Asta Literature Retrieval: Research SCN9A Nav1.7 sodium channel function in human

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 63
• Snippets retrieved: 20

Relevant Papers

[1] Painless Nav1.7 mutations reveal function-critical residues in the outer vestibule and N-terminus

• Authors: Nivedita Sarveswaran, I. Drissi, Samiha S. Shaikh, M. Nahorski, Fiona Cusdin et al.
• Year: 2025
• Venue: bioRxiv
• URL: https://www.semanticscholar.org/paper/c48d4918f0695924376cbdac19b96b7a48bba365
• DOI: 10.1101/2025.05.12.653536
• Summary: Functional analysis and in silico modelling reveal critical roles for residues in the extracellular vestibule, ion selectivity filter and unexpectedly, the N-terminus in voltage-gated sodium channel Nav1.7, a key modulator of nociceptor excitability and associated with congenital painlessness.

[2] Comprehensive Proteomic Profiling of Human Nav1.7-Interacting Proteins Reveals Conserved Regulatory Networks Involved in Nociceptive Signaling

• Authors: Xuelong Zhou, Jing Zhao
• Year: 2025
• Venue: Neuroscience Insights
• URL: https://www.semanticscholar.org/paper/3033c52f684cffa5b6a3f676b4bc177da7ef8f43
• DOI: 10.1177/26331055251405071
• PMID: 41393971
• PMCID: 12698995
• Summary: This study employed tandem affinity purification (TAP) combined with high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) to systematically characterize the protein-protein interaction (PPI) network of hNav1.7, offering potential targets for modulating channel function in pain pathophysiology.

[3] A Review of the Therapeutic Targeting of SCN9A and Nav1.7 for Pain Relief in Current Human Clinical Trials

• Authors: A. Dormer, Mahesh Narayanan, J. Schentag, D. Achinko, E. Norman et al.
• Year: 2023
• Venue: Journal of Pain Research
• URL: https://www.semanticscholar.org/paper/bc7f32892fa6b4ed6ec47cf1ff74f0269c0df16c
• DOI: 10.2147/JPR.S388896
• PMID: 37168847
• PMCID: 10166096
• Citations: 27
• Influential citations: 7
• Summary: The review will look at the genomics associated with SCN1A and proteomic of Nav1.7 as a foundation to explain the mechanism of the therapeutic interventions targeting Nav 1.7 for the relief of chronic pain in humans.
• Evidence snippets:
• Snippet 1 (score: 0.579)
  > A Review of the Therapeutic Targeting of SCN9A and Nav1.7 for Pain Relief in Current Human Clinical Trials
• Snippet 2 (score: 0.527)
  > Neuronal sodium channels are coding by a family of genes, one of which is called sodium voltage-gated channel alpha subunit 9 (SCN9A). 1 This gene encodes for sodium channels that are designed to assist in the transportation of positively charged sodium atoms (Na + ions) into the cell. This action plays a vital role in the generation and the propagation of electrical signals along the neuron. 2 A study which included 95 individuals was conducted of which from these persons 27 different tissues were examined to determine the SCN9A expression. The determination of SCN9A protein coding gene tissue-specificity was analyzed using RNA-seq. It was found that SCN9A was expressed in all 27 different tissues at variant degree. The highest expression of SCN9A in non-neuronal tissues was in testis, placenta, and colon. [3][4][5] SCN9A consists of 180,803 nucleotides which encodes a 1988 amino acid Nav1.7 protein. 6 Nav1.7 is the sodium channel expression protein of the SCN9A gene. 7 The pain signals that are transmitted to the brain are facilitated by Nav1.7 nociceptors preferentially expressed on the neurons that are part of the peripheral nervous system. 8 The peripheral nervous system (PNS) is connected to the central nervous system (CNS) which consists of the brain and the spinal cord. 9 Nociceptors, which are part of the PNS, consist of cells that have the ability to detect many different types of sensation including pain, smell, and taste. 10 Neuronal structures consisting of nociceptors are designed primarily in the transmission of pain signals. 11 It is within the cell bodies that the centers of nociceptors are found. Those centers are located within the dorsal root ganglion of the spinal cord. 12 The nerve fibers that extend from those cells' bodies come from all over the human body receiving sensory information from the periphery that will be transmitted to the brain. 12 SCN9A which is the gene that encodes for the voltage-gated Nav1.7 sodium channel have a major role in the proper functioning of the nociceptive signaling. 13 Mutations within SCN9A gene have been associated with

[4] ProTx-II, a Selective Inhibitor of NaV1.7 Sodium Channels, Blocks Action Potential Propagation in Nociceptors

• Authors: W. Schmalhofer, Jeffrey D Calhoun, R. Burrows, Timothy Bailey, M. Kohler et al.
• Year: 2008
• Venue: Molecular Pharmacology
• URL: https://www.semanticscholar.org/paper/8e6ab4b971046295c7403903b927f3f046272326
• DOI: 10.1124/mol.108.047670
• PMID: 18728100
• Citations: 307
• Influential citations: 26
• Summary: The 125I-ProTx-II binding assay, described here, offers a new tool in the search for novel NaV1.7-selective channel blockers, suggesting that ProTx- II binds to a novel site, which may be more conducive to conferring subtype selectivity than the site occupied by traditional local anesthetics and anticonvulsants.

[5] Effect of NaV1.7 blockers on post-ganglionic sympathetic nerve function

• Authors: Joyce Kim, S. Meeker, Fei Ru, Minh Tran, Tanja S Zabka et al.
• Year: 2024
• Venue: Physiology
• URL: https://www.semanticscholar.org/paper/195e7388967320cac98395e112bf72e8ce8cab72
• DOI: 10.1152/physiol.2024.39.s1.803
• Summary: The hypothesis that pharmacological inhibition of NaV1.7 using selective inhibitors has the potential to reduce sympathetic function in specific vascular beds is supported, and the hypothesis that NaV1.7 blockers may be effective non-opioids analgesics is supported.

[6] Preclinical Animal Models to Investigate the Role of Nav1.7 Ion Channels in Pain

• Authors: Alvaro Yogi, Umberto Banderali, M. Moreno, Marzia Martina
• Year: 2025
• Venue: Life
• URL: https://www.semanticscholar.org/paper/00eb8fca4ec7091f9a6d18318ec0e711f9714fa2
• DOI: 10.3390/life15040640
• PMID: 40283194
• PMCID: 12028925
• Citations: 11
• Summary: This review summarizes the pain behavior profiles mediated by Nav1.7 reported in multiple preclinical models, outlining the current knowledge of the biophysical, physiological, and distribution properties required for a Nav1.7 inhibitor to produce analgesia.

[7] NaV1.7 mRNA and protein expression in putative projection neurons of the human spinal dorsal horn

• Authors: Stephanie I. Shiers, G. Funk, Anna M. Cervantes, Peter Horton, G. Dussor et al.
• Year: 2023
• Venue: bioRxiv
• URL: https://www.semanticscholar.org/paper/8a1ee0238e21f3870db4056d942489e1e80293d8
• DOI: 10.1101/2023.02.04.527110
• PMID: 36778234
• PMCID: 9915702
• Citations: 2
• Summary: It is reported for the first time that NaV1.7 mRNA is expressed in putative projection neurons (NK1R+) in the human spinal dorsal horn, predominantly in lamina 1 and 2, as well as in deep dorsal horn neurons and motor neurons in the ventral horn.

[8] Mepyramine targets mutant Nav1.7 channels to relieve pain and erythema in primary erythromelalgia patients

• Authors: Myriam-Isabelle Ducrocq, Virginie Penalba, Laura Castillo, C. Bodemer, Céline Greco et al.
• Year: 2025
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/b125daffdd3185c5f0fb970f2e586344b52576aa
• DOI: 10.3389/fmed.2025.1744968
• PMID: 41458489
• PMCID: 12740923
• Summary: It is demonstrated that mepyramine, a compound previously shown to alleviate pain in animal models, effectively targets hNav1.7 channels carrying PEM-associated gain-of-function mutations, providing substantial pain relief in PEM patients.

[9] Structure-function and rational design of a spider toxin Ssp1a at human voltage-gated sodium channel subtypes

• Authors: Y. Dongol, D. Wilson, N. Daly, Fernanda C Cardoso, Richard J. Lewis
• Year: 2023
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/a540fab54dcceb089ee32a5bfd3293a57f8d8381
• DOI: 10.3389/fphar.2023.1277143
• PMID: 38034993
• PMCID: 10682951
• Citations: 2
• Summary: The challenge of developing subtype-selective spider toxin inhibitors across multiple NaV subtypes that might offer a more effective therapeutic approach is highlighted, with S7R-E18K-rSsp1a and N14D-P27R- rSSP1a identified as promising leads.

