{"gene":"SCN9A","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2006,"finding":"Homozygous nonsense mutations (S459X, I767X, W897X) in SCN9A cause loss of function of Nav1.7; co-expression of mutant Nav1.7 with sodium channel β1 and β2 subunits in HEK293 cells produced no currents above background, establishing Nav1.7 as an essential, non-redundant requirement for nociception in humans.","method":"Co-expression of wild-type or mutant Nav1.7 with β1/β2 subunits in HEK293 cells, whole-cell patch-clamp electrophysiology","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro functional assay with loss-of-function confirmed at channel level; three independent mutations tested, replicated across families","pmids":["17167479"],"is_preprint":false},{"year":2004,"finding":"Missense mutations in SCN9A (T2573A and T2543C) cause primary erythermalgia, identifying Nav1.7 as causative for this gain-of-function pain disorder in sensory and sympathetic neurons.","method":"Linkage analysis and Sanger sequencing of SCN9A in affected family and sporadic patient","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic mapping plus mutation identification in two independent cases, but no in vitro functional assay reported in this paper","pmids":["14985375"],"is_preprint":false},{"year":2005,"finding":"A gain-of-function mutation in Nav1.7 (erythromelalgia-associated) produces a hyperpolarizing shift in activation and a depolarizing shift in steady-state inactivation, lowering thresholds for single action potentials and high-frequency firing in dorsal root ganglion neurons.","method":"Whole-cell patch-clamp electrophysiology in DRG neurons expressing mutant Nav1.7; current-clamp recordings","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct electrophysiological characterization in native DRG neurons with mechanistic biophysical analysis; replicated across multiple erythromelalgia mutations in subsequent work","pmids":["15958509"],"is_preprint":false},{"year":2007,"finding":"The erythromelalgia mutation N395K, located within the local anaesthetic binding site of Nav1.7, attenuates lidocaine inhibition; IC50 for inactivated Nav1.7-N395K was ~2.8 mM versus ~500 µM for wild-type, establishing residue N395 as critical for lidocaine binding.","method":"Whole-cell patch-clamp electrophysiology of Nav1.7-N395K expressed in HEK293 cells; pharmacological IC50 determination and use-dependent block assays","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with site-specific mutant and direct pharmacological quantification; single lab but multiple orthogonal electrophysiological methods","pmids":["17430993"],"is_preprint":false},{"year":2006,"finding":"The S241T erythromelalgia mutation in the domain I S4-S5 linker of Nav1.7 causes a hyperpolarizing shift in activation, slowed deactivation, and enhanced slow inactivation; S241A had no effect while S241L mimicked S241T, demonstrating that side-chain size at position 241 modulates channel gating.","method":"Whole-cell voltage-clamp in HEK293 cells expressing wild-type or mutant Nav1.7 (S241T, S241A, S241L)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-function mutagenesis with multiple substitutions in a single rigorous in vitro study","pmids":["17008310"],"is_preprint":false},{"year":2009,"finding":"The erythromelalgia mutation V400M in Nav1.7 alters activation, deactivation, steady-state inactivation, and ramp currents; carbamazepine at therapeutic concentrations selectively normalises the voltage dependence of activation and inactivation of V400M but not wild-type Nav1.7, explaining the clinical carbamazepine-responsiveness.","method":"Whole-cell patch-clamp of V400M and wild-type Nav1.7 cell lines; pharmacological CBZ application","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with drug pharmacology and biophysical characterisation; single lab, multiple orthogonal electrophysiological endpoints","pmids":["19557861"],"is_preprint":false},{"year":2013,"finding":"SUMOylation of the Nav1.7-binding partner CRMP2 at K374 controls Nav1.7 surface expression; expression of SUMOylation-incompetent CRMP2-K374A in CAD cells selectively reduces huwentoxin-IV-sensitive Nav1.7 currents and decreases surface Nav1.7 levels (biotinylation assay), without affecting Nav1.1 or Nav1.3 currents; deSUMOylation by SENP1/SENP2 similarly decreases surface Nav1.7.","method":"CRMP2-K374A mutagenesis, surface biotinylation, whole-cell patch-clamp, SENP1/SENP2 overexpression in CAD and HEK293 cells stably expressing Nav1.7; Ubc9 dependency confirmed","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (mutagenesis, biotinylation, electrophysiology, protease overexpression); isoform specificity tested; single lab","pmids":["23836888"],"is_preprint":false},{"year":2016,"finding":"CRMP2 SUMOylation is enhanced by prior phosphorylation by CDK5 and antagonized by Fyn phosphorylation; SUMOylated CRMP2 binds Nav1.7 and maintains membrane localisation and current density; loss of CRMP2 SUMOylation triggers Nav1.7 internalisation via clathrin-dependent endocytosis involving E3 ubiquitin ligase Nedd4-2 and adaptor proteins Numb and EPS15.","method":"Hierarchical post-translational modification analysis, co-immunoprecipitation of CRMP2 and Nav1.7, dominant-negative/kinase inhibitor experiments, surface biotinylation, current-clamp in DRG neurons","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal Co-IP, mutagenesis, multiple PTM writers identified, functional electrophysiology, clathrin dependency assay; single lab with multiple orthogonal methods","pmids":["27940916"],"is_preprint":false},{"year":2015,"finding":"Crystal structures of Nav1.7 voltage-sensor domain IV (VSD4) in complex with isoform-selective antagonists (GX-936 and related acylsulfonamides) show that these inhibitors bind the activated state of VSD4 by engaging the fourth arginine gating charge on the S4 helix with an anionic aryl sulfonamide warhead, opposing VSD4 deactivation via a voltage-sensor trapping mechanism; residues on S2 and S3 helices determine isoform selectivity; bound phospholipids implicate the membrane as a modulator.","method":"Protein-engineering and X-ray crystallography of Nav1.7 VSD4–inhibitor complexes; structure-guided mutagenesis to define selectivity determinants","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with functional validation; multiple inhibitor complexes; isoform-selectivity residues defined by mutagenesis","pmids":["26680203"],"is_preprint":false},{"year":2019,"finding":"Cryo-EM and X-ray crystal structures of ProTx2 (Peruvian green velvet tarantula inhibitor cystine-knot peptide) in complex with Nav1.7 VSD2 reveal that ProTx2 partitions into the membrane to access VSD2, positions two basic residues into the extracellular vestibule to electrostatically antagonise S4 gating-charge movement, and traps both activated and deactivated states of VSD2 showing ~10 Å S4 helix translation.","method":"X-ray crystallography and cryo-EM of Nav1.7 VSD2–ProTx2 complexes; functional electrophysiology validation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution structures by two independent structural methods with functional electrophysiology; defines gating mechanism","pmids":["30661758"],"is_preprint":false},{"year":2012,"finding":"Conditional deletion of Nav1.7 (SCN9A) in all sensory neurons (Advillin-Cre) abolishes mechanical pain, inflammatory pain, and heat withdrawal reflexes, while deletion limited to Nav1.8-positive nociceptors retains heat-evoked pain; neuropathic pain and hotplate responses require deletion in both sensory and sympathetic neurons, demonstrating a distinct role for Nav1.7 in sympathetic neurons for neuropathic pain.","method":"Cell-type-specific conditional knockout mice (Advillin-Cre, Nav1.8-Cre); behavioural pain testing across multiple modalities","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean cell-type-specific genetic KO with defined behavioural phenotypes across multiple pain modalities; replicated across multiple Cre lines","pmids":["22531176"],"is_preprint":false},{"year":2011,"finding":"Loss of Nav1.7 function (SCN9A knockout) abolishes odour-evoked synaptic signalling from olfactory sensory neuron axon terminals at the first olfactory synapse without preventing action potential generation in those neurons, causing anosmia; Nav1.7-null human patients also lack odour perception.","method":"Conditional knockout of Nav1.7 in olfactory sensory neurons; in vivo odour-guided behavioural assays; electrophysiology of olfactory sensory neurons; human patient phenotyping","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with synaptic electrophysiology and behavioural readout; validated in both mouse model and human patients","pmids":["21441906"],"is_preprint":false},{"year":2015,"finding":"Loss of Nav1.7 (SCN9A deletion) upregulates the enkephalin precursor Penk mRNA and met-enkephalin protein specifically in sensory neurons; the opioid antagonist naloxone potentiates noxious spinal input and dramatically reduces analgesia in Nav1.7-null mice and a human Nav1.7-null mutant, indicating that Nav1.7 deletion drives endogenous opioid tone that contributes to the pain-free phenotype.","method":"RNA-seq/qPCR of Nav1.7-null sensory neurons; naloxone pharmacology in Nav1.7-null mice and human patient; spinal cord in vivo electrophysiology","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with mechanistic molecular (transcriptomic) and pharmacological (naloxone rescue) validation; confirmed in human Nav1.7-null subject","pmids":["26634308"],"is_preprint":false},{"year":2011,"finding":"Nav1.7 is the predominant sodium channel transcript in rat and mouse olfactory sensory neurons (OSNs), with Nav1.7 immunoreactivity localised to peripheral presynaptic OSN axons; Nav1.6 is primarily postsynaptic in olfactory bulb glomeruli, providing a mechanistic basis for anosmia upon Nav1.7 loss.","method":"Multiplex PCR-RFLP, in situ hybridisation, and immunohistochemistry in rat and mouse olfactory epithelium and bulb","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple complementary anatomical/molecular methods establishing channel identity and localisation; no direct functional manipulation in this paper","pmids":["21569247"],"is_preprint":false},{"year":2012,"finding":"Nav1.7 immunoreactivity extends from peripheral intraepidermal terminals in skin through DRG somata to central presynaptic terminals in spinal cord dorsal horn, supporting roles in action potential electrogenesis, axonal conduction, and presynaptic depolarisation along the entire nociceptive pathway.","method":"Immunocytochemistry in rat DRG, sciatic nerve, skin, and dorsal horn","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multi-tissue immunohistochemical mapping with multiple co-labels; anatomical localisation without direct functional manipulation","pmids":["23134641"],"is_preprint":false},{"year":2007,"finding":"A stop codon mutation in SCN9A (Y328X) truncates Nav1.7 before all pore-forming regions; expression of the truncated gene in cell lines produces no functional sodium currents and no compensatory changes in endogenous voltage-gated sodium currents, confirming complete loss of function.","method":"Functional expression in cell lines; whole-cell patch-clamp; species expression comparison by in situ hybridisation","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro electrophysiology confirming channel loss-of-function; species expression analysis providing mechanistic context for non-lethality in humans","pmids":["17597096"],"is_preprint":false},{"year":2010,"finding":"Two non-truncating Nav1.7 mutations causing CIP (R896Q missense and ΔR1370-L1374 in-frame deletion) both map to the channel pore region and cause significant reduction in membrane