of pigeons.","date":"1992","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/1531359","citation_count":17,"is_preprint":false},{"pmid":"30046661","id":"PMC_30046661","title":"SCN11A Arg225Cys mutation causes nociceptive pain without detectable peripheral nerve pathology.","date":"2018","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30046661","citation_count":16,"is_preprint":false},{"pmid":"31385361","id":"PMC_31385361","title":"Protein kinase C-α upregulates sodium channel Nav1.9 in nociceptive dorsal root ganglion neurons in an inflammatory arthritis pain model of rat.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31385361","citation_count":16,"is_preprint":false},{"pmid":"33254755","id":"PMC_33254755","title":"Insights into the photocatalysis mechanism of the novel 2D/3D Z-Scheme g-C3N4/SnS2 heterojunction photocatalysts with excellent photocatalytic performances.","date":"2020","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/33254755","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50782,"output_tokens":7668,"usd":0.133683,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17380,"output_tokens":4391,"usd":0.098337,"stage2_stop_reason":"end_turn"},"total_usd":0.23202,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Sequence analysis, Northern blot, in situ hybridization, axotomy model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — original cloning and characterization paper with multiple orthogonal methods; independently replicated across many subsequent studies\",\n      \"pmids\": [\"9671787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro pulldown, co-expression in mammalian cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding demonstrated by yeast two-hybrid and in vitro pulldown with domain-mapping mutagenesis in a single rigorous study\",\n      \"pmids\": [\"11376006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation from DRG tissue and transfected CHO cells, co-localization by immunofluorescence, surface expression assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP from native tissue and heterologous cells, functional consequence (surface expression) demonstrated, single lab\",\n      \"pmids\": [\"11581273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Western blot, enzymatic deglycosylation, whole-cell patch-clamp electrophysiology, neuraminidase treatment\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical deglycosylation combined with functional electrophysiology with pharmacological intervention, rigorous controls, single lab\",\n      \"pmids\": [\"11739573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro and in vivo GDNF treatment, whole-cell patch-clamp, RT-PCR, Western blot, genetic null mouse model\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods in vitro and in vivo, genetic confirmation with SNS-null mice, replicated across conditions\",\n      \"pmids\": [\"11102483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp, RT-PCR, single-cell profiling, immunostaining\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology, molecular biology, immunostaining) in native tissue\",\n      \"pmids\": [\"12684457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Gene knockout, whole-cell patch-clamp, behavioral testing (von Frey, Hargreaves, formalin, CFA, nerve ligation models)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with electrophysiological and behavioral phenotyping; replicated by multiple subsequent KO studies\",\n      \"pmids\": [\"15964986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp in Nav1.8-null and wild-type mouse DRG neurons, pertussis toxin and cholera toxin pharmacological dissection\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro electrophysiology with pharmacological pathway dissection using specific toxins, confirmed in two genetic backgrounds\",\n      \"pmids\": [\"15374752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Single-channel and whole-cell patch-clamp in ND7/23 cells stably expressing human Nav1.9, GTPγS intracellular dialysis\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-channel biophysical analysis with mechanistic GTPγS experiments establishing G-protein potentiation mechanism at single-channel level\",\n      \"pmids\": [\"23359282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Nav1.9 global knockout (exons 4-5 deletion), whole-cell patch-clamp, GTPγS intracellular dialysis, rescue by hNav1.9 transfection\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null with electrophysiological confirmation and rescue experiment; mechanistically definitive\",\n      \"pmids\": [\"18096591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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).\",\n      \"method\": \"Nav1.9 gene targeting (knockout), whole-cell patch-clamp (CsCl and KCl pipettes), computer modeling, pharmacological inflammatory mediator application\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout combined with multiple electrophysiological paradigms and computational modeling; coincident detection mechanism demonstrated with orthogonal recording conditions\",\n      \"pmids\": [\"18270172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Single-channel and whole-cell patch-clamp from cultured DRG and myenteric neurons, comparison of CsCl vs. CsF pipette solutions\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-channel gating analysis with defined pharmacological manipulation, mechanistic detail at biophysical level\",\n      \"pmids\": [\"15121184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Exome sequencing, knock-in mouse model, whole-cell patch-clamp, behavioral testing\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics plus knock-in mouse model with electrophysiological characterization; mechanistic gain-of-function confirmed by multiple methods\",\n      \"pmids\": [\"24036948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Exome sequencing, Sanger sequencing, whole-cell patch-clamp in transfected mouse DRG neurons\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional expression in native DRG neurons with electrophysiological phenotyping, cosegregation in two independent families\",\n      \"pmids\": [\"24207120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-exome sequencing, whole-cell patch-clamp electrophysiology, current-clamp of mouse sensory neurons\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiological characterization of mutant channel and cellular hyperexcitability in native sensory neurons\",\n      \"pmids\": [\"26645915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Voltage-clamp in superior cervical ganglion neurons, current-clamp in DRG neurons, site-directed mutagenesis\",\n      \"journal\": \"Neuromolecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-function analysis with