[10] Design, synthesis, structure-activity relationship (SAR) and analgesic effect studies of novel arylsulfonamides as selective Nav1.7 inhibitors.

• Authors: Ruokun Wu, Wenfeng Chen, Xueyuan Wang, Xinran Ye, Hang Miao et al.
• Year: 2025
• Venue: European journal of medicinal chemistry
• URL: https://www.semanticscholar.org/paper/c2311d63427be8ad1fedb39a79efbac8980b0308
• DOI: 10.1016/j.ejmech.2025.118069
• PMID: 40882438
• Summary: Compound 50 was found to show favorable microsomal stability, in vivo safety, high selectivity and a low potential risk of cardiotoxicity, and results suggested that compound 50 might be a potent candidate for the treatment of neuropathic pain.

[11] Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7

• Authors: M. S. Minett, Vanessa Pereira, Shafaq Sikandar, A. Matsuyama, S. Lolignier et al.
• Year: 2015
• Venue: Nature Communications
• URL: https://www.semanticscholar.org/paper/8ebed48db0a93c9478ce8b71a6160058492eb1f6
• DOI: 10.1038/ncomms9967
• PMID: 26634308
• PMCID: 4686868
• Citations: 180
• Influential citations: 16
• Summary: Evidence is provided that Nav1.7 deletion leads to transcriptional upregulation of opioid peptides in sensory neurons, and that treatment with the opioid blocker naloxone helps reverse analgesia in mice and human Nav.7 nulls.

[12] Uncoupling sodium channel dimers restores the phenotype of a pain‐linked Nav1.7 channel mutation

• Authors: Annika H Rühlmann, Jannis Körner, R. Hausmann, Nikolay Bebrivenski, C. Neuhof et al.
• Year: 2020
• Venue: British Journal of Pharmacology
• URL: https://www.semanticscholar.org/paper/99fcd5eb49be2ed659877ac82adbb1d54286dc7e
• DOI: 10.1111/bph.15196
• PMID: 32663327
• PMCID: 7484505
• Citations: 21
• Influential citations: 2
• Summary: This work investigated how the inactivation particle binds to the channel, how this mechanism is altered by the hNav1.7/A1632E mutation, and how dimerization modifies function of the pain‐linked mutation.

[13] Functional confirmation that the R1488* variant in SCN9A results in complete loss-of-function of Nav1.7

• Authors: Wen He, G. Young, Baohong Zhang, Peter J. Cox, L. T. Cho et al.
• Year: 2018
• Venue: BMC Medical Genetics
• URL: https://www.semanticscholar.org/paper/091bfa419798d09f0ae5642a0f37cbf5deec2d50
• DOI: 10.1186/s12881-018-0643-4
• PMID: 30037327
• PMCID: 6057094
• Citations: 8
• Influential citations: 1
• Summary: Functional characterisations of some of these SCN9A mutations show that they result in complete loss-of-function of Nav1.7, which is consistent with reports on other variants in this gene in subjects with CIP.
• Evidence snippets:
• Snippet 1 (score: 0.616)
  > Functional confirmation that the R1488* variant in SCN9A results in complete loss-of-function of Nav1.7

[14] Loss-of-function mutations in sodium channel Nav1.7 cause anosmia

• Authors: J. Weiss, M. Pyrski, Eric Jacobi, B. Bufe, V. Willnecker et al.
• Year: 2011
• Venue: Nature
• URL: https://www.semanticscholar.org/paper/aa894eb1b536c670be80ac6243848192bd12c6bb
• DOI: 10.1038/nature09975
• PMID: 21441906
• PMCID: 3674497
• Citations: 280
• Influential citations: 20
• Summary: This study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell as well as establishing the essential role of Nav1.7 in odour perception.

[15] Abstract 5904: Targeting NaV1.7 channels in pancreatic cancer: Implications for EF2K and P-Src/P-Fak/integrin β1 signaling pathways

• Authors: M. Erdoğan, Ayse Caner
• Year: 2024
• Venue: Cancer Research
• URL: https://www.semanticscholar.org/paper/955b3c3a2acd4394744974052ba9690f435fd49d
• DOI: 10.1158/1538-7445.am2024-5904
• Summary: NaV1.7 channel isoforms play a significant role in the development, progression, and metastasis of pancreatic cancer and present as a potential therapeutic target in PaCa, according to this pioneering study.

[16] Function and role of voltage-gated sodium channel NaV1.7 expressed in aortic smooth muscle cells.

• Authors: K. Meguro, H. Iida, Haruhito Takano, T. Morita, M. Sata et al.
• Year: 2009
• Venue: American journal of physiology. Heart and circulatory physiology
• URL: https://www.semanticscholar.org/paper/a5185f4d56339f3428b9a54ea9b2a7d32c4ce633
• DOI: 10.1152/ajpheart.00960.2008
• PMID: 18978189
• Citations: 36
• Influential citations: 1
• Summary: It is shown that I(Na) is expressed in cultured and diseased conditions but not in normal aorta, and the Na(V)1.7 plays an important role in cell migration, endocytosis, and secretion.

[17] Network topology of NaV1.7 mutations in sodium channel-related painful disorders

• Authors: D. Kapetis, J. Sassone, Yang Yang, B. Galbardi, M. Xenakis et al.
• Year: 2017
• Venue: BMC Systems Biology
• URL: https://www.semanticscholar.org/paper/67e431bb30ead26c4c703479331c750602a7cf0b
• DOI: 10.1186/s12918-016-0382-0
• PMID: 28235406
• PMCID: 5324268
• Citations: 31
• Summary: The authors' in-silico analyses predict that pain-related pathogenic NaV1.7 mutations may affect the network topological properties of the protein and suggest |ΔBct| value as a potential in- silico marker.
• Evidence snippets:
• Snippet 1 (score: 0.537)
  > SCN9A gene encodes the alpha-subunit of voltage-gated sodium channel NaV1.7 that is expressed in dorsal root ganglion (DRG) nociceptors and in sympathetic neurons. NaV1.7 is folded into four homologous domains, each containing six transmembrane helices (S1-S6). S1-S4 helices form the voltage-sensing domain (VSD) and highly conserved basic residues in S4 sense the electric field across the membrane. S5-S6 helices with the reentrant extracellular loop in between form the pore domain (PD) [1]. Membrane depolarisation induces a conformational change in the VSD that, through the S4-S5 linker, is transmitted to the PD and prompt the gate to open, allowing the passage of sodium ions through the pore [2]. Opening and closing of the channel modulate the subthreshold membrane potential of nociceptors and play a key role in regulating their firing.
  > Missense mutations in SCN9A have been associated to a spectrum of painful conditions in humans [3], including inherited erythromelalgia (IEM), [4][5][6][7][8][9][10][11][12][13], paroxysmal extreme pain disorder (PEPD) [14][15][16][17], and small fibre neuropathy (SFN) [18,19]. Voltage-clamp recording, performed in transfected cell lines and DRG neurons in vitro, showed that IEM-related mutations enhance the activation of NaV1.7 through a hyperpolarising shift and a slower deactivation that keeps the channel open longer once it is activated [3], thus generating a larger-thannormal inward sodium current, with greater biophysical changes at higher temperature [20]. PEPD-related NaV1.7 mutations impair channel inactivation and prolong action potentials and repetitive nociceptor firing in response to provoking stimuli, such as stretching and exposure to cold temperatures [14,16,21].

[18] Analgesia linked to Nav1.7 loss of function requires µ-and δ-opioid receptors [version 1; peer review: 2 approved]

• Authors: V. Pereira, Queensta Millet, J. Aramburu, C. López-Rodríguez, C. Gavériaux-Ruff et al.
• Year: 2022
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/66ab9b96f25aaa128c0bdd991653e018c4e40b74
• Summary: Functional deletion of the Scn9a gene encoding sodium channel Nav1.7 makes humans and mice pain-free and the regulation of proenkephalin expression by the transcription factor Nfat5 that binds upstream of the Penk gene is examined.

[19] Loss‐of‐function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations

• Authors: Y. Goldberg, J. Macfarlane, M. Macdonald, Jay Thompson, M. Dubé et al.
• Year: 2007
• Venue: Clinical Genetics
• URL: https://www.semanticscholar.org/paper/e0ae0f882c88769dd625fdd4a1a6479e2b3b6766
• DOI: 10.1111/j.1399-0004.2007.00790.x
• PMID: 17470132
• Citations: 451
• Influential citations: 15
• Summary: Genetic data further support the evidence that Nav1.7 plays an essential role in mediating pain in humans, and that SCN9A mutations identified in multiple different populations underlie CIP.