localisation and complete loss of sodium channel function, demonstrating that pore-region mutations impair both trafficking and conductance.","method":"Transient transfection of PC12 cells; confocal microscopy for membrane localisation; voltage-clamp of HEK293 cells","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — combined trafficking and functional electrophysiology in two cell lines; two independent mutations studied","pmids":["20635406"],"is_preprint":false},{"year":2009,"finding":"The SCN9A common polymorphism R1150W depolarises Nav1.7 activation by ~8–11 mV and depolarises resting membrane potential by ~6 mV, increasing firing frequency ~2-fold in DRG neurons, showing that naturally occurring polymorphisms in Nav1.7 can modulate nociceptor excitability.","method":"Whole-cell voltage-clamp and current-clamp of DRG neurons expressing R1150W or wild-type Nav1.7; comparison across multiple assay formats","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct electrophysiology in native DRG neurons with multiple assay formats; single lab","pmids":["20033988"],"is_preprint":false},{"year":2014,"finding":"In DRG neurons, dynamic-clamp delivery of the erythromelalgia L858H Nav1.7 mutation at physiological conductance levels produces a 27-fold amplification of net sodium influx during subthreshold depolarisations, providing a quantitative mechanistic link between altered channel biophysics and nociceptor hyperexcitability underlying pain.","method":"Dynamic-clamp electrophysiology in small DRG neurons expressing wild-type or L858H Nav1.7 at calibrated physiological conductance levels","journal":"Journal of neurophysiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative dynamic-clamp reconstitution at physiological levels; establishes direct biophysical mechanism for hyperexcitability","pmids":["24401712"],"is_preprint":false},{"year":2013,"finding":"The erythromelalgia mutation A1632T shifts steady-state fast inactivation to depolarised potentials (normally a PEPD characteristic) without slowing open-state inactivation or increasing resurgent currents; DRG neurons expressing A1632T show hyperexcitability and spontaneous firing. This demonstrates that depolarised fast inactivation without increased resurgent currents produces an IEM rather than PEPD phenotype.","method":"Whole-cell patch-clamp of HEK293 and DRG neurons transfected with A1632T Nav1.7; comparison with A1632E and wild-type","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution in two cell types; mechanistic comparison across related mutations; single lab","pmids":["24311784"],"is_preprint":false},{"year":2015,"finding":"The erythromelalgia mutation Q875E produces a large −18 mV hyperpolarising shift in Nav1.7 activation; the mutant glutamate at position 875 is spatially proximate to gating charge Arg-214 in domain I voltage sensor (confirmed by engineered disulfide bridge), suggesting a salt bridge that stabilises the activated VSD conformation; extracellular Ca2+ or Mg2+ reverses the gating shift by electrostatic screening.","method":"Whole-cell patch-clamp; 3D homology modelling; engineered disulfide bridge approach; divalent cation pharmacology in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-function analysis combining modelling, engineered disulfide bridge validation, and pharmacological rescue; single lab but multiple orthogonal methods","pmids":["25575597"],"is_preprint":false},{"year":2011,"finding":"Nav1.7 accumulates in transected axons of experimental rat neuromas and co-localises with phosphorylated ERK1/2 (pERK1/2), suggesting that MAP kinase signalling at sites of injury may modulate Nav1.7 properties and contribute to spontaneous ectopic firing.","method":"Immunohistochemistry and co-immunolabelling of Nav1.7 and pERK1/2 in rat sciatic nerve neuromas 2 weeks post-ligation","journal":"Experimental neurology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single immunohistochemical co-localisation; no direct functional manipulation of Nav1.7 or ERK in this study","pmids":["21601570"],"is_preprint":false},{"year":2017,"finding":"Loss of Nav1.7 leads to decreased pronociceptive serotonergic (5-HT4/Gαs/PKA/RIIβ) signalling and increased efficacy of antinociceptive mu-opioid (Gαi) signalling in sensory neurons; opioids more efficiently inhibit TTX-resistant sodium currents in Nav1.7-null nociceptors, shifting the balance of GPCR signalling toward antinociception.","method":"Phosphoproteomics and GPCR signalling assays in Nav1.7-null DRG neurons; western blot for RIIβ; electrophysiology measuring opioid inhibition of TTX-R currents; comparison with Nav1.8-null neurons","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple molecular and functional methods in isogenic KO neurons; isoform specificity controlled with Nav1.8-null comparison; single lab","pmids":["28074005"],"is_preprint":false},{"year":2018,"finding":"Both µ- and δ-opioid receptors are required for the analgesic phenotype of Nav1.7-null mice; pharmacological or genetic co-ablation of µ- and δ-opioid receptors (but not κ) abolishes the pain-free phenotype; enkephalins (Penk-encoded) are upregulated in Nav1.7 nulls but Nfat5 deletion also upregulates Penk without producing analgesia, indicating that endogenous opioid upregulation is necessary but not sufficient for the Nav1.7-null analgesic state.","method":"Pharmacological opioid receptor antagonism; µ- and δ-opioid receptor double-null mouse genetics; Nfat5-null mouse Penk expression analysis; behavioural thermal pain assays","journal":"Wellcome open research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological double-dissection of opioid receptor subtypes; epistasis with Nfat5 to separate opioid production from analgesia; multiple orthogonal approaches","pmids":["30271888"],"is_preprint":false},{"year":2021,"finding":"Preventing CRMP2 SUMOylation (via compound 194 targeting CRMP2-Ubc9 interaction, or CRMP2-K374A mutation) selectively reduces Nav1.7 surface expression and current density in DRG neurons and produces antinociception in rodent pain models; analgesia conferred by compound 194 is opioid-receptor dependent.","method":"In silico compound screening; in vitro Nav1.7 electrophysiology; ex vivo DRG surface biotinylation; rodent behavioural pain models; opioid receptor dependency assay","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vitro, ex vivo and in vivo approaches; mechanistic link between CRMP2 SUMOylation and Nav1.7 trafficking validated; replicated across pain models","pmids":["34757807"],"is_preprint":false},{"year":2023,"finding":"Nav1.7 is required for the initiation of C-fiber action potentials in vivo; genetic removal or selective pharmacological inhibition of Nav1.7 blocks C-fiber AP initiation as shown by laser speckle contrast imaging and in vivo electrophysiology; enkephalin upregulation upon Nav1.7 deletion is restricted to cLTMR (low-threshold mechanoreceptor) neurons and does not contribute to the analgesic phenotype.","method":"Single-cell RNA-seq; behavioural pharmacology; laser speckle contrast imaging; in vivo C-fiber electrophysiology in Nav1.7 conditional knockouts","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo electrophysiology directly measuring C-fiber AP initiation; scRNA-seq for cell-type specificity; pharmacological and genetic approaches combined","pmids":["37352856"],"is_preprint":false},{"year":2021,"finding":"Paclitaxel treatment increases vesicular trafficking flux and surface expression of Nav1.7 in sensory axons in a concentration-dependent manner (low concentrations increase flux; high concentrations decrease flux) without requiring increased Nav1.7 mRNA pool; inflammatory mediators further amplify this trafficking increase, providing a mechanism for Nav1.7-dependent peripheral sensitisation in chemotherapy-induced neuropathy.","method":"Live imaging of Halo-tagged Nav1.7 vesicular transport in DRG sensory axons; surface biotinylation; qPCR and whole-cell patch-clamp for endogenous Nav1.7 current density","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — real-time live imaging with multiple concentrations and conditions; complementary biochemical and electrophysiological methods; single lab","pmids":["33734317"],"is_preprint":false},{"year":2024,"finding":"Nav1.8 amplifies DRG neuron excitability driven by gain-of-function Nav1.7 (L848H) near action potential threshold; at threshold voltage (−21.9 mV), Nav1.8 open-probability exceeds Nav1.7-WT open-probability ninefold; dynamic-clamp reduction of Nav1.8 conductance by 25–50% reverses hyperexcitability in neurons expressing Nav1.7-L848H by increasing rheobase and reducing AP firing probability.","method":"Dynamic-clamp electrophysiology; kinetic Markov modelling of Nav1.8; Nav1.7L848H gain-of-function expression in DRG neurons","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative dynamic-clamp reconstitution with kinetic modelling; defines interplay between Nav1.7 and Nav1.8 at threshold; single lab, multiple methods","pmids":["39378238"],"is_preprint":false},{"year":2007,"finding":"The erythromelalgia mutation L858F differentially shifts the voltage dependence of activation in a cooling-dependent manner (depolarising shift with cooling for L858F but not wild-type Nav1.7), providing a biophysical explanation for symptomatic relief upon limb cooling in affected patients.","method":"Whole-cell voltage-clamp of wild-type and L858F Nav1.7 in HEK293 cells at different temperatures","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro temperature-dependent electrophysiology; mechanistic inference to clinical phenotype; single lab, single method","pmids":["17239250"],"is_preprint":false},{"year":2008,"finding":"Nav1.7 (SCN9A) expression in cultured human aortic smooth muscle cells contributes to TTX-sensitive sodium current; SCN9A siRNA knockdown abolishes this current and significantly inhibits cell migration, endocytosis (HRP uptake), and matrix metalloproteinase-2 secretion, without affecting proliferation; Nav1.7 is also expressed in rabbit aorta after balloon injury.","method":"SCN9A siRNA knockdown; whole-cell voltage-clamp; migration and HRP uptake assays; qRT-PCR; immunostaining","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple functional readouts; electrophysiology confirming current identity; single lab","pmids":["18978189"],"is_preprint":false},{"year":2018,"finding":"SCN9A (Nav1.7) expression is upregulated in senescent cells during oncogene-induced senescence (OIS) via NF-κB transcription factors; Nav1.7 induction leads to plasma membrane depolarisation, which activates a calcium/Rb/E2F pathway to repress mitotic genes and promote senescence; loss of SCN9A allows cells to escape OIS.","method":"Loss-of-function genetic screen; NF-κB dependency assays; plasma membrane potential measurements; calcium signalling assays; Rb/E2F pathway analysis","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen plus mechanistic pathway dissection with multiple downstream assays; single lab","pmids":["29446526"],"is_preprint":false},{"year":2019,"finding":"iPSC-derived sensory nociceptors from IEM patients carrying Nav1.7/I848T show decreased firing threshold, enhanced action potential upstroke and afterhyperpolarization; the IEM mutation causes a hyperpolarising shift of tetrodotoxin-sensitive Nav activation; Nav1.7 is not active during subthreshold depolarisations but its activity defines AP threshold and contributes to AP upstroke in human sensory neurons.","method":"iPSC differentiation into sensory nociceptors; whole-cell patch-clamp with prepulse voltage protocol; action potential recording in patient-derived cells","journal":"Pain","confidence":"High","confidence_rationale":"Tier 1 / Moderate — functional characterisation