mutagenesis, dual voltage- and current-clamp in defined cellular contexts\",\n      \"pmids\": [\"25791876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Nav1.9 knockout mice, antisense knockdown in rats, whole-cell patch-clamp, behavioral cold pain testing, oxaliplatin neuropathy model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and antisense KD with electrophysiological and behavioral confirmation across multiple models\",\n      \"pmids\": [\"25959819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Stable HEK-293 expression of human/mouse/rat Nav1.9, whole-cell patch-clamp, site-directed mutagenesis (K799N), pharmacological profiling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis with functional electrophysiology in heterologous system, single lab, no structural validation\",\n      \"pmids\": [\"27556810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Chimeric channel construction, patch-clamp and two-electrode voltage-clamp, site-directed mutagenesis (S360Y, IFM motif)\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chimera and mutagenesis strategy with functional electrophysiological characterization, mechanistically definitive for gating and TTX-resistance determinants\",\n      \"pmids\": [\"25916202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Voltage-clamp in transfected heterologous cells, current-clamp in transfected rat DRG neurons\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual voltage- and current-clamp with two mutations, mechanistic model with U-shaped relationship established\",\n      \"pmids\": [\"28530638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Scn11a knockout, electrophysiology of dural afferent neurons, behavioral testing, CGRP secretion assay, mast cell degranulation assay, signaling network analysis (PKA)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple functional readouts (electrophysiology, secretion assays, behavioral), signaling mechanism identified\",\n      \"pmids\": [\"31534133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Nav1.9 fluorescent knock-in mouse line, Nav1.9 knockout, gain-of-function knock-in (L799P), patch-clamp, behavioral scratching assays with pruritogens\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic mouse models with electrophysiological and behavioral characterization, single lab\",\n      \"pmids\": [\"30395542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Nav1.9 knockout mice, antisense knockdown in rats, behavioral testing (von Frey, Hargreaves, dynamic weight bearing), immunohistochemistry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent loss-of-function approaches (genetic KO and antisense KD) across multiple behavioral modalities\",\n      \"pmids\": [\"21857998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"CFA-induced arthritis rat model, PKC activator/inhibitor in vitro and in vivo, qPCR, Western blot, immunofluorescence\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological manipulation with in vitro and in vivo confirmation, multiple readouts, but no direct kinase-substrate interaction assay\",\n      \"pmids\": [\"31385361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Antisense oligodeoxynucleotide knockdown in rats, behavioral testing (hyperalgesia, allodynia)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — negative result from antisense KD with behavioral assays, single lab, no electrophysiological confirmation of knockdown efficacy reported\",\n      \"pmids\": [\"10393873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Single-fiber recordings from isolated skin, compound action potential recordings from sciatic nerve, Hargreaves test, CGRP release assay from KO vs WT mice\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal electrophysiological techniques plus neurochemical readout in genetic KO, mechanistically detailed\",\n      \"pmids\": [\"27780178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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).\",\n      \"method\": \"Scn11a knockout, behavioral tests, dural afferent electrophysiology\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple functional mechanistic readouts; full mechanistic detail reported in PMID 31534133\",\n      \"pmids\": [\"31534133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry, whole-cell patch-clamp in cultured MSC, negative control for Nav1.8\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — immunohistochemistry plus electrophysiology in native cells, single lab, no genetic confirmation\",\n      \"pmids\": [\"24424281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Confocal immunofluorescence with double-labeling (Nav1.9 + calbindin), Western blot\",\n      \"journal\": \"Journal of pediatric surgery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — immunohistochemistry and Western blot, single lab, no electrophysiological confirmation\",\n      \"pmids\": [\"27297039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp from acutely isolated rat trigeminal ganglion neurons, concentration-response analysis\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro pharmacological characterization with state-dependence analysis, single lab, no mutagenesis to confirm binding site\",\n      \"pmids\": [\"24228717\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Nav1.9 (SCN11A) is a tetrodotoxin-resistant, voltage-gated sodium channel alpha-subunit preferentially expressed in small-diameter nociceptive DRG, trigeminal, and myenteric sensory neurons, where it generates a persistent, low-threshold Na+ current that sets resting membrane potential and amplifies subthreshold depolarizations; its activity is potentiated by coincident inflammatory mediator signaling through Gi/o G-proteins (increasing channel open probability and mean open time), regulated by glycosylation (which shifts steady-state inactivation), and modulated by nitric oxide and PKCα, while its surface expression is facilitated by direct interaction with the cell adhesion molecule contactin; gain-of-function mutations cause a spectrum of pain disorders (from familial episodic pain to congenital pain insensitivity) by either depolarizing nociceptors to the point of action potential failure or by rendering them hyperexcitable, depending on the magnitude of the resting membrane potential shift.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #6]. 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 [#8, #10]. 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 [#7, #8, #10]. Channel behavior is further shaped by developmentally regulated glycosylation, which sets the steady-state inactivation of the persistent current [#3], and by nitric oxide signaling under tonic PKA control, which drives CGRP secretion in dural nociceptors during medication-overuse headache [#20]. 