Affinage

SCN9A

Sodium channel protein type 9 subunit alpha · UniProt Q15858

Length
1988 aa
Mass
226.4 kDa
Annotated
2026-06-10
100 papers in source corpus 42 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2004 Medium

    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

    PMID:14985375

    Open questions at the time
    • No in vitro functional assay in this report to confirm gain-of-function
    • Cellular mechanism of pain unspecified
  2. 2005 High

    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

    PMID:15958509

    Open questions at the time
    • Quantitative link between gating shift and AP output not yet established
    • Did not address loss-of-function spectrum
  3. 2006 High

    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

    PMID:17008310 PMID:17167479

    Open questions at the time
    • Mechanism of pain-free phenotype beyond channel loss unaddressed
    • Why anosmia accompanies CIP not yet explained
  4. 2007 High

    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

    PMID:17239250 PMID:17430993 PMID:17597096

    Open questions at the time
    • Single-lab pharmacology
    • Clinical correlation inferred, not directly measured in patients
  5. 2009 High

    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

    PMID:19557861 PMID:20033988

    Open questions at the time
    • In vivo confirmation of CBZ mechanism not provided
    • Population-level effect of R1150W not assessed
  6. 2011 High

    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

    PMID:21441906 PMID:21569247

    Open questions at the time
    • Molecular basis for presynaptic-specific failure not fully resolved
    • ERK co-localization at neuromas (idx 21) remains correlative
  7. 2012 High

    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

    PMID:22531176 PMID:23134641

    Open questions at the time
    • Mechanism of sympathetic contribution to neuropathic pain unresolved
    • Heat-pain channel redundancy not fully explained
  8. 2013 High

    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

    PMID:23836888 PMID:24311784

    Open questions at the time
    • Upstream regulators of CRMP2 SUMOylation not yet identified at this stage
    • Endocytic machinery not defined
  9. 2014 High

    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

    PMID:24401712 PMID:24557103

    Open questions at the time
    • Physiological relevance of anandamide IC50 (~27 µM) uncertain
    • In vivo confirmation of 27-fold amplification not provided
  10. 2015 High

    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

    PMID:25575597 PMID:26634308

    Open questions at the time
    • Whether opioid upregulation is sufficient for analgesia not yet tested
    • Receptor subtype dependence unresolved at this stage
  11. 2015 High

    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

    PMID:26680203

    Open questions at the time
    • Engineered VSD4 construct, not full-length channel
    • Pore-domain and inactivation coupling not captured
  12. 2016 High

    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

    PMID:27765894 PMID:27940916

    Open questions at the time
    • In vivo physiological relevance of full endocytic cascade incompletely tested
    • miR-30b effects single-lab
  13. 2017 High

    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

    PMID:28074005 PMID:29194125

    Open questions at the time
    • Causal chain from channel loss to serotonergic downregulation incompletely defined
    • Conduction-velocity effect mechanism unspecified
  14. 2018 Medium

    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

    PMID:29446526 PMID:30271888 PMID:30425258

    Open questions at the time
    • The necessary-but-not-sufficient factors completing analgesia remain unidentified
    • Senescence role single-lab and outside neurons
  15. 2019 High

    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

    PMID:30661758 PMID:30720580 PMID:30927332

    Open questions at the time
    • VSD2 construct lacks full-channel context
    • Cancer-cell signalling mechanism correlative
  16. 2021 High

    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

    PMID:33734317 PMID:34757807

    Open questions at the time
    • Opioid dependence of compound 194 mechanism not fully resolved
    • Paclitaxel trafficking pathway components undefined
  17. 2023 High

    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

    PMID:37352856

    Open questions at the time
    • Reconciliation with earlier opioid-tone findings on enkephalin contribution incomplete
    • Sympathetic-neuron component not addressed here
  18. 2024 High

    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

    PMID:39378238

    Open questions at the time
    • In vivo validation of Nav1.8-dependent amplification pending
    • Generalizability across mutations untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No single intervention reproduces the full genetic pain-free phenotype
  • Integrated in vivo mechanism linking surface-density control to opioid rebalancing unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-9609507 Protein localization 4 R-HSA-162582 Signal Transduction 3
Partners
CRMP2EPS15NEDD4LNUMBSCN1BSCN2B