in patient-derived human nociceptors using multiple electrophysiological protocols; direct mechanistic insight into Nav1.7 role in AP threshold","pmids":["30720580"],"is_preprint":false},{"year":2016,"finding":"miR-30b directly targets the 3′ UTR of SCN9A; overexpression of miR-30b in spared-nerve-injury rats inhibits SCN9A transcription and Nav1.7 protein, reducing pain hypersensitivity; miR-30b knockdown increases Nav1.7 expression and induces mechanical hypersensitivity in naïve rats.","method":"Bioinformatics target prediction; luciferase 3′-UTR reporter assay; in vivo miR-30b agomir/antagomir microinjection; western blot and qRT-PCR in DRG","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validation of direct miRNA-mRNA interaction plus in vivo gain/loss-of-function; single lab","pmids":["27765894"],"is_preprint":false},{"year":2018,"finding":"miR-182 directly pairs with the SCN9A 3′ UTR (verified by luciferase assay); miR-182 agomir overexpression in SNI rats reverses the pathological Nav1.7 increase in DRG at both mRNA and protein levels and attenuates mechanical hypersensitivity.","method":"Luciferase 3′-UTR reporter assay; miR-182 agomir/antagomir injection in SNI rats; western blot and qRT-PCR","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct miRNA-target validation by reporter assay plus in vivo functional manipulation; single lab","pmids":["30425258"],"is_preprint":false},{"year":2020,"finding":"NGF triggers sustained Nav1.7 upregulation in DRG via an NGF/TrkA–SGK1–Nedd4-2 phosphorylation pathway; conditional nociceptor-specific Nav1.7 knockout confirms Nav1.7's requirement for NGF-induced and post-surgical pain; pharmacological blockade of this pathway reduces Nav1.7 upregulation and spinal sensitisation.","method":"Nociceptor-specific Nav1.7 conditional KO; western blot and immunostaining for pathway components; pharmacological inhibition of SGK1 and Nedd4-2 phosphorylation; behavioural pain testing","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO confirms Nav1.7 requirement; pathway identified by pharmacological intervention; single lab, multiple methods","pmids":["33063281"],"is_preprint":false},{"year":2014,"finding":"In mouse pancreatic β-cells, Nav1.7 (Scn9a) accounts for >85% of the voltage-gated Na+ current; knockout of Scn9a lowers β-cell Na+ current by >85% but glucagon and insulin secretion are unaffected in Scn9a-deficient islets, because Nav1.7 is largely inactive at physiological membrane potentials due to its unusually negative voltage dependence of inactivation in β-cells.","method":"Single-cell PCR; Scn9a knockout islet electrophysiology; insulin/glucagon secretion assays","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — genetic KO with direct electrophysiology confirming channel identity; functional secretion assays; single lab, multiple methods","pmids":["25172946"],"is_preprint":false},{"year":2015,"finding":"Nav1.7 is expressed in smooth muscle cells of cutaneous arterioles and arteriole-venule shunts, as well as in endothelial cells lining these vessels and in sensory/sympathetic fibres innervating them, suggesting that mutant Nav1.7 activity in skin vasculature (not only in neurons) contributes to skin reddening in erythromelalgia and PEPD.","method":"Immunohistochemistry of human skin sections with Nav1.7, smooth muscle, endothelial, and neural markers","journal":"Molecular pain","confidence":"Low","confidence_rationale":"Tier 3 / Weak — immunolocalisation only; no functional manipulation; single lab","pmids":["25957174"],"is_preprint":false},{"year":2017,"finding":"In conditional NaV1.7 knockout (advillin-Cre) sensory neurons, C-fiber axonal conduction velocity is 20% slower than wild-type; activity-dependent slowing of conduction is markedly reduced; a large subpopulation of C-fibers is functionally absent by compound AP recording; heat-evoked CGRP release is normal, indicating Nav1.7 loss impairs C-fiber conduction but not peptide release per se.","method":"Single-fiber recordings from isolated skin-nerve preparation; compound AP recording from saphenous nerve; CGRP release assay; rheobase/chronaxy measurements","journal":"Pain","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct single-fiber and compound nerve electrophysiology in conditional KO; multiple axon function parameters measured; single lab","pmids":["29194125"],"is_preprint":false},{"year":2019,"finding":"SCN9A-encoded Nav1.7 in prostate cancer cells (Mat-LyLu) modulates RhoA and Rac1 Rho GTPase activity in a Nav1.7-dependent manner; Nav1.7 activator JZTX-I increases and inhibitor HNTX-III decreases cell migration/invasion; proteomic analysis identified 64 differentially expressed membrane proteins including cytoskeletal regulators (fascin, muskelin, annexin A2, cofilin-1).","method":"Peptide toxin activation/inhibition (JZTX-I/HNTX-III); migration and invasion assays; comparative membrane proteomics; western blot validation; Rho GTPase pharmacology","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological gain/loss-of-function with proteomic and functional validation of downstream pathway; single lab","pmids":["30927332"],"is_preprint":false},{"year":2014,"finding":"Anandamide inhibits Nav1.7 sodium currents in a concentration-dependent manner (IC50 ~27 µM) in Xenopus oocytes, causing a depolarising shift of activation and hyperpolarising shift of inactivation, and shows use-dependent block; this is a direct pharmacological action on the channel.","method":"Two-electrode voltage-clamp of Nav1.7 α-subunit with β1 co-expression in Xenopus oocytes; concentration-response and gating analysis","journal":"Anesthesia and analgesia","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro reconstitution electrophysiology; single lab; pharmacological characterisation only","pmids":["24557103"],"is_preprint":false},{"year":2015,"finding":"The synthetic α-scorpion toxin OD1 and its analogs potently inhibit Nav1.7 fast inactivation by prolonging channel flickering between open and closed states; single-channel recordings confirm that toxins slow inactivation via a voltage-sensor trapping mechanism on domain IV, consistent with the gating-modifier model.","method":"Whole-cell and single-channel patch-clamp of Nav1.7 in the presence of OD1 and analogs","journal":"Channels (Austin, Tex.)","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct single-channel electrophysiology defining mechanism of inactivation inhibition; single lab; one toxin class","pmids":["26646206"],"is_preprint":false},{"year":2022,"finding":"Buthus martensii Karsch scorpion toxin Makatoxin-3 acts on the S3-S4 loop of Nav1.7 VSD4, causing a hyperpolarising shift in steady-state fast inactivation and impairing inactivation kinetics; key residues mediating this interaction are distinct from those of other α-toxins, defining new structure-function relationships for toxin-Nav1.7 interactions.","method":"Nav1.7 subtype-selective pharmacology with venom and purified Makatoxin-3; chimeric Nav1.7 mutagenesis; electrophysiology in mouse DRG and cell lines; behavioural pain assays","journal":"Pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chimeric/mutant channel mapping plus functional electrophysiology and in vivo validation; single lab","pmids":["34252912"],"is_preprint":false}],"current_model":"Nav1.7 (SCN9A) is a voltage-gated sodium channel α-subunit expressed in peripheral nociceptors, sympathetic neurons, and olfactory sensory neurons that sets the threshold for action potential initiation and C-fiber AP propagation; gain-of-function mutations enhance activation and/or impair inactivation causing inherited pain syndromes (erythromelalgia, PEPD, small-fiber neuropathy), while loss-of-function mutations abolish nociception and olfaction; channel surface density is regulated by hierarchical CRMP2 SUMOylation/phosphorylation controlling clathrin-dependent endocytosis via Nedd4-2, by miR-30b and miR-182 targeting SCN9A mRNA, and by paclitaxel-dependent vesicular trafficking; Nav1.7 loss additionally upregulates enkephalin and rebalances GPCR signalling toward µ/δ-opioid antinociception, explaining why pharmacological blockade alone incompletely replicates the genetic pain-free phenotype; inhibitors can trap VSD4 in an activated/inactivated state (acylsulfonamides) or antagonise VSD2 gating-charge movement (ProTx2), with structural blueprints defined by crystal and cryo-EM structures."},"narrative":{"mechanistic_narrative":"SCN9A encodes Nav1.7, a voltage-gated sodium channel α-subunit that sets the threshold for action potential initiation in peripheral sensory neurons and is an essential, non-redundant requirement for human nociception and olfaction [PMID:17167479, PMID:21441906]. In nociceptors, Nav1.7 activity defines the action potential threshold and contributes to the upstroke; it is required for initiation of C-fiber action potentials in vivo and for normal C-fiber conduction velocity [PMID:37352856, PMID:30720580, PMID:29194125]. The channel is expressed along the entire nociceptive pathway from intraepidermal terminals through DRG somata to central presynaptic terminals, and it is the predominant sodium channel of olfactory sensory neurons where it drives odour-evoked synaptic transmission at the first olfactory synapse [PMID:21569247, PMID:23134641, PMID:21441906]. Inherited gain-of-function missense mutations cause erythromelalgia by hyperpolarizing activation and/or depolarizing steady-state inactivation, lowering firing threshold and amplifying subthreshold sodium influx to produce nociceptor hyperexcitability, with distinct biophysical signatures distinguishing erythromelalgia from PEPD phenotypes [PMID:14985375, PMID:15958509, PMID:24401712, PMID:24311784]; complete loss-of-function truncating and pore-region mutations abolish current and cause congenital insensitivity to pain [PMID:17167479, PMID:17597096, PMID:20635406]. The pain-free state of Nav1.7-null animals and humans is not explained by channel loss alone: deletion upregulates the enkephalin precursor Penk and rebalances GPCR signalling away from pronociceptive serotonergic toward antinociceptive µ- and δ-opioid tone, an endogenous opioid mechanism necessary for the analgesic phenotype [PMID:26634308, PMID:28074005, PMID:30271888]. Channel surface density is set post-translationally by hierarchical CRMP2 SUMOylation—promoted by CDK5 and antagonized by Fyn—that maintains membrane Nav1.7 and, when lost, triggers clathrin-dependent endocytosis via Nedd4-2 with adaptors Numb and EPS15; disrupting CRMP2 SUMOylation reduces surface Nav1.7 and is antinociceptive [PMID:23836888, PMID:27940916, PMID:34757807]. Trafficking and abundance are further controlled by NGF/TrkA–SGK1–Nedd4-2 signalling, paclitaxel-dependent vesicular transport, and direct 3′-UTR targeting by miR-30b and miR-182 [PMID:33063281, PMID:33734317, PMID:27765894, PMID:30425258]. Structural and pharmacological work has mapped how acylsulfonamides trap VSD4 in an activated state via the S4 gating charge and how the peptide ProTx2 antagonises VSD2 gating-charge movement from within the membrane, providing blueprints for isoform-selective inhibition [PMID:26680203, PMID:30661758]. Beyond neurons, Nav1.7 has been assigned roles in oncogene-induced senescence via NF-κB-driven depolarization and a Ca2+/Rb/E2F axis, and in cancer-cell and vascular smooth-muscle migration [PMID:29446526, PMID:18978189, PMID:30927332].","teleology":[{"year":2004,"claim":"Established Nav1.7 as a disease gene by linking SCN9A missense mutations to an inherited pain disorder, the first causal genetic tie to human pain.","evidence":"Linkage analysis and Sanger sequencing of SCN9A in erythermalgia families","pmids":["14985375"],"confidence":"Medium","gaps":["No in vitro functional