[20] Post-transcriptional regulation and protein-protein interactions of the voltage-gated sodium channel Nav1.7

• Authors: J. Koenig
• Year: 2015
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/9079a2ce82785d07a67f83947752d6bc76d2f6f8
• Citations: 1
• Summary: The aim of this thesis was to gain a greater understanding of Nav1.7, a promising analgesic drug target as individuals with loss of function mutations are normal except for a complete inability to perceive pain and having anosmia, and is a potential candidate gene for individuals with chronic pain disorders that map to the SCN9A locus.

[21] Voltage‐dependent Nav1.7 sodium channels: multiple roles in adrenal chromaffin cells and peripheral nervous system

• Authors: A. Wada, E. Wanke, F. Gullo, E. Schiavon
• Year: 2007
• Venue: Acta Physiologica
• URL: https://www.semanticscholar.org/paper/2ec226b9ec674ac45b815fcc8b1738bd86a734d4
• DOI: 10.1111/j.1748-1716.2007.01810.x
• Citations: 29
• Influential citations: 1
• Summary: Various extra‐ and intracellular signals, as well as therapeutic drugs modulate the activity of Nav1.7, which seems to play an increasing number of crucial roles in health, disease and therapeutics.

[22] Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors

• Authors: Vanessa Pereira, Queensta Millet, J. Aramburu, C. López-Rodríguez, C. Gavériaux-Ruff et al.
• Year: 2018
• Venue: Wellcome Open Research
• URL: https://www.semanticscholar.org/paper/154dd8ed313d28ae9c773c7a8262990c40477a80
• DOI: 10.12688/wellcomeopenres.14687.1
• PMID: 30271888
• PMCID: 6134336
• Citations: 27
• Influential citations: 1
• Summary: Higher levels of endogenous enkephalins, potentiated opioid receptors, diminished electrical excitability and loss of neurotransmitter release together contribute to the analgesic phenotype found in Nav1.7-null mouse and human mutants.

[23] Pharmacological characterization of a rat Nav1.7 loss-of-function model with insensitivity to pain.

• Authors: Lubin Chen, Philip R. Effraim, Jennifer Carrara, P. Zhao, Fadia B. Dib-Hajj et al.
• Year: 2020
• Venue: Pain
• URL: https://www.semanticscholar.org/paper/31ddc6cd0c6919172e87af1b0853992879ddf2cf
• DOI: 10.1097/j.pain.0000000000001807
• PMID: 31977939
• Citations: 20
• Summary: It is found that both the opioid receptor antagonist naloxone and cannabinoid receptor blockers SR141716A (rimonabant) and SR144528 fail to restore acute pain sensitivity in Nav1.7 loss-of-function rats, and this data suggest that endogenous opioid and cannabinoid systems are not required for insensitivity to pain in the absence of Nav 1.7 channels.

[24] Paroxysmal extreme pain disorder M1627K mutation in human Nav1.7 renders DRG neurons hyperexcitable

• Authors: S. Dib-Hajj, M. Estacion, Brian W. Jarecki, L. Tyrrell, Tanya Z. Fischer et al.
• Year: 2008
• Venue: Molecular Pain
• URL: https://www.semanticscholar.org/paper/9d8bcb953c00ae3be10211ae6e629d1cea0b504c
• DOI: 10.1186/1744-8069-4-37
• PMID: 18803825
• PMCID: 2556659
• Citations: 133
• Influential citations: 3
• Summary: It is shown that M1627K does not alter development of closed-state inactivation, and that M 1627K channels recover from fast-inactivation faster than wild type channels, and produce larger currents in response to a slow ramp stimulus, and render DRG neurons hyperexcitable.

[25] Voltage-Gated Sodium Channel Nav1.7 Maintains the Membrane Potential and Regulates the Activation and Chemokine-Induced Migration of a Monocyte-Derived Dendritic Cell Subset

• Authors: K. Kis‐Tóth, P. Hajdú, I. Bacskai, Orsolya Szilágyi, F. Papp et al.
• Year: 2011
• Venue: The Journal of Immunology
• URL: https://www.semanticscholar.org/paper/f2291852cfee759fda6d51f1edc52b0ae13e8fde
• DOI: 10.4049/jimmunol.1003345
• PMID: 21715690
• Citations: 55
• Influential citations: 3
• Summary: Fine-tuning of IDC functions by a voltage-gated sodium channel emerges as a new regulatory mechanism modulating the migration and cytokine responses of these DC subsets.

[26] Regulation of Nav1.7: A Conserved SCN9A Natural Antisense Transcript Expressed in Dorsal Root Ganglia

• Authors: J. Koenig, R. Werdehausen, J. Linley, Abdella M. Habib, J. Vernon et al.
• Year: 2015
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/c17104b3928397bbed2b56950964fea8bdce301c
• DOI: 10.1371/journal.pone.0128830
• PMID: 26035178
• PMCID: 4452699
• Citations: 31
• Influential citations: 3
• Summary: The results strongly suggest the SCN9A NAT as a prime candidate for new therapies based upon augmentation of existing antisense RNAs in the treatment of chronic pain conditions in man.

[27] Insensitivity to Pain upon Adult-Onset Deletion of Nav1.7 or Its Blockade with Selective Inhibitors

• Authors: S. Shields, L. Deng, Rebecca M. Reese, M. Dourado, Janet Tao et al.
• Year: 2018
• Venue: The Journal of Neuroscience
• URL: https://www.semanticscholar.org/paper/cd746099682fd84a984b52626039a345762f7e99
• DOI: 10.1523/JNEUROSCI.1049-18.2018
• PMID: 30301756
• Citations: 83
• Influential citations: 11
• Summary: It is demonstrated that selective Nav1.7 inhibitors can approximate the effects of genetic loss of function, which previously has not been directly established, and show robust analgesic and antinociceptive activity acutely after a single dose in mouse pain models shown to be Nav2.7-dependent.

[28] Treatment of Nav1.7‐mediated pain in inherited erythromelalgia using a novel sodium channel blocker

• Authors: Y. P. Goldberg, N. Price, R. Namdari, C. Cohen, M. H. Lamers et al.
• Year: 2012
• Venue: Pain
• URL: https://www.semanticscholar.org/paper/d73c926daaefe80f1c7423cf738973c0ab4f047a
• DOI: 10.1016/j.pain.2011.09.008
• PMID: 22035805
• Citations: 139
• Influential citations: 3
• Summary: This pilot study showed that XEN402 blocks Nav1.7‐mediated pain associated with IEM, thereby demonstrating target engagement in humans and underscoring the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof‐of‐concept for novel analgesics.

[29] Analgesia linked to Nav1.7 loss of function requires μ and δ opioid receptors

• Authors: Vanessa Pereira, Queensta Millet, J. Aramburu, C. López-Rodríguez, Claire Gaveriaux Ruff et al.
• Year: 2018
• Venue: bioRxiv
• URL: https://www.semanticscholar.org/paper/51fcdb097c5e91c03e9ad521d4da78caebc984ef
• DOI: 10.1101/297184
• Citations: 1
• Summary: It is shown that the pharmacological block or deletion of both μ and δ opioid receptors is required to abolish Nav1.7 null opioid-related analgesia and this data confirm that a combination of events linked to SCN9A gene loss is required for analgesia.

[30] Mining the NaV1.7 interactome: Opportunities for chronic pain therapeutics

• Authors: Lindsey A. Chew, S. Bellampalli, E. Dustrude, R. Khanna
• Year: 2019
• Venue: Biochemical pharmacology
• URL: https://www.semanticscholar.org/paper/f80dbd90600cb2a5bf68a8c95937c87677789566
• DOI: 10.1016/j.bcp.2019.01.018
• PMID: 30699328
• PMCID: 6470000
• Citations: 37
• Influential citations: 2
• Summary: This work mines the literature for the known interactome of NaV1.7 with a focus on protein interactors that affect the channel’s trafficking or link it to opioid signaling, and presents antinociceptive evidence of allosteric regulation of NaV1.7 by the cytosolic collapsin response mediator protein 2 (CRMP2).

[31] Nav1.7 and Nav1.8 form supramolecular active clusters with TRKB in mouse and human DRG neurons during development of neuropathic pain

• Authors: L. Sun, H. Xian, Y. Shi, T. Yang, H. Shuai et al.
• Year: 2022
• Venue: medRxiv
• URL: https://www.semanticscholar.org/paper/a3d7ed67d8e3a5d55230fc0f4b933e2e8a173848
• DOI: 10.1101/2022.11.05.22281929
• Summary: These findings suggest that supramolecular active clusters of Nav1.8 and TRKB might need be targeted for curing neuropathic pain, and that inhibition of both Nav 1.7 and Nav.8 might be required to achieve efficient relief of neuropathicPain.