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. Co-expression of wild-type or mutant Nav1.7 with β1/β2 subunits in HEK293 cells, whole-cell patch-clamp electrophysiology Nature High 17167479
2004 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. Linkage analysis and Sanger sequencing of SCN9A in affected family and sporadic patient Journal of medical genetics Medium 14985375
2005 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. Whole-cell patch-clamp electrophysiology in DRG neurons expressing mutant Nav1.7; current-clamp recordings Brain : a journal of neurology High 15958509
2007 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. Whole-cell patch-clamp electrophysiology of Nav1.7-N395K expressed in HEK293 cells; pharmacological IC50 determination and use-dependent block assays The Journal of physiology High 17430993
2006 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. Whole-cell voltage-clamp in HEK293 cells expressing wild-type or mutant Nav1.7 (S241T, S241A, S241L) The Journal of biological chemistry High 17008310
2009 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. Whole-cell patch-clamp of V400M and wild-type Nav1.7 cell lines; pharmacological CBZ application Annals of neurology High 19557861
2013 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. CRMP2-K374A mutagenesis, surface biotinylation, whole-cell patch-clamp, SENP1/SENP2 overexpression in CAD and HEK293 cells stably expressing Nav1.7; Ubc9 dependency confirmed The Journal of biological chemistry High 23836888
2016 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. Hierarchical post-translational modification analysis, co-immunoprecipitation of CRMP2 and Nav1.7, dominant-negative/kinase inhibitor experiments, surface biotinylation, current-clamp in DRG neurons Proceedings of the National Academy of Sciences of the United States of America High 27940916
2015 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. Protein-engineering and X-ray crystallography of Nav1.7 VSD4–inhibitor complexes; structure-guided mutagenesis to define selectivity determinants Science (New York, N.Y.) High 26680203
2019 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. X-ray crystallography and cryo-EM of Nav1.7 VSD2–ProTx2 complexes; functional electrophysiology validation Cell High 30661758
2012 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. Cell-type-specific conditional knockout mice (Advillin-Cre, Nav1.8-Cre); behavioural pain testing across multiple modalities Nature communications High 22531176
2011 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. Conditional knockout of Nav1.7 in olfactory sensory neurons; in vivo odour-guided behavioural assays; electrophysiology of olfactory sensory neurons; human patient phenotyping Nature High 21441906
2015 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. RNA-seq/qPCR of Nav1.7-null sensory neurons; naloxone pharmacology in Nav1.7-null mice and human patient; spinal cord in vivo electrophysiology Nature communications High 26634308
2011 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. Multiplex PCR-RFLP, in situ hybridisation, and immunohistochemistry in rat and mouse olfactory epithelium and bulb Molecular pain Medium 21569247
2012 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. Immunocytochemistry in rat DRG, sciatic nerve, skin, and dorsal horn Molecular pain Medium 23134641
2007 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. Functional expression in cell lines; whole-cell patch-clamp; species expression comparison by in situ hybridisation Human molecular genetics High 17597096
2010 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. Transient transfection of PC12 cells; confocal microscopy for membrane localisation; voltage-clamp of HEK293 cells Human mutation High 20635406
2009 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. Whole-cell voltage-clamp and current-clamp of DRG neurons expressing R1150W or wild-type Nav1.7; comparison across multiple assay formats Annals of neurology High 20033988
2014 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. Dynamic-clamp electrophysiology in small DRG neurons expressing wild-type or L858H Nav1.7 at calibrated physiological conductance levels Journal of neurophysiology High 24401712
2013 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. Whole-cell patch-clamp of HEK293 and DRG neurons transfected with A1632T Nav1.7; comparison with A1632E and wild-type The Journal of biological chemistry High 24311784
2015 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. Whole-cell patch-clamp; 3D homology modelling; engineered disulfide bridge approach; divalent cation pharmacology in HEK293 cells The Journal of biological chemistry High 25575597