assay in this report to confirm gain-of-function","Cellular mechanism of pain unspecified"]},{"year":2005,"claim":"Defined the biophysical mechanism of gain-of-function pain mutations—hyperpolarized activation and depolarized inactivation lowering firing threshold in native nociceptors.","evidence":"Whole-cell and current-clamp recordings of mutant Nav1.7 in DRG neurons","pmids":["15958509"],"confidence":"High","gaps":["Quantitative link between gating shift and AP output not yet established","Did not address loss-of-function spectrum"]},{"year":2006,"claim":"Demonstrated Nav1.7 is an absolute, non-redundant requirement for human nociception by showing homozygous nonsense mutations produce no current.","evidence":"Heterologous expression of truncating mutants with β1/β2 and patch-clamp in HEK293","pmids":["17167479","17008310"],"confidence":"High","gaps":["Mechanism of pain-free phenotype beyond channel loss unaddressed","Why anosmia accompanies CIP not yet explained"]},{"year":2007,"claim":"Resolved pharmacology and trafficking consequences of pain mutations, including residues governing local-anaesthetic block and temperature-dependent gating.","evidence":"Patch-clamp IC50/use-dependence of mutants in HEK293; truncating LoF confirmation","pmids":["17430993","17239250","17597096"],"confidence":"High","gaps":["Single-lab pharmacology","Clinical correlation inferred, not directly measured in patients"]},{"year":2009,"claim":"Connected channel biophysics to drug responsiveness and to common-variant excitability, showing carbamazepine normalizes specific mutants and R1150W tunes nociceptor firing.","evidence":"Patch-clamp with CBZ pharmacology; voltage/current-clamp of R1150W in DRG neurons","pmids":["19557861","20033988"],"confidence":"High","gaps":["In vivo confirmation of CBZ mechanism not provided","Population-level effect of R1150W not assessed"]},{"year":2011,"claim":"Identified an olfactory role: Nav1.7 is the dominant OSN sodium channel and is required for odour-evoked synaptic signalling, explaining anosmia in Nav1.7-null humans.","evidence":"OSN-specific knockout, synaptic electrophysiology, expression mapping, human phenotyping","pmids":["21441906","21569247"],"confidence":"High","gaps":["Molecular basis for presynaptic-specific failure not fully resolved","ERK co-localization at neuromas (idx 21) remains correlative"]},{"year":2012,"claim":"Dissected cell-type-specific contributions, showing sensory-neuron Nav1.7 drives most pain modalities while sympathetic-neuron Nav1.7 is required for neuropathic pain.","evidence":"Advillin-Cre and Nav1.8-Cre conditional knockouts with multimodal behavioural testing","pmids":["22531176","23134641"],"confidence":"High","gaps":["Mechanism of sympathetic contribution to neuropathic pain unresolved","Heat-pain channel redundancy not fully explained"]},{"year":2013,"claim":"Revealed that Nav1.7 surface density is post-translationally controlled via SUMOylation of its partner CRMP2.","evidence":"CRMP2-K374A mutagenesis, surface biotinylation, SENP overexpression, patch-clamp in CAD/HEK293","pmids":["23836888","24311784"],"confidence":"High","gaps":["Upstream regulators of CRMP2 SUMOylation not yet identified at this stage","Endocytic machinery not defined"]},{"year":2014,"claim":"Quantified how mutant gating translates into hyperexcitability and identified endocannabinoid block, linking biophysics to amplified subthreshold sodium influx.","evidence":"Dynamic-clamp in DRG neurons; two-electrode voltage-clamp of anandamide block in oocytes","pmids":["24401712","24557103"],"confidence":"High","gaps":["Physiological relevance of anandamide IC50 (~27 µM) uncertain","In vivo confirmation of 27-fold amplification not provided"]},{"year":2015,"claim":"Identified the endogenous opioid mechanism behind the Nav1.7-null pain-free state—Penk/met-enkephalin upregulation reversible by naloxone—and resolved structure-function salt-bridge determinants of activation.","evidence":"RNA-seq/qPCR, naloxone pharmacology in mice and human null; engineered disulfide and divalent-cation analysis","pmids":["26634308","25575597"],"confidence":"High","gaps":["Whether opioid upregulation is sufficient for analgesia not yet tested","Receptor subtype dependence unresolved at this stage"]},{"year":2015,"claim":"Provided the first high-resolution structural basis for isoform-selective inhibition by trapping VSD4 in its activated state.","evidence":"X-ray crystallography of Nav1.7 VSD4–acylsulfonamide complexes with selectivity mutagenesis","pmids":["26680203"],"confidence":"High","gaps":["Engineered VSD4 construct, not full-length channel","Pore-domain and inactivation coupling not captured"]},{"year":2016,"claim":"Mapped the upstream PTM hierarchy and downstream endocytic machinery controlling Nav1.7 surface levels, and identified miRNA control of SCN9A mRNA.","evidence":"CDK5/Fyn PTM analysis, CRMP2–Nav1.7 Co-IP, Nedd4-2/Numb/EPS15 endocytosis assays; miR-30b luciferase and in vivo manipulation","pmids":["27940916","27765894"],"confidence":"High","gaps":["In vivo physiological relevance of full endocytic cascade incompletely tested","miR-30b effects single-lab"]},{"year":2017,"claim":"Showed Nav1.7 loss rebalances GPCR signalling toward antinociception and impairs C-fiber conduction, broadening its role beyond simple threshold-setting.","evidence":"Phosphoproteomics/GPCR assays and opioid inhibition of TTX-R currents in null DRG; single-fiber and compound AP recording","pmids":["28074005","29194125"],"confidence":"High","gaps":["Causal chain from channel loss to serotonergic downregulation incompletely defined","Conduction-velocity effect mechanism unspecified"]},{"year":2018,"claim":"Established that µ- and δ-opioid receptors are required—but enkephalin upregulation alone is not sufficient—for Nav1.7-null analgesia, and added a second miRNA regulator and a senescence role.","evidence":"µ/δ double-null genetics with Nfat5 epistasis; miR-182 luciferase/in vivo; OIS genetic screen and pathway dissection","pmids":["30271888","30425258","29446526"],"confidence":"Medium","gaps":["The necessary-but-not-sufficient factors completing analgesia remain unidentified","Senescence role single-lab and outside neurons"]},{"year":2019,"claim":"Defined the gating-modifier mechanism of peptide inhibition (ProTx2 at VSD2) and confirmed Nav1.7's role in defining AP threshold in human patient-derived nociceptors.","evidence":"Cryo-EM/crystallography of VSD2–ProTx2; patch-clamp of IEM iPSC-derived nociceptors; cancer-cell Rho GTPase study","pmids":["30661758","30720580","30927332"],"confidence":"High","gaps":["VSD2 construct lacks full-channel context","Cancer-cell signalling mechanism correlative"]},{"year":2021,"claim":"Demonstrated therapeutic and pathological control of Nav1.7 trafficking—CRMP2-SUMOylation inhibition is opioid-dependent analgesic, while paclitaxel drives surface accumulation.","evidence":"Compound 194 screening with ex vivo biotinylation and rodent pain models; live imaging of Halo-Nav1.7 vesicular transport","pmids":["34757807","33734317"],"confidence":"High","gaps":["Opioid dependence of compound 194 mechanism not fully resolved","Paclitaxel trafficking pathway components undefined"]},{"year":2023,"claim":"Established directly in vivo that Nav1.7 is required for C-fiber AP initiation and refined the cell-type specificity of enkephalin upregulation.","evidence":"scRNA-seq, laser speckle imaging, in vivo C-fiber electrophysiology in conditional knockouts","pmids":["37352856"],"confidence":"High","gaps":["Reconciliation with earlier opioid-tone findings on enkephalin contribution incomplete","Sympathetic-neuron component not addressed here"]},{"year":2024,"claim":"Showed Nav1.7 gain-of-function hyperexcitability depends on Nav1.8 amplification at threshold, defining channel interplay as a therapeutic node.","evidence":"Dynamic-clamp with Nav1.8 Markov modelling in DRG neurons expressing Nav1.7-L848H","pmids":["39378238"],"confidence":"High","gaps":["In vivo validation of Nav1.8-dependent amplification pending","Generalizability across mutations untested"]},{"year":null,"claim":"It remains unresolved which additional factor(s), beyond endogenous opioid upregulation, are required to complete the Nav1.7-null analgesic state, and how Nav1.7 trafficking, PTM control, and Nav1.8 interplay can be jointly leveraged for selective, fully efficacious analgesia.","evidence":"","pmids":[],"confidence":"High","gaps":["No single intervention reproduces the full genetic pain-free phenotype","Integrated in vivo mechanism linking surface-density control to opioid rebalancing unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,2,15,35]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,7,14,26]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[26]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,11,18,25,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[22,23,34]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[6,7,24,26]}],"complexes":[],"partners":["CRMP2","NEDD4L","NUMB","EPS15","SCN1B","SCN2B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15858","full_name":"Sodium channel protein type 9 subunit alpha","aliases":["Neuroendocrine sodium channel","hNE-Na","Peripheral sodium channel 1","PN1","Sodium channel protein type IX subunit alpha","Voltage-gated sodium channel subunit alpha Nav1.7"],"length_aa":1988,"mass_kda":226.4,"function":"Pore-forming subunit of Nav1.7, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient. The influx of Na(+) ions provokes membrane depolarization, initiating the propagation of electrical signals throughout cells and tissues (PubMed:15385606, PubMed:16988069, PubMed:17145499, PubMed:17167479, PubMed:19369487, PubMed:24311784, PubMed:25240195, PubMed:26680203, PubMed:7720699). Nav1.7 plays a crucial role in controlling the excitability and action potential propagation from nociceptor neurons, thereby contributing to the sensory perception of pain (PubMed:17145499, PubMed:17167479, PubMed:19369487, PubMed:24311784)","subcellular_location":"Cell membrane; Cell projection, neuron projection; Cell projection, axon","url":"https://www.uniprot.org/uniprotkb/Q15858/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SCN9A","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":[],"url":"https://opencell.sf.czbiohub.org/search/SCN9A","total_profiled":1310},"omim":[{"mim_id":"614594","title":"OLMSTED SYNDROME 1; OLMS1","url":"https://www.omim.org/entry/614594"},{"mim_id":"613863","title":"GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 7; GEFSP7","url":"https://www.omim.org/entry/613863"},{"mim_id":"611916","title":"COLLAGEN, TYPE VI, ALPHA-5; COL6A5","url":"https://www.omim.org/entry/611916"},{"mim_id":"611270","title":"NSF ATTACHMENT PROTEIN BETA; NAPB","url":"https://www.omim.org/entry/611270"},{"mim_id":"607208","title":"DRAVET SYNDROME; DRVT","url":"https://www.omim.org/entry/607208"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Actin filaments","reliability":"Approved"},{"location":"Focal adhesion sites","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":5.7}],"url":"https://www.proteinatlas.org/search/SCN9A"},"hgnc":{"alias_symbol":["Nav1.7","PN1","NE-NA","NENA","ETHA"],"prev_symbol":[]},"alphafold":{"accession":"Q15858","domains":[{"cath_id":"-","chopping":"2-33_50-103","consensus_level":"medium","plddt":75.0127,"start":2,"end":103},{"cath_id":"-","chopping":"271-336","consensus_level":"medium","plddt":82.5736,"start":271,"end":336},{"cath_id":"1.20.120.350","chopping":"727-849","consensus_level":"medium","plddt":82.7744,"start":727,"end":849},{"cath_id":"1.10.287.70","chopping":"867-973","consensus_level":"medium","plddt":86.2991,"start":867,"end":973},{"cath_id":"1.20.120,1.20.120","chopping":"1192-1239_1248-1266_1275-1304","consensus_level":"medium","plddt":85.5943,"start":1192,"end":1304},{"cath_id":"1.10.287.70","chopping":"1306-1379_1389-1456","consensus_level":"medium","plddt":87.8623,"start":1306,"end":1456},{"cath_id":"1.20.120.350","chopping":"1508-1625","consensus_level":"medium","plddt":83.0265,"start":1508,"end":1625},{"cath_id":"1.10.238.10","chopping":"1773-1905","consensus_level":"high","plddt":75.3075,"start":1773,"end":1905}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15858","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15858-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15858-F1-predicted_aligned_error_v6.png","plddt_mean":69.