[32] Voltage-Gated Sodium Channel Nav1.7 Maintains the Membrane Potential and Regulates Chemokine-Induced Migration of a Subpopulation of Monocyte-Derived Dendritic Cells

• Authors: P. Hajdú, K. Kis‐Tóth, F. Papp, A. Szántó, E. Posta et al.
• Year: 2011
• Venue: Biophysical Journal
• URL: https://www.semanticscholar.org/paper/f7f0387fe0985d7ffc3bb85fe3c58759a1f65969
• DOI: 10.1016/J.BPJ.2010.12.709
• Summary: The control of IDC function by a voltage-gated sodium channel emerges as a new regulatory mechanism modulating the migration and other responses of these DC subsets.

[33] Nav1.7-P610T mutation in 2 siblings with persistent ocular pain after corneal axon transection: impaired slow-inactivation and hyperexcitable trigeminal neurons.

• Authors: Mohammad-Reza Ghovanloo, Philip R. Effraim, Jun-Hui Yuan, Betsy R. Schulman, D. Jacobs et al.
• Year: 2023
• Venue: Journal of neurophysiology
• URL: https://www.semanticscholar.org/paper/9580c3e5a63259e142d2ff4f0ecec554f6aaeeaa
• DOI: 10.1152/jn.00457.2022
• PMID: 36722722
• Citations: 15
• Summary: The biophysical and electrophysiological profiling of the P610T-Nav1.7 mutation found in two male siblings with persistent ocular pain after refractive surgery indicates that this mutation impairs the slow inactivation of Nav1.

[34] Selective Targeting of Nav1.7 with Engineered Spider Venom-Based Peptides

• Authors: R. Neff, A. Wickenden
• Year: 2021
• Venue: Channels
• URL: https://www.semanticscholar.org/paper/7593bb3a3d9b9b80d058a7644e8fdac32d3a59f7
• DOI: 10.1080/19336950.2020.1860382
• PMID: 33427574
• PMCID: 7808416
• Citations: 10
• Influential citations: 1
• Summary: A summary of research that has focused on engineering peptides found in spider venoms to produce Nav1.7 selective antagonists is presented, discussing the progress that has been made on various scaffolds from different venom families and highlighting the challenges that remain.

[35] Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons

• Authors: M. S. Minett, Mohammed A. Nassar, A. Clark, G. Passmore, A. Dickenson et al.
• Year: 2012
• Venue: Nature Communications
• URL: https://www.semanticscholar.org/paper/c4295be5ab37d3a6f50b993403370dd724ad8332
• DOI: 10.1038/ncomms1795
• PMID: 22531176
• PMCID: 3337979
• Citations: 271
• Influential citations: 21
• Summary: It is shown that Nav1.7 expression in different sets of mouse sensory and sympathetic neurons underlies distinct types of pain sensation, and possible insights into the mechanisms that underlie gain-of-function Nav 1.7-dependent pain conditions are provided.
• Evidence snippets:
• Snippet 1 (score: 0.612)
  > Human acute and inflammatory pain requires the expression of voltage-gated sodium channel Nav1.7 but its significance for neuropathic pain is unknown. Here we show that Nav1.7 expression in different sets of mouse sensory and sympathetic neurons underlies distinct types of pain sensation. Ablating Nav1.7 gene (SCN9A) expression in all sensory neurons using Advillin-Cre abolishes mechanical pain, inflammatory pain and reflex withdrawal responses to heat. In contrast, heat-evoked pain is retained when SCN9A is deleted only in Nav1.8-positive nociceptors. Surprisingly, responses to the hotplate test, as well as neuropathic pain, are unaffected when SCN9A is deleted in all sensory neurons. However, deleting SCN9A in both sensory and sympathetic neurons abolishes these pain sensations and recapitulates the pain-free phenotype seen in humans with SCN9A loss-of-function mutations. These observations demonstrate an important role for Nav1.7 in sympathetic neurons in neuropathic pain, and provide possible insights into the mechanisms that underlie gain-of-function Nav1.7-dependent pain conditions. Sodium channel Nav1.7 is essential for acute human pain but its role in chronic neuropathic pain is unclear. Minett and colleagues show that Nav1.7 expression specifically in sympathetic neurons, rather than sensory neurons, is required for the development of chronic neuropathic pain after injury.

[36] Nav1.7 target modulation and efficacy can be measured in nonhuman primate assays

• Authors: R. Kraus, Fuqiang Zhao, Parul S. Pall, Dan Zhou, Joshua D. Vardigan et al.
• Year: 2021
• Venue: Science Translational Medicine
• URL: https://www.semanticscholar.org/paper/cc0301d2639f8e88e8e01e626c42c64213ba5492
• DOI: 10.1126/scitranslmed.aay1050
• PMID: 34011626
• Citations: 16
• Influential citations: 3
• Summary: It is demonstrated that it is possible to measure Nav1.7 target modulation in rhesus macaques and determine the plasma concentration required to produce a predetermined level of inhibition, and the calculated plasma concentration for preclinical efficacy could be used to guide human efficacious exposure estimates.

[37] Sodium channel protein alpha subunit genomics: building an integrated knowledgebase to translate between family members

• Authors: Jacob Zieba, Amy M. Wilstermann, Angel Hernández, Jeremy W. Prokop
• Year: 2023
• Venue: Physiology
• URL: https://www.semanticscholar.org/paper/45fd400431c4b3f7b80c5f0e89e51ffc681bfc37
• DOI: 10.1152/physiol.2023.38.s1.5735085
• Summary: An exciting and promising new tool for ortholog genomic mapping that can support clinical variant insights into physiological outcomes (genotype-to-phenotype relationship) is shown, which should be applied to other cellular ion channels and transporters.

[38] Rational Drug Design for Pain Medicine: A New Nav1.7 Inhibitor.

• Authors: S. Waxman
• Year: 2020
• Venue: Anesthesiology
• URL: https://www.semanticscholar.org/paper/795216560b786e51bf0a11eb7ce45ebcc7cdbe51
• DOI: 10.1097/ALN.0000000000003447
• PMID: 32788556
• Citations: 1
• Summary: This study used a powerful computer-aided strategy to virtually assess about 1.5 million compounds known to inhibit Nav1.7, and followed with molecular docking and molecular dynamic studies to demonstrate the power of rational drug design in this search.

[39] Navigating a new path to Nav1.7 for pain

• Authors: Katie Kingwell
• Year: 2021
• Venue: Nature Reviews Drug Discovery
• URL: https://www.semanticscholar.org/paper/38bb7bf2e4c4d1d3c59720041c80c3c3925112a9
• DOI: 10.1038/d41573-021-00197-2
• PMID: 34824392
• Citations: 8
• Summary: A small molecule is reported on, indirectly regulating Nav1.7 activity and producing analgesia in animal models of pain, which is part of a nine-member family of closely related Nav channels, many of which have important roles in cardiovascular, respiratory and neuronal function.

[40] Depolarized Inactivation Overcomes Impaired Activation to Produce DRG Neuron Hyperexcitability in a Nav1.7 Mutation in a Patient with Distal Limb Pain

• Authors: Jianying Huang, Yang Yang, S. Dib-Hajj, Michael van Es, P. Zhao et al.
• Year: 2014
• Venue: The Journal of Neuroscience
• URL: https://www.semanticscholar.org/paper/9555348eee17c1c9875d14c80f14658d6a28cf16
• DOI: 10.1523/JNEUROSCI.2773-14.2014
• PMID: 25209274
• Citations: 19
• Summary: Observations indicate that the dominant proexcitatory gating changes associated with this mutation, including depolarized steady-state fast, slow, and closed-state inactivation, faster repriming, and larger ramp currents, override the depolarizing shift of activation, to produce hyperexcitability and spontaneous firing of nociceptive neurons that underlie pain.

[41] The physiological function of different voltage-gated sodium channels in pain

• Authors: G. Goodwin, S. McMahon
• Year: 2021
• Venue: Nature Reviews Neuroscience
• URL: https://www.semanticscholar.org/paper/e046b846350f79d618cd87fe9f6b08a7ab919289
• DOI: 10.1038/s41583-021-00444-w
• PMID: 33782571
• Citations: 145
• Influential citations: 23
• Summary: The contribution of individual channel subtypes in three key physiological processes necessary for transmission of sensory information to the CNS: transduction of stimuli at peripheral nerve terminals, axonal transmission of action potentials and neurotransmitter release from central terminals is reviewed.