2011 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. Immunohistochemistry and co-immunolabelling of Nav1.7 and pERK1/2 in rat sciatic nerve neuromas 2 weeks post-ligation Experimental neurology Low 21601570
2017 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. 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 Science signaling High 28074005
2018 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. Pharmacological opioid receptor antagonism; µ- and δ-opioid receptor double-null mouse genetics; Nfat5-null mouse Penk expression analysis; behavioural thermal pain assays Wellcome open research High 30271888
2021 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. In silico compound screening; in vitro Nav1.7 electrophysiology; ex vivo DRG surface biotinylation; rodent behavioural pain models; opioid receptor dependency assay Science translational medicine High 34757807
2023 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. Single-cell RNA-seq; behavioural pharmacology; laser speckle contrast imaging; in vivo C-fiber electrophysiology in Nav1.7 conditional knockouts Neuron High 37352856
2021 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. 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 Brain : a journal of neurology High 33734317
2024 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. Dynamic-clamp electrophysiology; kinetic Markov modelling of Nav1.8; Nav1.7L848H gain-of-function expression in DRG neurons The Journal of general physiology High 39378238
2007 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. Whole-cell voltage-clamp of wild-type and L858F Nav1.7 in HEK293 cells at different temperatures Molecular pain Medium 17239250
2008 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. SCN9A siRNA knockdown; whole-cell voltage-clamp; migration and HRP uptake assays; qRT-PCR; immunostaining American journal of physiology. Heart and circulatory physiology Medium 18978189
2018 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. Loss-of-function genetic screen; NF-κB dependency assays; plasma membrane potential measurements; calcium signalling assays; Rb/E2F pathway analysis Aging cell Medium 29446526
2019 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. iPSC differentiation into sensory nociceptors; whole-cell patch-clamp with prepulse voltage protocol; action potential recording in patient-derived cells Pain High 30720580
2016 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. Bioinformatics target prediction; luciferase 3′-UTR reporter assay; in vivo miR-30b agomir/antagomir microinjection; western blot and qRT-PCR in DRG Molecular pain Medium 27765894
2018 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. Luciferase 3′-UTR reporter assay; miR-182 agomir/antagomir injection in SNI rats; western blot and qRT-PCR Scientific reports Medium 30425258
2020 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. Nociceptor-specific Nav1.7 conditional KO; western blot and immunostaining for pathway components; pharmacological inhibition of SGK1 and Nedd4-2 phosphorylation; behavioural pain testing Molecular neurobiology Medium 33063281
2014 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. Single-cell PCR; Scn9a knockout islet electrophysiology; insulin/glucagon secretion assays The Journal of physiology High 25172946
2015 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. Immunohistochemistry of human skin sections with Nav1.7, smooth muscle, endothelial, and neural markers Molecular pain Low 25957174
2017 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. Single-fiber recordings from isolated skin-nerve preparation; compound AP recording from saphenous nerve; CGRP release assay; rheobase/chronaxy measurements Pain High 29194125
2019 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). Peptide toxin activation/inhibition (JZTX-I/HNTX-III); migration and invasion assays; comparative membrane proteomics; western blot validation; Rho GTPase pharmacology The FEBS journal Medium 30927332
2014 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. Two-electrode voltage-clamp of Nav1.7 α-subunit with β1 co-expression in Xenopus oocytes; concentration-response and gating analysis Anesthesia and analgesia Medium 24557103
2015 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. Whole-cell and single-channel patch-clamp of Nav1.7 in the presence of OD1 and analogs Channels (Austin, Tex.) Medium 26646206
2022 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. 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 Pain Medium 34252912