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SCN9A","jax_strain_url":"https://www.jax.org/strain/search?query=SCN9A"},"sequence":{"accession":"Q15858","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15858.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15858/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15858"}},"corpus_meta":[{"pmid":"17167479","id":"PMC_17167479","title":"An 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mutant Nav1.7 with β1/β2 subunits in HEK293 cells, whole-cell patch-clamp electrophysiology\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro functional assay with loss-of-function confirmed at channel level; three independent mutations tested, replicated across families\",\n      \"pmids\": [\"17167479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Missense mutations in SCN9A (T2573A and T2543C) cause primary erythermalgia, identifying Nav1.7 as causative for this gain-of-function pain disorder in sensory and sympathetic neurons.\",\n      \"method\": \"Linkage analysis and Sanger sequencing of SCN9A in affected family and sporadic patient\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic mapping plus mutation identification in two independent cases, but no in vitro functional assay reported in this paper\",\n      \"pmids\": [\"14985375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A gain-of-function mutation in Nav1.7 (erythromelalgia-associated) produces a hyperpolarizing shift in activation and a depolarizing shift in steady-state inactivation, lowering thresholds for single action potentials and high-frequency firing in dorsal root ganglion neurons.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology in DRG neurons expressing mutant Nav1.7; current-clamp recordings\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct electrophysiological characterization in native DRG neurons with mechanistic biophysical analysis; replicated across multiple erythromelalgia mutations in subsequent work\",\n      \"pmids\": [\"15958509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The erythromelalgia mutation N395K, located within the local anaesthetic binding site of Nav1.7, attenuates lidocaine inhibition; IC50 for inactivated Nav1.7-N395K was ~2.8 mM versus ~500 µM for wild-type, establishing residue N395 as critical for lidocaine binding.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology of Nav1.7-N395K expressed in HEK293 cells; pharmacological IC50 determination and use-dependent block assays\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with site-specific mutant and direct pharmacological quantification; single lab but multiple orthogonal electrophysiological methods\",\n      \"pmids\": [\"17430993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The S241T erythromelalgia mutation in the domain I S4-S5 linker of Nav1.7 causes a hyperpolarizing shift in activation, slowed deactivation, and enhanced slow inactivation; S241A had no effect while S241L mimicked S241T, demonstrating that side-chain size at position 241 modulates channel gating.\",\n      \"method\": \"Whole-cell voltage-clamp in HEK293 cells expressing wild-type or mutant Nav1.7 (S241T, S241A, S241L)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-function mutagenesis with multiple substitutions in a single rigorous in vitro study\",\n      \"pmids\": [\"17008310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The erythromelalgia mutation V400M in Nav1.7 alters activation, deactivation, steady-state inactivation, and ramp currents; carbamazepine at therapeutic concentrations selectively normalises the voltage dependence of activation and inactivation of V400M but not wild-type Nav1.7, explaining the clinical carbamazepine-responsiveness.\",\n      \"method\": \"Whole-cell patch-clamp of V400M and wild-type Nav1.7 cell lines; pharmacological CBZ application\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with drug pharmacology and biophysical characterisation; single lab, multiple orthogonal electrophysiological endpoints\",\n      \"pmids\": [\"19557861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SUMOylation of the Nav1.7-binding partner CRMP2 at K374 controls Nav1.7 surface expression; expression of SUMOylation-incompetent CRMP2-K374A in CAD cells selectively reduces huwentoxin-IV-sensitive Nav1.7 currents and decreases surface Nav1.7 levels (biotinylation assay), without affecting Nav1.1 or Nav1.3 currents; deSUMOylation by SENP1/SENP2 similarly decreases surface Nav1.7.\",\n      \"method\": \"CRMP2-K374A mutagenesis, surface biotinylation, whole-cell patch-clamp, SENP1/SENP2 overexpression in CAD and HEK293 cells stably expressing Nav1.7; Ubc9 dependency confirmed\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (mutagenesis, biotinylation, electrophysiology, protease overexpression); isoform specificity tested; single lab\",\n      \"pmids\": [\"23836888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CRMP2 SUMOylation is enhanced by prior phosphorylation by CDK5 and antagonized by Fyn phosphorylation; SUMOylated CRMP2 binds Nav1.7 and maintains membrane localisation and current density; loss of CRMP2 SUMOylation triggers Nav1.7 internalisation via clathrin-dependent endocytosis involving E3 ubiquitin ligase Nedd4-2 and adaptor proteins Numb and EPS15.\",\n      \"method\": \"Hierarchical post-translational modification analysis, co-immunoprecipitation of CRMP2 and Nav1.7, dominant-negative/kinase inhibitor experiments, surface biotinylation, current-clamp in DRG neurons\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal Co-IP, mutagenesis, multiple PTM writers identified, functional electrophysiology, clathrin dependency assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27940916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of Nav1.7 voltage-sensor domain IV (VSD4) in complex with isoform-selective antagonists (GX-936 and related acylsulfonamides) show that these inhibitors bind the activated state of VSD4 by engaging the fourth arginine gating charge on the S4 helix with an anionic aryl sulfonamide warhead, opposing VSD4 deactivation via a voltage-sensor trapping mechanism; residues on S2 and S3 helices determine isoform selectivity; bound phospholipids implicate the membrane as a modulator.\",\n      \"method\": \"Protein-engineering and X-ray crystallography of Nav1.7 VSD4–inhibitor complexes; structure-guided mutagenesis to define selectivity determinants\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with functional validation; multiple inhibitor complexes; isoform-selectivity residues defined by mutagenesis\",\n      \"pmids\": [\"26680203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cryo-EM and X-ray crystal structures of ProTx2 (Peruvian green velvet tarantula inhibitor cystine-knot peptide) in complex with Nav1.7 VSD2 reveal that ProTx2 partitions into the membrane to access VSD2, positions two basic residues into the extracellular vestibule to electrostatically antagonise S4 gating-charge movement, and traps both activated and deactivated states of VSD2 showing ~10 Å S4 helix translation.\",\n      \"method\": \"X-ray crystallography and cryo-EM of Nav1.7 VSD2–ProTx2 complexes; functional electrophysiology validation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution structures by two independent structural methods with functional electrophysiology; defines gating mechanism\",\n      \"pmids\": [\"30661758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Conditional deletion of Nav1.7 (SCN9A) in all sensory neurons (Advillin-Cre) abolishes mechanical pain, inflammatory pain, and heat withdrawal reflexes, while deletion limited to Nav1.8-positive nociceptors retains heat-evoked pain; neuropathic pain and hotplate responses require deletion in both sensory and sympathetic neurons, demonstrating a distinct role for Nav1.7 in sympathetic neurons for neuropathic pain.\",\n      \"method\": \"Cell-type-specific conditional knockout mice (Advillin-Cre, Nav1.8-Cre); behavioural pain testing across multiple modalities\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean cell-type-specific genetic KO with defined behavioural phenotypes across multiple pain modalities; replicated across multiple Cre lines\",\n      \"pmids\": [\"22531176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss of Nav1.7 function (SCN9A knockout) abolishes odour-evoked synaptic signalling from olfactory sensory neuron axon terminals at the first olfactory synapse without preventing action potential generation in those neurons, causing anosmia; Nav1.7-null human patients also lack odour perception.\",\n      \"method\": \"Conditional knockout of Nav1.7 in olfactory sensory neurons; in vivo odour-guided behavioural assays; electrophysiology of olfactory sensory neurons; human patient phenotyping\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with synaptic electrophysiology and behavioural readout; validated in both mouse model and human patients\",\n      \"pmids\": [\"21441906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of Nav1.7 (SCN9A deletion) upregulates the enkephalin precursor Penk mRNA and met-enkephalin protein specifically in sensory neurons; the opioid antagonist naloxone potentiates noxious spinal input and dramatically reduces analgesia in Nav1.7-null mice and a human Nav1.7-null mutant, indicating that Nav1.7 deletion drives endogenous opioid tone that contributes to the pain-free phenotype.\",\n      \"method\": \"RNA-seq/qPCR of Nav1.7-null sensory neurons; naloxone pharmacology in Nav1.7-null mice and human patient; spinal cord in vivo electrophysiology\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with mechanistic molecular (transcriptomic) and pharmacological (naloxone rescue) validation; confirmed in human Nav1.7-null subject\",\n      \"pmids\": [\"26634308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Nav1.7 is the predominant sodium channel transcript in rat and mouse olfactory sensory neurons (OSNs), with Nav1.7 immunoreactivity localised to peripheral presynaptic OSN axons; Nav1.6 is primarily postsynaptic in olfactory bulb glomeruli, providing a mechanistic basis for anosmia upon Nav1.7 loss.\",\n      \"method\": \"Multiplex PCR-RFLP, in situ hybridisation, and immunohistochemistry in rat and mouse olfactory epithelium and bulb\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple complementary anatomical/molecular methods establishing channel identity and localisation; no direct functional manipulation in this paper\",\n      \"pmids\": [\"21569247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nav1.7 immunoreactivity extends from peripheral intraepidermal terminals in skin through DRG somata to central presynaptic terminals in spinal cord dorsal horn, supporting roles in action potential electrogenesis, axonal conduction, and presynaptic depolarisation along the entire nociceptive pathway.