[42] Long-lasting Analgesia via Targeted in vivo Epigenetic Repression of Nav1.7

• Authors: Ana M. Moreno, G. F. Catroli, F. Alemán, Andrew Pla, S. Woller et al.
• Year: 2019
• Venue: bioRxiv
• URL: https://www.semanticscholar.org/paper/8a9ed4da69edb72a51df426a6ca14657e056e7da
• DOI: 10.1101/711812
• Citations: 5
• Summary: This work investigates targeted epigenetic repression of NaV1.7 via genome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins as a potential treatment for chronic pain and demonstrates effective repression in lumbar dorsal root ganglia.

[43] NaV1.7 Splice Variant from Human Heart Compared with Neuronal hNaV1.7

• Authors: A. Guia, Huimin Tao, V. Geft, V. Ferraro, Crystal Bantados et al.
• Year: 2012
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/e5463a7cb31835e5e2548f5744cf2a8ea0852aca
• DOI: 10.1016/j.bpj.2011.11.2885
• Summary: Cloned and characterized a NaV1.7 subtype predominantly expressed in the human heart, a novel splice variant, missing one exon, may impact drug safety for this emerging family of analgesics.

[44] An SCN9A channelopathy causes congenital inability to experience pain

• Authors: J. Cox, F. Reimann, A. Nicholas, G. Thornton, E. Roberts et al.
• Year: 2006
• Venue: Nature
• URL: https://www.semanticscholar.org/paper/22790c3f02f934eecd6984f982ed80b6a4d9c42b
• DOI: 10.1038/nature05413
• PMID: 17167479
• Citations: 1582
• Influential citations: 85
• Summary: The data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans, and should stimulate the search for novel analgesics that selectively target this sodium channel subunit.

[45] Human sensory neurons exhibit cell-type-specific, pain-associated differences in intrinsic excitability and expression of SCN9A and SCN10A

• Authors: Jiwon Yi, Lite Yang, A. Widman, Alexa Toliver, Zach Bertels et al.
• Year: 2025
• Venue: bioRxiv
• URL: https://www.semanticscholar.org/paper/e7da59d13ca08303eff387e39add9967333bee83
• DOI: 10.1101/2025.03.25.645367
• PMID: 40196681
• PMCID: 11974934
• Citations: 6
• Summary: This study uses Patch-seq recordings in hDRG to link electrical properties to transcriptionally defined cell types and finds that donor’s pain history is associated with E-type-specific differences in electrical properties, some of which may be associated with higher expression of voltage-gated sodium channels.

[46] SCN9A Epileptic Encephalopathy Mutations Display a Gain-of-function Phenotype and Distinct Sensitivity to Oxcarbazepine

• Authors: Shuzhang Zhang, Zhiping Zhang, Yuan Shen, Yudan Zhu, Kun Du et al.
• Year: 2019
• Venue: Neuroscience Bulletin
• URL: https://www.semanticscholar.org/paper/7d51cc2770bb0a0e3f8edf5ac913fc847ceb2a2c
• DOI: 10.1007/s12264-019-00413-5
• PMID: 31372899
• Citations: 26
• Summary: The results indicated that SCN9A mutants contribute to an increase in seizure, and show distinct sensitivity to OXC, one of the antiepileptic drugs targeting VGSCs.

[47] A sodium channel gene SCN9A polymorphism that increases nociceptor excitability

• Authors: M. Estacion, T. Harty, Jin-Sung Choi, L. Tyrrell, S. Dib-Hajj et al.
• Year: 2009
• Venue: Annals of Neurology
• URL: https://www.semanticscholar.org/paper/cf0174fcb83c9c65b6e736b2c10ee615dc8f8993
• DOI: 10.1002/ana.21895
• PMID: 20033988
• Citations: 103
• Influential citations: 7
• Summary: The results suggest that polymorphisms in the NaV1.7 channel may influence susceptibility to pain and the R1150W allele depolarizes activation and increases the firing frequency in response to depolarization in DRG neurons in which this channel is normally expressed.

[48] Characterisation of Nav1.7 functional expression in rat dorsal root ganglia neurons by using an electrical field stimulation assay

• Authors: A. Fouillet, J. Watson, A. D. Piekarz, Xiaofang Huang, Baolin Li et al.
• Year: 2017
• Venue: Molecular Pain
• URL: https://www.semanticscholar.org/paper/62e034120f5e64f6d04ff4f04b05d240d9088e0e
• DOI: 10.1177/1744806917745179
• PMID: 29166836
• PMCID: 5731621
• Citations: 10
• Summary: The findings presented here point to a selective effect of Protoxin-II in sensory neurons and helped to validate a new method for investigating and comparing Nav1.7 pharmacology in sensory versus central nervous system neurons, which will provide the basis for the development of higher throughput models for enabling pain-relevant phenotypic screening.

[49] Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels

• Authors: M. Baker, Mohammed A. Nassar
• Year: 2020
• Venue: Pflugers Archiv
• URL: https://www.semanticscholar.org/paper/8740391c40ee522e75fecf7f4ff7842faee08d76
• DOI: 10.1007/s00424-020-02419-9
• PMID: 32601768
• PMCID: 7351857
• Citations: 49
• Influential citations: 8
• Summary: The critical roles these channels play in pain along with their low expression in the CNS and heart muscle suggest they are valid targets for novel analgesic drugs.

[50] Sodium channel genes in pain-related disorders: phenotype-genotype associations and recommendations for clinical use.

• Authors: S. Waxman, I. Merkies, M. Gerrits, S. Dib-Hajj, G. Lauria et al.
• Year: 2014
• Venue: The Lancet. Neurology
• URL: https://www.semanticscholar.org/paper/69b6c5ff35590fca02c87742f8450dd4bc81d054
• DOI: 10.1016/S1474-4422(14)70150-4
• PMID: 25316021
• Citations: 164
• Influential citations: 8
• Summary: Human studies have firmly implicated voltage-gated sodium channels in human pain disorders, and targeted and massively parallel genomic sequencing is beginning to be used in clinical practice to determine which sodium channel variants are involved.

[51] Unraveling the Tapestry of Pain: A Comprehensive Review of Ethnic Variations, Cultural Influences, and Physiological Mechanisms in Pain Management and Perception

• Authors: Neelay Shah, Rida-e-Maria Qazi, Xiang-Ping Chu
• Year: 2024
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/ea27415543698cf12fd0fd0a05e31eb66c8e1e6c
• DOI: 10.7759/cureus.60692
• PMID: 38899250
• PMCID: 11186588
• Citations: 9
• Summary: By acknowledging diverse influences on pain experiences, clinicians can provide personalized care, dismantle systemic barriers, and contribute to closing knowledge gaps, impacting individual and public health, well-being, and overall quality of life.
• Evidence snippets:
• Snippet 1 (score: 0.651)
  > Voltage-gated sodium channels, such as Nav1.7,Nav1.8, and Nav1.9, are primarily found in sensory neurons involved in perceiving pain [34].These channels play a significant role in initiating and spreading action potentials, which help transmit pain signals from peripheral tissues to the central nervous system [34].Nav1.7 (SCN9A): Nav1.7, also known as SCN9A, is a voltage-gated sodium channel predominantly found in sensory neurons responsible for the perception of pain [11].This sodium channel is of paramount importance in the field of pain research due to its central role in nociception.Mutations in the SCN9A gene that encodes Nav1.7 have been extensively associated with various pain disorders, emphasizing its critical role in pain perception and management [35].These genetic variations can lead to either a loss of function, resulting in congenital insensitivity to pain, or a gain of function, causing inherited erythromelalgia or paroxysmal extreme pain disorder.Nav1.7 is crucial for initiating and propagating action potentials within sensory neurons, making it a key player in transmitting pain signals from peripheral tissues to the central nervous system [36].Its function is highly specialized, allowing it to sense and transmit pain signals with remarkable precision.The mechanism by which it accomplishes this involves a fast and selective sodium ion conductance, which contributes to the depolarization of the neuron's membrane, ultimately leading to the firing of action potentials.Understanding Nav1.7's functions and genetic associations is not only essential for basic neuroscience research but also holds promise for the development of potential therapeutic approaches to manage pain effectively.Researchers and pharmaceutical companies have been actively exploring drugs that target these sodium channels, including Nav1.7, as potential treatments for various chronic pain conditions [37].The hope is that by modulating the activity of Nav1.7, it may be possible to provide relief to those who suffer from debilitating chronic pain, thereby significantly improving their quality of life [38].