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 An SCN9A channelopathy causes congenital inability to experience pain. Nature 1182 17167479
2004 Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. Journal of medical genetics 610 14985375
2005 Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Brain : a journal of neurology 380 15958509
2007 Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. The Journal of clinical investigation 277 18060017
2015 Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist. Science (New York, N.Y.) 257 26680203
2012 Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons. Nature communications 228 22531176
2011 Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature 227 21441906
2003 ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Antimicrobial agents and chemotherapy 227 14638486
2012 Expression of Nav1.7 in DRG neurons extends from peripheral terminals in the skin to central preterminal branches and terminals in the dorsal horn. Molecular pain 169 23134641
2016 Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief. Expert opinion on therapeutic targets 161 26941184
2019 Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin. Cell 152 30661758
2010 NENA, a Lotus japonicus homolog of Sec13, is required for rhizodermal infection by arbuscular mycorrhiza fungi and rhizobia but dispensable for cortical endosymbiotic development. The Plant cell 152 20675572
2007 A stop codon mutation in SCN9A causes lack of pain sensation. Human molecular genetics 149 17597096
2007 A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity. The Journal of physiology 145 17430993
2015 Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7. Nature communications 143 26634308
2014 Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain. PloS one 133 25188265
2009 A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia. Annals of neurology 116 19557861
2016 Hierarchical CRMP2 posttranslational modifications control NaV1.7 function. Proceedings of the National Academy of Sciences of the United States of America 113 27940916
2009 Abnormal expression of voltage-gated sodium channels Nav1.7, Nav1.3 and Nav1.8 in trigeminal neuralgia. Neuroscience 102 19699781
2010 Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations. Human mutation 91 20635406
2013 CRMP2 protein SUMOylation modulates NaV1.7 channel trafficking. The Journal of biological chemistry 88 23836888
2012 Nav1.7-related small fiber neuropathy: impaired slow-inactivation and DRG neuron hyperexcitability. Neurology 82 22539570
2019 The role of Nav1.7 in human nociceptors: insights from human induced pluripotent stem cell-derived sensory neurons of erythromelalgia patients. Pain 80 30720580
2015 Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG. Chemistry & biology 78 26097035
2014 Paroxysmal itch caused by gain-of-function Nav1.7 mutation. Pain 78 24820863
2014 Na+ current properties in islet α- and β-cells reflect cell-specific Scn3a and Scn9a expression. The Journal of physiology 77 25172946
2018 Insensitivity to Pain upon Adult-Onset Deletion of Nav1.7 or Its Blockade with Selective Inhibitors. The Journal of neuroscience : the official journal of the Society for Neuroscience 76 30301756
2009 A sodium channel gene SCN9A polymorphism that increases nociceptor excitability. Annals of neurology 75 20033988
2006 Size matters: Erythromelalgia mutation S241T in Nav1.7 alters channel gating. The Journal of biological chemistry 74 17008310
2010 Familial pain syndromes from mutations of the NaV1.7 sodium channel. Annals of the New York Academy of Sciences 72 20146699
2014 Dynamic-clamp analysis of wild-type human Nav1.7 and erythromelalgia mutant channel L858H. Journal of neurophysiology 71 24401712
2012 A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia. BMC musculoskeletal disorders 68 22348792
2016 Inherited erythromelalgia due to mutations in SCN9A: natural history, clinical phenotype and somatosensory profile. Brain : a journal of neurology 65 26920677
2016 MicroRNA-30b regulates expression of the sodium channel Nav1.7 in nerve injury-induced neuropathic pain in the rat. Molecular pain 64 27765894
2013 A novel SCN9A mutation responsible for primary erythromelalgia and is resistant to the treatment of sodium channel blockers. PloS one 64 23383113
2013 Inherited pain: sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation. The Journal of biological chemistry 62 24311784
2021 Paclitaxel increases axonal localization and vesicular trafficking of Nav1.7. Brain : a journal of neurology 58 33734317