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 [#6, #16, #21, #22, #25]. 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 [#2], and its C-terminus binds FHF1B [#1]. 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 [#12, #13, #14, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cloning, sequence analysis, Northern blot and in situ hybridization in DRG/trigeminal ganglia, with axotomy model\",\n      \"pmids\": [\"9671787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not directly demonstrate which current the channel carries\", \"Functional electrophysiology of the cloned channel not yet shown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified the first direct protein partners of Nav1.9, addressing how the channel is targeted to and stabilized at the axonal membrane.\",\n      \"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\",\n      \"pmids\": [\"11376006\", \"11581273\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of FHF1B binding on gating not determined\", \"Structural basis of contactin-Nav1.9 interaction unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed that post-translational glycosylation tunes Nav1.9 gating, answering how the channel's inactivation properties change developmentally.\",\n      \"evidence\": \"Western blot with enzymatic deglycosylation and neuraminidase treatment coupled to whole-cell patch-clamp in neonatal vs adult DRG neurons\",\n      \"pmids\": [\"11739573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific glycosylation sites not mapped\", \"Enzymes mediating developmental glycosylation change unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"15964986\", \"10393873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Modest baseline acute nociception phenotype left role in normal sensation uncertain\", \"Antisense vs knockout discrepancies not fully reconciled\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the biophysical and signaling mechanism of Nav1.9 potentiation, answering how G-proteins and inflammatory mediators amplify the persistent current.\",\n      \"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\",\n      \"pmids\": [\"15374752\", \"23359282\", \"18096591\", \"18270172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct G-protein subunit contact site on the channel not mapped\", \"Identity of all converging mediator receptors incomplete\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Characterized resting-state gating control and pharmacological state-dependence, establishing the channel's bias toward opening and modulator binding determinants.\",\n      \"evidence\": \"Single-channel and whole-cell analysis with fluoride manipulation; amitriptyline concentration-response; lysine K799 mutagenesis affecting local anesthetic potency\",\n      \"pmids\": [\"15121184\", \"24228717\", \"27556810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural validation of K799 in a binding pocket\", \"Amitriptyline binding site not confirmed by mutagenesis\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Solved the heterologous-expression barrier and mapped structural determinants of TTX resistance and slow inactivation, enabling mechanistic dissection of the channel.\",\n      \"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\",\n      \"pmids\": [\"25916202\", \"27556810\", \"25791876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of native Nav1.9\", \"Determinants limiting native trafficking incompletely defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended Nav1.9 function to acute mechanical and thermal nociception at the C-fiber level, refining the view that it acts only in inflammation.\",\n      \"evidence\": \"Single-fiber and compound action potential recordings, Hargreaves testing, and CGRP-release assays in knockout vs WT mice\",\n      \"pmids\": [\"27780178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution to specific fiber subtypes not fully resolved\", \"Coupling to receptor potentials of individual transducers not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined Nav1.9 as a subthreshold amplifier in cold-sensitive nociceptors, linking it to cold pain and chemotherapy-induced cold hypersensitivity.\",\n      \"evidence\": \"Knockout mice, antisense knockdown in rats, patch-clamp, cold-pain behavior, and oxaliplatin neuropathy model\",\n      \"pmids\": [\"25959819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling cold transducers to Nav1.9 not detailed\", \"Cold-specific regulation of channel activity unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a role for Nav1.9 in itch signaling, broadening its sensory function beyond pain.\",\n      \"evidence\": \"Fluorescent knock-in, knockout, and L799P gain-of-function knock-in mice with patch-clamp and pruritogen scratching assays\",\n      \"pmids\": [\"30395542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pruritogen receptor coupling to Nav1.9 not defined\", \"Distinction from pain pathways in shared neurons unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established SCN11A as a human pain-disease gene with a bidirectional genotype-phenotype relationship, explaining how both gain and loss of function impair pain.\",\n      \"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\",\n      \"pmids\": [\"24036948\", \"24207120\", \"26645915\", \"25791876\", \"28530638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why specific mutations bias toward hyper- vs hypoexcitability not fully predictable\", \"Therapeutic targeting of mutant channels not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"31534133\", \"31385361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct NO modification site on Nav1.9 not mapped\", \"PKC-alpha-Nav1.9 regulation lacks a direct kinase-substrate assay\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Detected Nav1.9 expression outside peripheral sensory neurons, raising the possibility of central and visceral roles.\",\n      \"evidence\": \"Immunohistochemistry and patch-clamp in supraoptic magnocellular neurosecretory cells; immunofluorescence and Western blot in human colon enteric neurons and Hirschsprung tissue\",\n      \"pmids\": [\"24424281\", \"27297039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genetic confirmation of functional role in these tissues\", \"Physiological significance of central/visceral expression undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 6, 8, 10]},\n      {\"term_id\": \"GO:0005216\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [10, 16, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 10, 25]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [16, 21, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 13, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CNTN1\", \"FHF1B\", \"TNC\", \"SCN1B\", \"SCN2B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}