[52] Ectopic expression of Nav1.7 in spinal dorsal horn neurons induced by NGF contributes to neuropathic pain in a mouse spinal cord injury model

• Authors: Yan Fu, Liting Sun, Fengting Zhu, W. Xia, Ting Wen et al.
• Year: 2023
• Venue: Frontiers in Molecular Neuroscience
• URL: https://www.semanticscholar.org/paper/ce9d2360e3158ffbe8439ecc4c9a832b73c4554e
• DOI: 10.3389/fnmol.2023.1091096
• PMID: 36937049
• PMCID: 10020601
• Citations: 12
• Influential citations: 1
• Summary: The findings showed that the upregulation of Nav1.7 was induced by SCI in both SDH and DRG neurons through increased expression of NGF/JUN, and the inhibition of Nav 1.7 in both peripheral and spinal neurons alleviated mechanical pain in SCI mice, suggesting that BBB permeable Nav1-7 blockers might relieve NP in patients with SCI and that blocking the up regulation of Nav2.7-targeted RNA drugs could be a strategy for therapy
• Evidence snippets:
• Snippet 1 (score: 0.625)
  > Moreover, Nav1.8 gainof-function mutations were found in patients with painful smallfiber neuropathy or with lower mechanical pain sensitivity (Faber et al., 2012;Duan et al., 2016;Han et al., 2018).
  > Nav1.7 (SCN9A, also named PN1), another member of VGSCs, was originally found in mice by Beckers et al. (1996) and Kozak and Sangameswaran (1996) and found to be principally expressed in peripheral neurons (Sangameswaran et al., 1997;Toledo-Aral et al., 1997). Lai et al. (2000) reported that knocking down the expression of Nav1.7 using Scn9a antisense in DRG neurons alleviated neuropathic pain. Following this, it was found that gain-of-function mutations of SCN9A caused inherited erythromelalgia, idiopathic small-fiber neuropathies, and spontaneous pain (Cummins et al., 2004;Yang et al., 2004;Faber et al., 2012;Xue et al., 2022). Knockout of Scn9a in DRG neurons of mice attenuated mechanical pain, inflammatory pain, and certain types of heat pain (Nassar et al., 2004;Minett et al., 2012), and the loss of function mutation of SCN9A leads to congenital insensitivity to pain in humans (Cox et al., 2006).
  > Given the strong clinical relevance of Nav1.7 and Nav1.8 in neuropathic pain, second-generation sodium channel blockers selectively targeting Nav1.7 or Nav1.8 have been developed since 2009, but none of them have yet achieved efficient effects in the attenuation of neuropathic pain in clinical trials. We previously found that Nav1.7 and Nav1.8 were upregulated in SDH neurons of peripheral nerve-injured mice and contributed to NP (Sun et al., 2021). It is unknown whether Nav1.7 and Nav1.8 is also ectopically expressed in SDH neurons to participate in NP following SCI.

[53] Mutations in Sodium Channel Gene SCN9A and the Pain Perception Disorders

• Authors: Danica Z. Marković, R. Jankovic, I. Veselinović
• Year: 2015
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/ec0c22a9315564728808a09b247777dd66622989
• DOI: 10.1155/2015/562378
• Citations: 10
• Summary: Further research of the SCN9A gene polymorphism influence on pain sensitivity is essential for the understanding of the pathophysiology of pain and the development of the appropriate targeted pain treatment.
• Evidence snippets:
• Snippet 1 (score: 0.584)
  > Voltage-gated sodium channels (NaV) play a crucial role in development and propagation of action potentials in neurons and muscle cells. NaV1.7 channels take a special place in modern science since it is believed that they contribute to nerve hyperexcitability. Mutations of the gene SCN9A, which codes the α subunit of NaV1.7 channels, are associated with pain perception disorders (primary erythermalgia, congenital analgesia, and paroxysmal pain disorder). It is considered that the SCN9A gene mutations may cause variations in sensitivity to pain, from complete insensitivity to extreme sensitivity. Further research of the SCN9A gene polymorphism influence on pain sensitivity is essential for the understanding of the pathophysiology of pain and the development of the appropriate targeted pain treatment.
• Snippet 2 (score: 0.567)
  > Channels NaV1.7 are also called the voltage-gated sodium channel type IV subunit. They are coded by the SCN9A gene and are highly expressed in sensory neurons of the dorsal roots, trigeminal ganglion, and sympathetic neurons ganglia, mainly in the nociceptors [2]. They are built out of 1977 amino acids (approximately 225 kDa) [6].
  > Immunohistochemical studies have shown that NaV1.7 is also present on the distal neurite ends, close to the impulse trigger zone. These channels show the possibility of depolarization even on minor stimuli and their biophysical function is to conduct stimuli which are below threshold. They are characterized by slow inactivation and slow recovery from inactivation. This allows them to answer to small depolarization stimuli and to amplify generation potentials on nerve endings. Scientists believe that the role of NaV1.7 is to contribute to nerve hyperexcitability [2,[6][7][8].

[54] Novel Mutations Mapping to the Fourth Sodium Channel Domain of Nav1.7 Result in Variable Clinical Manifestations of Primary Erythromelalgia

• Authors: R. Cregg, B. Laguda, R. Werdehausen, J. Cox, J. Linley et al.
• Year: 2013
• Venue: Neuromolecular Medicine
• URL: https://www.semanticscholar.org/paper/532f369cd21ebc07f75ee43ef00113f9327b7762
• DOI: 10.1007/s12017-012-8216-8
• PMID: 23292638
• PMCID: 3650253
• Citations: 62
• Influential citations: 3
• Summary: It is demonstrated that mutations encoding for DIV of Nav1.7 can not only be linked to congenital insensitivity to pain or paroxysmal extreme pain disorder but can also be causative of PEM, if voltage dependency of channel activation is affected.
• Evidence snippets:
• Snippet 1 (score: 0.578)
  > Recent studies have confirmed a pivotal role for the Nav1.7 voltage-gated sodium channel in human familial gainof-function (Yang et al. 2004;Fertleman et al. 2006) and loss-of-function pain syndromes (Cox et al. 2006). Nav1.7, encoded by SCN9A, is preferentially expressed in nociceptive dorsal root ganglia (DRG) and sympathetic ganglia (Sangameswaran et al. 1997;Toledo-Aral et al. 1997) and is thought to serve a threshold triggering function, enabling depolarizing stimuli to elicit action potential propagation (Cummins et al. 1998;Rush et al. 2007). By identifying patients with novel mutations in SCN9A and analyzing the biophysical properties of the mutant Nav1.7 channels, we aim to provide insights into how this important channel functions and contributes to neuronal action potential firing, potentially suggesting ways in which its function could be normalized in affected individuals.
  > Recessive loss-of-function mutations in SCN9A result in congenital insensitivity to pain (CIP), whereas gainof-function, dominant mutations lead to sensory neuronal hyperexcitability and the development of painful phenotypes described as inherited or primary erythromelalgia (PEM or IEM) (Yang et al. 2004;Dib-Hajj et al. 2005) and paroxysmal extreme pain disorder (PEPD) (Fertleman et al. 2006;Choi et al. 2011). PEM is classically described as a peripheral, bilateral disorder associated with erythema and severe burning pain of affected extremities that is triggered by stress, exhaustion and warmth and often relieved by cooling of the affected sites (Segerdahl et al. 2012). Clinical onset has been reported previously as within 1 year after birth in some cases, while in the majority of cases, symptoms of PEM develop within the first decade of life (Fischer and Waxman 2010).

[55] Novel Mutations Mapping to the Fourth Sodium Channel Domain of Nav1.7 Result in Variable Clinical Manifestations of Primary Erythromelalgia

• Authors: R. Cregg, B. Laguda, R. Werdehausen, J. Cox, J. Linley et al.
• Year: 2013
• Venue: NeuroMolecular Medicine
• URL: https://www.semanticscholar.org/paper/5c4126ab76eaea90fb5a812174236881212f2db9
• DOI: 10.1007/s12017-012-8216-8
• Citations: 1
• Summary: It is demonstrated that mutations encoding for DIV of Nav1.7 can not only be linked to congenital insensitivity to pain or paroxysmal extreme pain disorder but can also be causative of PEM, if voltage dependency of channel activation is affected.
• Evidence snippets:
• Snippet 1 (score: 0.578)
  > Recent studies have confirmed a pivotal role for the Nav1.7 voltage-gated sodium channel in human familial gainof-function (Yang et al. 2004;Fertleman et al. 2006) and loss-of-function pain syndromes (Cox et al. 2006). Nav1.7, encoded by SCN9A, is preferentially expressed in nociceptive dorsal root ganglia (DRG) and sympathetic ganglia (Sangameswaran et al. 1997;Toledo-Aral et al. 1997) and is thought to serve a threshold triggering function, enabling depolarizing stimuli to elicit action potential propagation (Cummins et al. 1998;Rush et al. 2007). By identifying patients with novel mutations in SCN9A and analyzing the biophysical properties of the mutant Nav1.7 channels, we aim to provide insights into how this important channel functions and contributes to neuronal action potential firing, potentially suggesting ways in which its function could be normalized in affected individuals.
  > Recessive loss-of-function mutations in SCN9A result in congenital insensitivity to pain (CIP), whereas gainof-function, dominant mutations lead to sensory neuronal hyperexcitability and the development of painful phenotypes described as inherited or primary erythromelalgia (PEM or IEM) (Yang et al. 2004;Dib-Hajj et al. 2005) and paroxysmal extreme pain disorder (PEPD) (Fertleman et al. 2006;Choi et al. 2011). PEM is classically described as a peripheral, bilateral disorder associated with erythema and severe burning pain of affected extremities that is triggered by stress, exhaustion and warmth and often relieved by cooling of the affected sites (Segerdahl et al. 2012). Clinical onset has been reported previously as within 1 year after birth in some cases, while in the majority of cases, symptoms of PEM develop within the first decade of life (Fischer and Waxman 2010).