2016 Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli. The Journal of neuroscience : the official journal of the Society for Neuroscience 57 27413160
2013 Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation. Neurology 57 23596073
2011 Nav1.7 is the predominant sodium channel in rodent olfactory sensory neurons. Molecular pain 53 21569247
2017 Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in Nav1.7 knockout mice. Science signaling 52 28074005
2021 Selective targeting of NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in rodents. Science translational medicine 51 34757807
2018 MicroRNA-182 Alleviates Neuropathic Pain by Regulating Nav1.7 Following Spared Nerve Injury in Rats. Scientific reports 51 30425258
2010 Hemolysin EthA in Edwardsiella tarda is essential for fish invasion in vivo and in vitro and regulated by two-component system EsrA-EsrB and nucleoid protein HhaEt. Fish & shellfish immunology 50 20832475
2020 Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels. Pflugers Archiv : European journal of physiology 46 32601768
2015 Novel SCN9A mutations underlying extreme pain phenotypes: unexpected electrophysiological and clinical phenotype correlations. The Journal of neuroscience : the official journal of the Society for Neuroscience 46 25995458
2023 Nav1.7 is essential for nociceptor action potentials in the mouse in a manner independent of endogenous opioids. Neuron 44 37352856
2016 Baeyer-Villiger Monooxygenases EthA and MymA Are Required for Activation of Replicating and Non-replicating Mycobacterium tuberculosis Inhibitors. Cell chemical biology 41 27321573
2008 Nav1.7 expression is increased in painful human dental pulp. Molecular pain 41 18426592
2021 Pain behavior in SCN9A (Nav1.7) and SCN10A (Nav1.8) mutant rodent models. Neuroscience letters 39 33775738
2018 Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V. PloS one 39 29723257
2011 Nav1.7 accumulates and co-localizes with phosphorylated ERK1/2 within transected axons in early experimental neuromas. Experimental neurology 39 21601570
2010 Two novel mutations of SCN9A (Nav1.7) are associated with partial congenital insensitivity to pain. European journal of pain (London, England) 39 20692858
2007 Temperature dependence of erythromelalgia mutation L858F in sodium channel Nav1.7. Molecular pain 39 17239250
2011 Severe case and literature review of primary erythromelalgia: novel SCN9A gene mutation. Vascular medicine (London, England) 37 22033523
2024 Interplay of Nav1.8 and Nav1.7 channels drives neuronal hyperexcitability in neuropathic pain. The Journal of general physiology 36 39378238
2018 NaV1.7 and pain: contribution of peripheral nerves. Pain 34 29194125
2007 Identification and characterization of the promoter region of the Nav1.7 voltage-gated sodium channel gene (SCN9A). Molecular and cellular neurosciences 31 18249135
2023 A Review of the Therapeutic Targeting of SCN9A and Nav1.7 for Pain Relief in Current Human Clinical Trials. Journal of pain research 30 37168847
2020 NGF-Induced Nav1.7 Upregulation Contributes to Chronic Post-surgical Pain by Activating SGK1-Dependent Nedd4-2 Phosphorylation. Molecular neurobiology 29 33063281
2018 Selective Ligands and Drug Discovery Targeting the Voltage-Gated Sodium Channel Nav1.7. Handbook of experimental pharmacology 29 29532179
2014 Exonic mutations in SCN9A (NaV1.7) are found in a minority of patients with erythromelalgia. Scandinavian journal of pain 29 29911575
2008 Function and role of voltage-gated sodium channel NaV1.7 expressed in aortic smooth muscle cells. American journal of physiology. Heart and circulatory physiology 29 18978189
2015 Sodium channel Nav1.7 in vascular myocytes, endothelium, and innervating axons in human skin. Molecular pain 28 25957174
2010 A nonsense mutation in the SCN9A gene in congenital insensitivity to pain. Dermatology (Basel, Switzerland) 28 20628234
2021 Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces and prevents pain chronification in a mouse model of oxaliplatin-induced neuropathic pain. Neurobiology of pain (Cambridge, Mass.) 27 35024498
2010 Chronic non-paroxysmal neuropathic pain - Novel phenotype of mutation in the sodium channel SCN9A gene. Journal of the neurological sciences 26 21094958
2018 Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors. Wellcome open research 25 30271888
2017 Genetic polymorphisms of SCN9A are associated with oxaliplatin-induced neuropathy. BMC cancer 25 28103821