\",\n      \"method\": \"Immunocytochemistry in rat DRG, sciatic nerve, skin, and dorsal horn\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multi-tissue immunohistochemical mapping with multiple co-labels; anatomical localisation without direct functional manipulation\",\n      \"pmids\": [\"23134641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A stop codon mutation in SCN9A (Y328X) truncates Nav1.7 before all pore-forming regions; expression of the truncated gene in cell lines produces no functional sodium currents and no compensatory changes in endogenous voltage-gated sodium currents, confirming complete loss of function.\",\n      \"method\": \"Functional expression in cell lines; whole-cell patch-clamp; species expression comparison by in situ hybridisation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro electrophysiology confirming channel loss-of-function; species expression analysis providing mechanistic context for non-lethality in humans\",\n      \"pmids\": [\"17597096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Two non-truncating Nav1.7 mutations causing CIP (R896Q missense and ΔR1370-L1374 in-frame deletion) both map to the channel pore region and cause significant reduction in membrane localisation and complete loss of sodium channel function, demonstrating that pore-region mutations impair both trafficking and conductance.\",\n      \"method\": \"Transient transfection of PC12 cells; confocal microscopy for membrane localisation; voltage-clamp of HEK293 cells\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — combined trafficking and functional electrophysiology in two cell lines; two independent mutations studied\",\n      \"pmids\": [\"20635406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The SCN9A common polymorphism R1150W depolarises Nav1.7 activation by ~8–11 mV and depolarises resting membrane potential by ~6 mV, increasing firing frequency ~2-fold in DRG neurons, showing that naturally occurring polymorphisms in Nav1.7 can modulate nociceptor excitability.\",\n      \"method\": \"Whole-cell voltage-clamp and current-clamp of DRG neurons expressing R1150W or wild-type Nav1.7; comparison across multiple assay formats\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiology in native DRG neurons with multiple assay formats; single lab\",\n      \"pmids\": [\"20033988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In DRG neurons, dynamic-clamp delivery of the erythromelalgia L858H Nav1.7 mutation at physiological conductance levels produces a 27-fold amplification of net sodium influx during subthreshold depolarisations, providing a quantitative mechanistic link between altered channel biophysics and nociceptor hyperexcitability underlying pain.\",\n      \"method\": \"Dynamic-clamp electrophysiology in small DRG neurons expressing wild-type or L858H Nav1.7 at calibrated physiological conductance levels\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative dynamic-clamp reconstitution at physiological levels; establishes direct biophysical mechanism for hyperexcitability\",\n      \"pmids\": [\"24401712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The erythromelalgia mutation A1632T shifts steady-state fast inactivation to depolarised potentials (normally a PEPD characteristic) without slowing open-state inactivation or increasing resurgent currents; DRG neurons expressing A1632T show hyperexcitability and spontaneous firing. This demonstrates that depolarised fast inactivation without increased resurgent currents produces an IEM rather than PEPD phenotype.\",\n      \"method\": \"Whole-cell patch-clamp of HEK293 and DRG neurons transfected with A1632T Nav1.7; comparison with A1632E and wild-type\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution in two cell types; mechanistic comparison across related mutations; single lab\",\n      \"pmids\": [\"24311784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The erythromelalgia mutation Q875E produces a large −18 mV hyperpolarising shift in Nav1.7 activation; the mutant glutamate at position 875 is spatially proximate to gating charge Arg-214 in domain I voltage sensor (confirmed by engineered disulfide bridge), suggesting a salt bridge that stabilises the activated VSD conformation; extracellular Ca2+ or Mg2+ reverses the gating shift by electrostatic screening.\",\n      \"method\": \"Whole-cell patch-clamp; 3D homology modelling; engineered disulfide bridge approach; divalent cation pharmacology in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-function analysis combining modelling, engineered disulfide bridge validation, and pharmacological rescue; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25575597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Nav1.7 accumulates in transected axons of experimental rat neuromas and co-localises with phosphorylated ERK1/2 (pERK1/2), suggesting that MAP kinase signalling at sites of injury may modulate Nav1.7 properties and contribute to spontaneous ectopic firing.\",\n      \"method\": \"Immunohistochemistry and co-immunolabelling of Nav1.7 and pERK1/2 in rat sciatic nerve neuromas 2 weeks post-ligation\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single immunohistochemical co-localisation; no direct functional manipulation of Nav1.7 or ERK in this study\",\n      \"pmids\": [\"21601570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of Nav1.7 leads to decreased pronociceptive serotonergic (5-HT4/Gαs/PKA/RIIβ) signalling and increased efficacy of antinociceptive mu-opioid (Gαi) signalling in sensory neurons; opioids more efficiently inhibit TTX-resistant sodium currents in Nav1.7-null nociceptors, shifting the balance of GPCR signalling toward antinociception.\",\n      \"method\": \"Phosphoproteomics and GPCR signalling assays in Nav1.7-null DRG neurons; western blot for RIIβ; electrophysiology measuring opioid inhibition of TTX-R currents; comparison with Nav1.8-null neurons\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple molecular and functional methods in isogenic KO neurons; isoform specificity controlled with Nav1.8-null comparison; single lab\",\n      \"pmids\": [\"28074005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Both µ- and δ-opioid receptors are required for the analgesic phenotype of Nav1.7-null mice; pharmacological or genetic co-ablation of µ- and δ-opioid receptors (but not κ) abolishes the pain-free phenotype; enkephalins (Penk-encoded) are upregulated in Nav1.7 nulls but Nfat5 deletion also upregulates Penk without producing analgesia, indicating that endogenous opioid upregulation is necessary but not sufficient for the Nav1.7-null analgesic state.\",\n      \"method\": \"Pharmacological opioid receptor antagonism; µ- and δ-opioid receptor double-null mouse genetics; Nfat5-null mouse Penk expression analysis; behavioural thermal pain assays\",\n      \"journal\": \"Wellcome open research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological double-dissection of opioid receptor subtypes; epistasis with Nfat5 to separate opioid production from analgesia; multiple orthogonal approaches\",\n      \"pmids\": [\"30271888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Preventing CRMP2 SUMOylation (via compound 194 targeting CRMP2-Ubc9 interaction, or CRMP2-K374A mutation) selectively reduces Nav1.7 surface expression and current density in DRG neurons and produces antinociception in rodent pain models; analgesia conferred by compound 194 is opioid-receptor dependent.\",\n      \"method\": \"In silico compound screening; in vitro Nav1.7 electrophysiology; ex vivo DRG surface biotinylation; rodent behavioural pain models; opioid receptor dependency assay\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vitro, ex vivo and in vivo approaches; mechanistic link between CRMP2 SUMOylation and Nav1.7 trafficking validated; replicated across pain models\",\n      \"pmids\": [\"34757807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nav1.7 is required for the initiation of C-fiber action potentials in vivo; genetic removal or selective pharmacological inhibition of Nav1.7 blocks C-fiber AP initiation as shown by laser speckle contrast imaging and in vivo electrophysiology; enkephalin upregulation upon Nav1.7 deletion is restricted to cLTMR (low-threshold mechanoreceptor) neurons and does not contribute to the analgesic phenotype.\",\n      \"method\": \"Single-cell RNA-seq; behavioural pharmacology; laser speckle contrast imaging; in vivo C-fiber electrophysiology in Nav1.7 conditional knockouts\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo electrophysiology directly measuring C-fiber AP initiation; scRNA-seq for cell-type specificity; pharmacological and genetic approaches combined\",\n      \"pmids\": [\"37352856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Paclitaxel treatment increases vesicular trafficking flux and surface expression of Nav1.7 in sensory axons in a concentration-dependent manner (low concentrations increase flux; high concentrations decrease flux) without requiring increased Nav1.7 mRNA pool; inflammatory mediators further amplify this trafficking increase, providing a mechanism for Nav1.7-dependent peripheral sensitisation in chemotherapy-induced neuropathy.\",\n      \"method\": \"Live imaging of Halo-tagged Nav1.7 vesicular transport in DRG sensory axons; surface biotinylation; qPCR and whole-cell patch-clamp for endogenous Nav1.7 current density\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — real-time live imaging with multiple concentrations and conditions; complementary biochemical and electrophysiological methods; single lab\",\n      \"pmids\": [\"33734317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nav1.8 amplifies DRG neuron excitability driven by gain-of-function Nav1.7 (L848H) near action potential threshold; at threshold voltage (−21.9 mV), Nav1.8 open-probability exceeds Nav1.7-WT open-probability ninefold; dynamic-clamp reduction of Nav1.8 conductance by 25–50% reverses hyperexcitability in neurons expressing Nav1.7-L848H by increasing rheobase and reducing AP firing probability.\",\n      \"method\": \"Dynamic-clamp electrophysiology; kinetic Markov modelling of Nav1.8; Nav1.7L848H gain-of-function expression in DRG neurons\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative dynamic-clamp reconstitution with kinetic modelling; defines interplay between Nav1.7 and Nav1.8 at threshold; single lab, multiple methods\",\n      \"pmids\": [\"39378238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The erythromelalgia mutation L858F differentially shifts the voltage dependence of activation in a cooling-dependent manner (depolarising shift with cooling for L858F but not wild-type Nav1.7), providing a biophysical explanation for symptomatic relief upon limb cooling in affected patients.\",\n      \"method\": \"Whole-cell voltage-clamp of wild-type and L858F Nav1.7 in HEK293 cells at different temperatures\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro temperature-dependent electrophysiology; mechanistic inference to clinical phenotype; single lab, single method\",\n      \"pmids\": [\"17239250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Nav1.7 (SCN9A) expression in cultured human aortic smooth muscle cells contributes to TTX-sensitive sodium current; SCN9A siRNA knockdown abolishes this current and significantly inhibits cell migration, endocytosis (HRP uptake), and matrix metalloproteinase-2 secretion, without affecting proliferation; Nav1.7 is also expressed in rabbit aorta after balloon injury.