[56] Matrix Metalloproteinase (MMP) Proteolysis of the Extracellular Loop of Voltage-gated Sodium Channels and Potential Alterations in Pain Signaling*

• Authors: A. Remacle, Sonu Kumar, K. Motamedchaboki, P. Cieplak, Swathi K. Hullugundi et al.
• Year: 2015
• Venue: The Journal of Biological Chemistry
• URL: https://www.semanticscholar.org/paper/7dacb95f8fcb16c39e74455c6b08375868e827ec
• DOI: 10.1074/jbc.C115.671107
• PMID: 26283785
• Citations: 15
• Influential citations: 1
• Summary: It is likely that the aberrantly accelerated MMP-9 proteolysis during neurogenesis is a biochemical rational for the functional inactivation in Nav1.7 and that the enhanced cleavage of the Nav 1.7-R907Q mutant is a cause of CIP in the Bedouin family.
• Evidence snippets:
• Snippet 1 (score: 0.572)
  > In human genome, the SCN9A gene codes for the ␣-subunit of the voltage-gated Nav1.7 sodium channel, the main pain signaling channel that is expressed in peripheral pain-sensing neurons (10). A number of gain-of-function mutations in SCN9A result in severe episodic neuropathic pain and the three distinct disorders known in humans such as paroxysmal extreme pain disorder, inherited/primary erythromelalgia, and small-fiber neurop-athy (reviewed in Ref. 7). In turn, multiple recently identified biallelic loss-of-function truncating mutations in SCN9A lead to either the dysfunctional Nav1.7 protein or, probably, to no protein being produced, and, consequently, to a disorder named autosomal recessive CIP (1,3,11,12,30). CIP patients are incapable of perceiving any form of pain, in any part of the body, but other modalities are normal. It is not entirely surprising that some of affected individuals make a living as street performers (5).
  > A non-truncating Nav1.7-R896Q mutation, however, has been found in a consanguineous Israeli Bedouin family (6). So far, this is the only missense mutation in Nav1.7 that causes CIP. This missense mutation was mapped to the exposed extracellular unstructured region (the pore region) linking the S5-S6 transmembrane segments in the DII domain of the human Nav1.7. The Nav1.7 channels exist in multiple, if not all, verte-FIGURE 2. Mass spectrometry analysis of MMP-9 proteolysis of the Nav1.7 peptides. A, MALDI monoisotopic MS spectra of the peptides. The wild-type TLPRWHMNDF (1316.48 Da), mutant TLPQWHMNDF (the CIP R907Q mutation is underlined; 1288.43

[57] Congenital Insensitivity to Pain: Novel SCN9A Missense and In-Frame Deletion Mutations

• Authors: J. J. Cox, Jony Sheynin, Z. Shorer, F. Reimann, A. Nicholas et al.
• Year: 2010
• Venue: Human Mutation
• URL: https://www.semanticscholar.org/paper/bb8cad2216b64a1a13ab4e11881330e8b543d4f5
• DOI: 10.1002/humu.21325
• PMID: 20635406
• PMCID: 2966863
• Citations: 127
• Influential citations: 5
• Summary: This study has identified critical amino acids needed for the normal subcellular localization and function of Nav1.7 sodium channel, a protein highly expressed in pain‐sensing neurons, and describes the identification and functional characterization of two novel non‐truncating mutations in families with CIP.
• Evidence snippets:
• Snippet 1 (score: 0.571)
  > SCN9Aencodes the voltage‐gated sodium channel Nav1.7, a protein highly expressed in pain‐sensing neurons. Mutations in SCN9A cause three human pain disorders: bi‐allelic loss of function mutations result in Channelopathy‐associated Insensitivity to Pain (CIP), whereas activating mutations cause severe episodic pain in Paroxysmal Extreme Pain Disorder (PEPD) and Primary Erythermalgia (PE). To date, all mutations in SCN9A that cause a complete inability to experience pain are protein truncating and presumably lead to no protein being produced. Here, we describe the identification and functional characterization of two novel non‐truncating mutations in families with CIP: a homozygously‐inherited missense mutation found in a consanguineous Israeli Bedouin family (Nav1.7‐R896Q) and a five amino acid in‐frame deletion found in a sporadic compound heterozygote (Nav1.7‐ΔR1370‐L1374). Both of these mutations map to the pore region of the Nav1.7 sodium channel. Using transient transfection of PC12 cells we found a significant reduction in membrane localization of the mutant protein compared to the wild type. Furthermore, voltage clamp experiments of mutant‐transfected HEK293 cells show a complete loss of function of the sodium channel, consistent with the absence of pain phenotype. In summary, this study has identified critical amino acids needed for the normal subcellular localization and function of Nav1.7. © 2010 Wiley‐Liss, Inc.

[58] Case Report: Mutant SCN9A Susceptible to Charcot Neuroarthropathy in a Patient With Congenital Insensitivity to Pain

• Authors: Xiaohui Xie, Jian-guang Tang, Zhonghua Liu, Shuijiao Peng, Zhuang-zhuang Yuan et al.
• Year: 2021
• Venue: Frontiers in Neuroscience
• URL: https://www.semanticscholar.org/paper/8ee37d0088b955f30a390064c9d87d77de6fc87f
• DOI: 10.3389/fnins.2021.697167
• PMID: 34335171
• PMCID: 8317969
• Summary: A patient with CIP from a consanguineous family susceptible to Charcot neuroarthropathy with a novel SCN9A mutation is reported, which is conducive to understanding the critical amino acids for maintaining the function of Nav1.7.
• Evidence snippets:
• Snippet 1 (score: 0.569)
  > Conversely, loss-of-function mutations in SCN9A contribute to CIP (Klein et al., 2013). To date, more than 100 mutations in SCN9A have been reported, but only 42 have been associated with CIP (Baker and Nassar, 2020; Supplementary Table 1 and Figure 2A). Among the SCN9A mutations identified in CIP patients, most were non-sense, frameshift, or splicing mutations, all of which produced non-functional and truncated Nav1.7 proteins; however, we identified a novel homozygous missense mutation (c.4015T > C, p. Cys1339Arg) in SCN9A in a patient with CIP, which abolished the current density and the Nav1.7 function. The variant site was localized in exon 21 of SCN9A, and the protein change was located in the extracellular linker joining S5 and S6 of domain III, which has not been reported previously (Figure 2). S5-P, P loop, and P-S6 are vital for the selective permeation of sodium ions (Catterall, 2017). Residue Cys1339 mapped to the S5-P, domain III of Nav1.7, is highly conserved among different species (Figure 1I) and plays a role in filtering sodium ions.
  > Loss-of-function mutations in the VGSC Nav1.7 cause CIP in human, making Nav1.7 an important target for novel analgesics. For humans, in most patients with CIP, the perception of nonnoxious touch and warmth is not affected, whereas the perception of noxious heat, pressure, and injury pain is completely lost. Therefore, loss of Nav1.7 did not lead to lethality or any disability (Zufall et al., 2012). Selective Nav1.7 channel blockers, as potential painkillers with improved safety and reduced unwanted side effects, will be increasingly favored by doctors and patients.