2017 Control of Neurotransmission by NaV1.7 in Human, Guinea Pig, and Mouse Airway Parasympathetic Nerves. The Journal of pharmacology and experimental therapeutics 25 28138042
2015 Regulation of Nav1.7: A Conserved SCN9A Natural Antisense Transcript Expressed in Dorsal Root Ganglia. PloS one 25 26035178
2018 The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway. Aging cell 24 29446526
2017 Network topology of NaV1.7 mutations in sodium channel-related painful disorders. BMC systems biology 24 28235406
2017 EthA/R-Independent Killing of Mycobacterium tuberculosis by Ethionamide. Frontiers in microbiology 24 28487681
2014 The endocannabinoid anandamide inhibits voltage-gated sodium channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 in Xenopus oocytes. Anesthesia and analgesia 24 24557103
2020 Activating Sirt1 by resveratrol suppresses Nav1.7 expression in DRG through miR-182 and alleviates neuropathic pain in rats. Channels (Austin, Tex.) 23 32089065
2019 Mechanistic insights into Nav1.7-dependent regulation of rat prostate cancer cell invasiveness revealed by toxin probes and proteomic analysis. The FEBS journal 23 30927332
2017 Whole-Transcriptome and -Genome Analysis of Extensively Drug-Resistant Mycobacterium tuberculosis Clinical Isolates Identifies Downregulation of ethA as a Mechanism of Ethionamide Resistance. Antimicrobial agents and chemotherapy 23 28993337
2019 SCN9A Epileptic Encephalopathy Mutations Display a Gain-of-function Phenotype and Distinct Sensitivity to Oxcarbazepine. Neuroscience bulletin 22 31372899
2015 Antihyperalgesic effects of ProTx-II, a Nav1.7 antagonist, and A803467, a Nav1.8 antagonist, in diabetic mice. Journal of experimental pharmacology 22 27186141
2016 Sodium channel Nav1.7 expression is upregulated in the dorsal root ganglia in a rat model of paclitaxel-induced peripheral neuropathy. SpringerPlus 21 27777872
2013 An atypical case of SCN9A mutation presenting with global motor delay and a severe pain disorder. Muscle & nerve 21 23893323
2013 NaV1.7: stress-induced changes in immunoreactivity within magnocellular neurosecretory neurons of the supraoptic nucleus. Molecular pain 21 23924059
2011 Two novel SCN9A gene heterozygous mutations may cause partial deletion of pain perception. Pain medicine (Malden, Mass.) 21 21939494
2020 Pharmacological characterization of a rat Nav1.7 loss-of-function model with insensitivity to pain. Pain 20 31977939
2020 Neuroprotective effects of ranolazine versus pioglitazone in experimental diabetic neuropathy: Targeting Nav1.7 channels and PPAR-γ. Life sciences 20 32184124
2018 Expression of pathogenic SCN9A mutations in the zebrafish: A model to study small-fiber neuropathy. Experimental neurology 20 30316835
2018 Pediatric Erythromelalgia and SCN9A Mutations: Systematic Review and Single-Center Case Series. The Journal of pediatrics 20 30416015
2013 A new Nav1.7 mutation in an erythromelalgia patient. Biochemical and biophysical research communications 20 23376079
2011 Kinetic modeling of Nav1.7 provides insight into erythromelalgia-associated F1449V mutation. Journal of neurophysiology 20 21289137
2015 Erythromelalgia mutation Q875E Stabilizes the activated state of sodium channel Nav1.7. The Journal of biological chemistry 19 25575597
2022 A Buthus martensii Karsch scorpion sting targets Nav1.7 in mice and mimics a phenotype of human chronic pain. Pain 18 34252912
2013 A novel mutation in SCN9A in a child with congenital insensitivity to pain. Pediatric neurology 18 24188911
2021 Inhibition of Nav1.7 channel by a novel blocker QLS-81 for alleviation of neuropathic pain. Acta pharmacologica Sinica 17 34103689
2020 Novel SCN9A missense mutations contribute to congenital insensitivity to pain: Unexpected correlation between electrophysiological characterization and clinical phenotype. Molecular pain 17 32420800
2019 No Association of Polymorphisms in Nav1.7 or Nerve Growth Factor Receptor Genes with Trigeminal Neuralgia. Pain medicine (Malden, Mass.) 17 30307573
2018 Variable epilepsy phenotypes associated with heterozygous mutation in the SCN9A gene: report of two cases. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 17 29500686
2015 Modulation of human Nav1.7 channel gating by synthetic α-scorpion toxin OD1 and its analogs. Channels (Austin, Tex.) 17 26646206
2019 NaV1.6 and NaV1.7 channels are major endogenous voltage-gated sodium channels in ND7/23 cells. PloS one 16 31419255
2018 Fenamates inhibit human sodium channel Nav1.7 and Nav1.8. Neuroscience letters 15 30528877

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