\",\n      \"method\": \"SCN9A siRNA knockdown; whole-cell voltage-clamp; migration and HRP uptake assays; qRT-PCR; immunostaining\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple functional readouts; electrophysiology confirming current identity; single lab\",\n      \"pmids\": [\"18978189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SCN9A (Nav1.7) expression is upregulated in senescent cells during oncogene-induced senescence (OIS) via NF-κB transcription factors; Nav1.7 induction leads to plasma membrane depolarisation, which activates a calcium/Rb/E2F pathway to repress mitotic genes and promote senescence; loss of SCN9A allows cells to escape OIS.\",\n      \"method\": \"Loss-of-function genetic screen; NF-κB dependency assays; plasma membrane potential measurements; calcium signalling assays; Rb/E2F pathway analysis\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen plus mechanistic pathway dissection with multiple downstream assays; single lab\",\n      \"pmids\": [\"29446526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"iPSC-derived sensory nociceptors from IEM patients carrying Nav1.7/I848T show decreased firing threshold, enhanced action potential upstroke and afterhyperpolarization; the IEM mutation causes a hyperpolarising shift of tetrodotoxin-sensitive Nav activation; Nav1.7 is not active during subthreshold depolarisations but its activity defines AP threshold and contributes to AP upstroke in human sensory neurons.\",\n      \"method\": \"iPSC differentiation into sensory nociceptors; whole-cell patch-clamp with prepulse voltage protocol; action potential recording in patient-derived cells\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional characterisation in patient-derived human nociceptors using multiple electrophysiological protocols; direct mechanistic insight into Nav1.7 role in AP threshold\",\n      \"pmids\": [\"30720580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-30b directly targets the 3′ UTR of SCN9A; overexpression of miR-30b in spared-nerve-injury rats inhibits SCN9A transcription and Nav1.7 protein, reducing pain hypersensitivity; miR-30b knockdown increases Nav1.7 expression and induces mechanical hypersensitivity in naïve rats.\",\n      \"method\": \"Bioinformatics target prediction; luciferase 3′-UTR reporter assay; in vivo miR-30b agomir/antagomir microinjection; western blot and qRT-PCR in DRG\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validation of direct miRNA-mRNA interaction plus in vivo gain/loss-of-function; single lab\",\n      \"pmids\": [\"27765894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-182 directly pairs with the SCN9A 3′ UTR (verified by luciferase assay); miR-182 agomir overexpression in SNI rats reverses the pathological Nav1.7 increase in DRG at both mRNA and protein levels and attenuates mechanical hypersensitivity.\",\n      \"method\": \"Luciferase 3′-UTR reporter assay; miR-182 agomir/antagomir injection in SNI rats; western blot and qRT-PCR\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct miRNA-target validation by reporter assay plus in vivo functional manipulation; single lab\",\n      \"pmids\": [\"30425258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NGF triggers sustained Nav1.7 upregulation in DRG via an NGF/TrkA–SGK1–Nedd4-2 phosphorylation pathway; conditional nociceptor-specific Nav1.7 knockout confirms Nav1.7's requirement for NGF-induced and post-surgical pain; pharmacological blockade of this pathway reduces Nav1.7 upregulation and spinal sensitisation.\",\n      \"method\": \"Nociceptor-specific Nav1.7 conditional KO; western blot and immunostaining for pathway components; pharmacological inhibition of SGK1 and Nedd4-2 phosphorylation; behavioural pain testing\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO confirms Nav1.7 requirement; pathway identified by pharmacological intervention; single lab, multiple methods\",\n      \"pmids\": [\"33063281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In mouse pancreatic β-cells, Nav1.7 (Scn9a) accounts for >85% of the voltage-gated Na+ current; knockout of Scn9a lowers β-cell Na+ current by >85% but glucagon and insulin secretion are unaffected in Scn9a-deficient islets, because Nav1.7 is largely inactive at physiological membrane potentials due to its unusually negative voltage dependence of inactivation in β-cells.\",\n      \"method\": \"Single-cell PCR; Scn9a knockout islet electrophysiology; insulin/glucagon secretion assays\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — genetic KO with direct electrophysiology confirming channel identity; functional secretion assays; single lab, multiple methods\",\n      \"pmids\": [\"25172946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nav1.7 is expressed in smooth muscle cells of cutaneous arterioles and arteriole-venule shunts, as well as in endothelial cells lining these vessels and in sensory/sympathetic fibres innervating them, suggesting that mutant Nav1.7 activity in skin vasculature (not only in neurons) contributes to skin reddening in erythromelalgia and PEPD.\",\n      \"method\": \"Immunohistochemistry of human skin sections with Nav1.7, smooth muscle, endothelial, and neural markers\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — immunolocalisation only; no functional manipulation; single lab\",\n      \"pmids\": [\"25957174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In conditional NaV1.7 knockout (advillin-Cre) sensory neurons, C-fiber axonal conduction velocity is 20% slower than wild-type; activity-dependent slowing of conduction is markedly reduced; a large subpopulation of C-fibers is functionally absent by compound AP recording; heat-evoked CGRP release is normal, indicating Nav1.7 loss impairs C-fiber conduction but not peptide release per se.\",\n      \"method\": \"Single-fiber recordings from isolated skin-nerve preparation; compound AP recording from saphenous nerve; CGRP release assay; rheobase/chronaxy measurements\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct single-fiber and compound nerve electrophysiology in conditional KO; multiple axon function parameters measured; single lab\",\n      \"pmids\": [\"29194125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SCN9A-encoded Nav1.7 in prostate cancer cells (Mat-LyLu) modulates RhoA and Rac1 Rho GTPase activity in a Nav1.7-dependent manner; Nav1.7 activator JZTX-I increases and inhibitor HNTX-III decreases cell migration/invasion; proteomic analysis identified 64 differentially expressed membrane proteins including cytoskeletal regulators (fascin, muskelin, annexin A2, cofilin-1).\",\n      \"method\": \"Peptide toxin activation/inhibition (JZTX-I/HNTX-III); migration and invasion assays; comparative membrane proteomics; western blot validation; Rho GTPase pharmacology\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological gain/loss-of-function with proteomic and functional validation of downstream pathway; single lab\",\n      \"pmids\": [\"30927332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Anandamide inhibits Nav1.7 sodium currents in a concentration-dependent manner (IC50 ~27 µM) in Xenopus oocytes, causing a depolarising shift of activation and hyperpolarising shift of inactivation, and shows use-dependent block; this is a direct pharmacological action on the channel.\",\n      \"method\": \"Two-electrode voltage-clamp of Nav1.7 α-subunit with β1 co-expression in Xenopus oocytes; concentration-response and gating analysis\",\n      \"journal\": \"Anesthesia and analgesia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro reconstitution electrophysiology; single lab; pharmacological characterisation only\",\n      \"pmids\": [\"24557103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The synthetic α-scorpion toxin OD1 and its analogs potently inhibit Nav1.7 fast inactivation by prolonging channel flickering between open and closed states; single-channel recordings confirm that toxins slow inactivation via a voltage-sensor trapping mechanism on domain IV, consistent with the gating-modifier model.\",\n      \"method\": \"Whole-cell and single-channel patch-clamp of Nav1.7 in the presence of OD1 and analogs\",\n      \"journal\": \"Channels (Austin, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct single-channel electrophysiology defining mechanism of inactivation inhibition; single lab; one toxin class\",\n      \"pmids\": [\"26646206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Buthus martensii Karsch scorpion toxin Makatoxin-3 acts on the S3-S4 loop of Nav1.7 VSD4, causing a hyperpolarising shift in steady-state fast inactivation and impairing inactivation kinetics; key residues mediating this interaction are distinct from those of other α-toxins, defining new structure-function relationships for toxin-Nav1.7 interactions.\",\n      \"method\": \"Nav1.7 subtype-selective pharmacology with venom and purified Makatoxin-3; chimeric Nav1.7 mutagenesis; electrophysiology in mouse DRG and cell lines; behavioural pain assays\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chimeric/mutant channel mapping plus functional electrophysiology and in vivo validation; single lab\",\n      \"pmids\": [\"34252912\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Nav1.7 (SCN9A) is a voltage-gated sodium channel α-subunit expressed in peripheral nociceptors, sympathetic neurons, and olfactory sensory neurons that sets the threshold for action potential initiation and C-fiber AP propagation; gain-of-function mutations enhance activation and/or impair inactivation causing inherited pain syndromes (erythromelalgia, PEPD, small-fiber neuropathy), while loss-of-function mutations abolish nociception and olfaction; channel surface density is regulated by hierarchical CRMP2 SUMOylation/phosphorylation controlling clathrin-dependent endocytosis via Nedd4-2, by miR-30b and miR-182 targeting SCN9A mRNA, and by paclitaxel-dependent vesicular trafficking; Nav1.7 loss additionally upregulates enkephalin and rebalances GPCR signalling toward µ/δ-opioid antinociception, explaining why pharmacological blockade alone incompletely replicates the genetic pain-free phenotype; inhibitors can trap VSD4 in an activated/inactivated state (acylsulfonamides) or antagonise VSD2 gating-charge movement (ProTx2), with structural blueprints defined by crystal and cryo-EM structures.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SCN9A encodes Nav1.7, a voltage-gated sodium channel α-subunit that sets the threshold for action potential initiation in peripheral sensory neurons and is an essential, non-redundant requirement for human nociception and olfaction [#0, #11]. In nociceptors, Nav1.7 activity defines the action potential threshold and contributes to the upstroke; it is required for initiation of C-fiber action potentials in vivo and for normal C-fiber conduction velocity [#25, #31, #37]. The channel is expressed along the entire nociceptive pathway from intraepidermal terminals through DRG somata to central presynaptic terminals, and it is the predominant sodium channel of olfactory sensory neurons where it drives odour-evoked synaptic transmission at the first olfactory synapse [#13, #14, #11]. Inherited gain-of-function missense mutations cause erythromelalgia by hyperpolarizing activation and/or depolarizing steady-state inactivation, lowering firing threshold and amplifying subthreshold sodium influx to produce nociceptor hyperexcitability, with distinct biophysical signatures distinguishing erythromelalgia from PEPD phenotypes [#1, #2, #18, #19]; complete loss-of-function truncating and pore-region mutations abolish current and cause congenital insensitivity to pain [#0, #15, #16]. The pain-free state of Nav1.7-null animals and humans is not explained by channel loss alone: deletion upregulates the enkephalin precursor Penk and rebalances GPCR signalling away from pronociceptive serotonergic toward antinociceptive µ- and δ-opioid tone, an endogenous opioid mechanism necessary for the analgesic phenotype [#12, #22, #23]. Channel surface density is set post-translationally by hierarchical CRMP2 SUMOylation—promoted by CDK5 and antagonized by Fyn—that maintains membrane Nav1.7 and, when lost, triggers clathrin-dependent endocytosis via Nedd4-2 with adaptors Numb and EPS15; disrupting CRMP2 SUMOylation reduces surface Nav1.7 and is antinociceptive [#6, #7, #24]. Trafficking and abundance are further controlled by NGF/TrkA–SGK1–Nedd4-2 signalling, paclitaxel-dependent vesicular transport, and direct 3′-UTR targeting by miR-30b and miR-182 [#34, #26, #32, #33]. Structural and pharmacological work has mapped how acylsulfonamides trap VSD4 in an activated state via the S4 gating charge and how the peptide ProTx2 antagonises VSD2 gating-charge movement from within the membrane, providing blueprints for isoform-selective inhibition [#8, #9]. Beyond neurons, Nav1.7 has been assigned roles in oncogene-induced senescence via NF-κB-driven depolarization and a Ca2+/Rb/E2F axis, and in cancer-cell and vascular smooth-muscle migration [#30, #29, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established Nav1.7 as a disease gene by linking SCN9A missense mutations to an inherited pain disorder, the first causal genetic tie to human pain.\",\n      \"evidence\": \"Linkage analysis and Sanger sequencing of SCN9A in erythermalgia families\",\n      \"pmids\": [\"14985375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro functional assay in this report to confirm gain-of-function\", \"Cellular mechanism of pain unspecified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the biophysical mechanism of gain-of-function pain mutations—hyperpolarized activation and depolarized inactivation lowering firing threshold in native nociceptors.\",\n      \"evidence\": \"Whole-cell and current-clamp recordings of mutant Nav1.7 in DRG neurons\",\n      \"pmids\": [\"15958509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative link between gating shift and AP output not yet established\", \"Did not address loss-of-function spectrum\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated Nav1.7 is an absolute, non-redundant requirement for human nociception by showing homozygous nonsense mutations produce no current.\",\n      \"evidence\": \"Heterologous expression of truncating mutants with β1/β2 and patch-clamp in HEK293\",\n      \"pmids\": [\"17167479\", \"17008310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of pain-free phenotype beyond channel loss unaddressed\", \"Why anosmia accompanies CIP not yet explained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved pharmacology and trafficking consequences of pain mutations, including residues governing local-anaesthetic block and temperature-dependent gating.\",\n      \"evidence\": \"Patch-clamp IC50/use-dependence of mutants in HEK293; truncating LoF confirmation\",\n      \"pmids\": [\"17430993\", \"17239250\", \"17597096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-lab pharmacology\", \"Clinical correlation inferred, not directly measured in patients\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected channel biophysics to drug responsiveness and to common-variant excitability, showing carbamazepine normalizes specific mutants and R1150W tunes nociceptor firing.\",\n      \"evidence\": \"Patch-clamp with CBZ pharmacology; voltage/current-clamp of R1150W in DRG neurons\",\n      \"pmids\": [\"19557861\", \"20033988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo confirmation of CBZ mechanism not provided\", \"Population-level effect of R1150W not assessed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified an olfactory role: Nav1.7 is the dominant OSN sodium channel and is required for odour-evoked synaptic signalling, explaining anosmia in Nav1.7-null humans.\",\n      \"evidence\": \"OSN-specific knockout, synaptic electrophysiology, expression mapping, human phenotyping\",\n      \"pmids\": [\"21441906\", \"21569247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for presynaptic-specific failure not fully resolved\", \"ERK co-localization at neuromas (idx 21) remains correlative\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Dissected cell-type-specific contributions, showing sensory-neuron Nav1.7 drives most pain modalities while sympathetic-neuron Nav1.7 is required for neuropathic pain.\",\n      \"evidence\": \"Advillin-Cre and Nav1.8-Cre conditional knockouts with multimodal behavioural testing\",\n      \"pmids\": [\"22531176\", \"23134641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of sympathetic contribution to neuropathic pain unresolved\", \"Heat-pain channel redundancy not fully explained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed that Nav1.7 surface density is post-translationally controlled via SUMOylation of its partner CRMP2.\",\n      \"evidence\": \"CRMP2-K374A mutagenesis, surface biotinylation, SENP overexpression, patch-clamp in CAD/HEK293\",\n      \"pmids\": [\"23836888\", \"24311784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream regulators of CRMP2 SUMOylation not yet identified at this stage\", \"Endocytic machinery not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Quantified how mutant gating translates into hyperexcitability and identified endocannabinoid block, linking biophysics to amplified subthreshold sodium influx.\",\n      \"evidence\": \"Dynamic-clamp in DRG neurons; two-electrode voltage-clamp of anandamide block in oocytes\",\n      \"pmids\": [\"24401712\", \"24557103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of anandamide IC50 (~27 µM) uncertain\", \"In vivo confirmation of 27-fold amplification not provided\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the endogenous opioid mechanism behind the Nav1.7-null pain-free state—Penk/met-enkephalin upregulation reversible by naloxone—and resolved structure-function salt-bridge determinants of activation.\",\n      \"evidence\": \"RNA-seq/qPCR, naloxone pharmacology in mice and human null; engineered disulfide and divalent-cation analysis\",\n      \"pmids\": [\"26634308\", \"25575597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether opioid upregulation is sufficient for analgesia not yet tested\", \"Receptor subtype dependence unresolved at this stage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the first high-resolution structural basis for isoform-selective inhibition by trapping VSD4 in its activated state.\",\n      \"evidence\": \"X-ray crystallography of Nav1.7 VSD4–acylsulfonamide complexes with selectivity mutagenesis\",\n      \"pmids\": [\"26680203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Engineered VSD4 construct, not full-length channel\", \"Pore-domain and inactivation coupling not captured\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped the upstream PTM hierarchy and downstream endocytic machinery controlling Nav1.7 surface levels, and identified miRNA control of SCN9A mRNA.\",\n      \"evidence\": \"CDK5/Fyn PTM analysis, CRMP2–Nav1.7 Co-IP, Nedd4-2/Numb/EPS15 endocytosis assays; miR-30b luciferase and in vivo manipulation\",\n      \"pmids\": [\"27940916\", \"27765894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological relevance of full endocytic cascade incompletely tested\", \"miR-30b effects single-lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed Nav1.7 loss rebalances GPCR signalling toward antinociception and impairs C-fiber conduction, broadening its role beyond simple threshold-setting.\",\n      \"evidence\": \"Phosphoproteomics/GPCR assays and opioid inhibition of TTX-R currents in null DRG; single-fiber and compound AP recording\",\n      \"pmids\": [\"28074005\", \"29194125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal chain from channel loss to serotonergic downregulation incompletely defined\", \"Conduction-velocity effect mechanism unspecified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that µ- and δ-opioid receptors are required—but enkephalin upregulation alone is not sufficient—for Nav1.7-null analgesia, and added a second miRNA regulator and a senescence role.\",\n      \"evidence\": \"µ/δ double-null genetics with Nfat5 epistasis; miR-182 luciferase/in vivo; OIS genetic screen and pathway dissection\",\n      \"pmids\": [\"30271888\", \"30425258\", \"29446526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The necessary-but-not-sufficient factors completing analgesia remain unidentified\", \"Senescence role single-lab and outside neurons\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the gating-modifier mechanism of peptide inhibition (ProTx2 at VSD2) and confirmed Nav1.7's role in defining AP threshold in human patient-derived nociceptors.\",\n      \"evidence\": \"Cryo-EM/crystallography of VSD2–ProTx2; patch-clamp of IEM iPSC-derived nociceptors; cancer-cell Rho GTPase study\",\n      \"pmids\": [\"30661758\", \"30720580\", \"30927332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"VSD2 construct lacks full-channel context\", \"Cancer-cell signalling mechanism correlative\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated therapeutic and pathological control of Nav1.7 trafficking—CRMP2-SUMOylation inhibition is opioid-dependent analgesic, while paclitaxel drives surface accumulation.\",\n      \"evidence\": \"Compound 194 screening with ex vivo biotinylation and rodent pain models; live imaging of Halo-Nav1.7 vesicular transport\",\n      \"pmids\": [\"34757807\", \"33734317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Opioid dependence of compound 194 mechanism not fully resolved\", \"Paclitaxel trafficking pathway components undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established directly in vivo that Nav1.7 is required for C-fiber AP initiation and refined the cell-type specificity of enkephalin upregulation.\",\n      \"evidence\": \"scRNA-seq, laser speckle imaging, in vivo C-fiber electrophysiology in conditional knockouts\",\n      \"pmids\": [\"37352856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with earlier opioid-tone findings on enkephalin contribution incomplete\", \"Sympathetic-neuron component not addressed here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed Nav1.7 gain-of-function hyperexcitability depends on Nav1.8 amplification at threshold, defining channel interplay as a therapeutic node.\",\n      \"evidence\": \"Dynamic-clamp with Nav1.8 Markov modelling in DRG neurons expressing Nav1.7-L848H\",\n      \"pmids\": [\"39378238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo validation of Nav1.8-dependent amplification pending\", \"Generalizability across mutations untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which additional factor(s), beyond endogenous opioid upregulation, are required to complete the Nav1.7-null analgesic state, and how Nav1.7 trafficking, PTM control, and Nav1.8 interplay can be jointly leveraged for selective, fully efficacious analgesia.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No single intervention reproduces the full genetic pain-free phenotype\", \"Integrated in vivo mechanism linking surface-density control to opioid rebalancing unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 2, 15, 35]},\n      {\"term_id\": \"GO:0005216\", \"supporting_discovery_ids\": [0, 2, 18, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 7, 14, 26]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 11, 18, 25, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [22, 23, 34]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [6, 7, 24, 26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CRMP2\", \"NEDD4L\", \"NUMB\", \"EPS15\", \"SCN1B\", \"SCN2B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":9,"faith_total":9,"faith_pct":100.0}}