[59] Novel SCN9A missense mutations contribute to congenital insensitivity to pain: Unexpected correlation between electrophysiological characterization and clinical phenotype

• Authors: Jiaoli Sun, Lulu Li, Luyao Yang, Guangyou Duan, Tingbin Ma et al.
• Year: 2020
• Venue: Molecular Pain
• URL: https://www.semanticscholar.org/paper/e8e352d50a9814a771c5713a7d609a6396ef1271
• DOI: 10.1177/1744806920923881
• PMID: 32420800
• PMCID: 7235659
• Citations: 19
• Influential citations: 2
• Summary: It is revealed that mutations in Nav1.7 in this congenital insensitivity to pain patient still retained partial channel function, but the patient showed completely painlessness, the unexpected genotypic-phenotypic relationship of SCN9A mutations in the authors' patient may challenge the previous findings “Nav 1.7 total loss-of-function leads to painlessness.”
• Evidence snippets:
• Snippet 1 (score: 0.569)
  > Congenital insensitivity to pain (OMIM 243000) is an extremely rare disorder caused by loss-of-function mutations in SCN9A encoding Nav1.7. Although the SCN9A mutations and phenotypes of painlessness and anosmia/hyposmia in patients are previously well documented, the complex relationship between genotype and phenotype of congenital insensitivity to pain remains unclear. Here, we report a congenital insensitivity to pain patient with novel SCN9A mutations. Functional significance of novel SCN9A mutations was assessed in HEK293 cells expressing Nav1.7, the results showed that p.Arg99His significantly decreased current density and reduced total Nav1.7 protein levels, whereas p.Trp917Gly almost abolished Nav1.7 sodium current without affecting its protein expression. These revealed that mutations in Nav1.7 in this congenital insensitivity to pain patient still retained partial channel function, but the patient showed completely painlessness, the unexpected genotypic-phenotypic relationship of SCN9A mutations in our patient may challenge the previous findings “Nav1.7 total loss-of-function leads to painlessness.” Additionally, these findings are helpful for understanding the critical amino acid for maintaining function of Nav1.7, thus contributing to the development of Nav1.7-targeted analgesics.

[60] Primary erythromelalgia: a review

• Authors: Zhaoli Tang, Zhao Chen, B. Tang, Hong Jiang
• Year: 2015
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/d75bcc302b60d400a834b514234a82d1a64ffe14
• DOI: 10.1186/s13023-015-0347-1
• PMID: 26419464
• PMCID: 4589109
• Citations: 94
• Influential citations: 5
• Summary: A genotype-channelopathy-phenotype correlation network underlying PE etiology is proposed which could provide guidance for future therapeutics and may help in the development of new drugs for PE.
• Evidence snippets:
• Snippet 1 (score: 0.561)
  > Since the identification of SCN9A, more than 20 PE mutations have been reported. Researches into PE have shed light upon the pivotal role of voltage-gated sodium channels in sensory neurons' physical properties and have elucidated the underlying pathogenic mechanisms caused by SCN9A-linked Nav1.7 mutations. Electrophysiology studies of mutant Nav1.7 channels have presented us a complex yet intriguing network of genotype-channelopathy-phenotype correlation, through looking into which more aspects of the nociception pathways can be clarified. Studies on CIP caused by lossof-function mutations in Nav1.7 and Nav1.7 knock-out mice models suggest that Nav1.7 is an ideal target for novel pain-relieving drugs. Furthermore, several novel Nav1.7-selectvie agents have showed satisfactory clinical efficacy. In order to delineate an overall picture of this rare and intricate pain disorder, several questions remain to be answered such as whether molecular modulators or non-coding regions of SCN9A also contribute to the mechanisms of PE? What explains for the disproportionate relationship between the level of channelopathies and phenotypes? Whether Nav1.7-specific blockers have therapeutic value in all gain-of-function SCN9A mutations? What remains elusive may be the keystone to bridge the gap between basic researches to clinical treatments for PE.
• Snippet 2 (score: 0.527)
  > Researchers have observed an interesting dual manifestation of PE, the divergent functional effects of SCN9A mutations on sensory neurons and sympathetic neurons. Mutant Nav1.7 channels render DRG neurons hyperexcitable but increase action potential threshold in sympathetic neurons [78]. Disparate to Nav1.7, Nav1.8 channels have a more depolarized voltage dependence of activation (−16 to -21 mV) and primarily underlie the action potential upstrokes [64]. Studies have shown that Nav1.7 channels are expressed at a high level in both sensory neurons and sympathetic neurons [79], while Nav1.8 channels are mostly expressed in sensory neurons [68]. Additionally, when co-expressed with L858H mutant channel in supra cervical ganglion (SCG) neurons, Nav1.8 tend to protect against the hyperexcitability caused by Nav1.7 mutant channels [68]. Thus, different cell backgrounds, in this case the expression levels of Nav1.8, might have impacts that correlate with direct effects of Nav1.7 mutations on neuron cells.

[61] Possible Anti-Pain Vaccines: A Narrative Review of Emerging Strategies and Clinical Prospects

• Authors: Y. Martins, Luciana Pereira de-Sousa, Peyton J. Murin, Hamed Sadeghipour, C. Daniel-Ribeiro
• Year: 2025
• Venue: Vaccines
• URL: https://www.semanticscholar.org/paper/f078eaca7fd4a5fccc19f79c62738aff54c517e1
• DOI: 10.3390/vaccines13090909
• PMID: 41012116
• PMCID: 12474396
• Summary: Current knowledge on therapeutic vaccines for pain is summarized, the immunological and technological advances in the field are discussed, and future directions are outlined.
• Evidence snippets:
• Snippet 1 (score: 0.558)
  > Voltage-Gated sodium channels (Nav) are involved in the generation and propagation of electrochemical impulses along nociceptors [52]. Nine Nav subtypes have been described, with Nav1.7, Nav1.8, and Nav1.9 being almost exclusively found in peripheral neurons. Nav1.7 is encoded by SCN9A. It is often called the "pain channel" because human genetic studies have shown it to be absolutely crucial for pain signaling, as loss-of-function mutations in SCN9A cause congenital insensitivity to pain, whereas gain-of-function mutations cause extreme pain disorders [53]. Nav1.7 is localized at nociceptor nerve endings and axons, where it amplifies depolarizations to initiate action potentials. Accordingly, Nav1.7 emerged as a key target for analgesic drug development, with the ultimate goal of creating a therapy that replicates congenital insensitivity to pain without causing additional side effects. Despite intense efforts over 15+ years, no selective small-molecule Nav1.7 blocker has yet succeeded clinically [54]. Many compounds showed good in vitro block but minimal analgesia in humans, potentially due to compensatory mechanisms or insufficient in vivo blockade. An immunotherapeutic approach to Nav1.7 could involve raising antibodies that bind the channel and inhibit its function. This concept is supported by precedent, as biological toxins such as tetrodotoxin (TTX) and certain peptide toxins are known to bind Nav channels with high affinity and specificity [55]. Researchers have also developed monoclonal antibodies and even single-domain antibodies (nanobodies) that target Nav1.7's voltage-sensor domains and can allosterically inhibit channel opening [50,56]. One such monoclonal antibody was reported to effectively reduce pain in rodent models by selective Nav1.7 blockade, though translating this to humans is complicated by the need for the antibody to access neuronal membranes and by potential off-target binding to other Nav channels [57].

[62] Pain triangle phenomenon in possible association with SCN9A: A case report

• Authors: M. Sopacua, J. Hoeijmakers, A. J. van der Kooi, I. Merkies, C. Faber
• Year: 2022
• Venue: Molecular Genetics & Genomic Medicine
• URL: https://www.semanticscholar.org/paper/5c8ba493ef54515a856f651ab3cba1aaff10b6c2
• DOI: 10.1002/mgg3.2026
• PMID: 36114697
• PMCID: 9544215
• Citations: 2
• Influential citations: 1
• Summary: Sodium channel Nav1.7, encoded by the SCN9A‐gene, has been of special interest in the last decades because missense gain‐of‐function mutations have been linked to a spectrum of neuropathic pain conditions, including inherited erythermalgia, paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy (SFN).
• Evidence snippets:
• Snippet 1 (score: 0.550)
  > Voltage‐gated sodium channels are essential for the generation and conduction of electrical impulses in excitable cells. Sodium channel Nav1.7, encoded by the SCN9A‐gene, has been of special interest in the last decades because missense gain‐of‐function mutations have been linked to a spectrum of neuropathic pain conditions, including inherited erythermalgia (IEM), paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy (SFN).

[63] Analgesia effect of lentivirus-siSCN9A infected neurons in vincristine induced neuropathic pain rats

• Authors: Baojun Fu, Rong Zhu
• Year: 2021
• Venue: Bioengineered
• URL: https://www.semanticscholar.org/paper/ef097b8a3870fdc2e129147abcc649a005e91291
• DOI: 10.1080/21655979.2021.2008696
• PMID: 34927536
• PMCID: 8810170
• Citations: 1
• Summary: It was concluded that the LV-siSCN9A infected neurons could play an analgesic role by down-regulating Nav1.7 expression induced by VCR in NP model.
• Evidence snippets:
• Snippet 1 (score: 0.545)
  > Nva1.6, and Nav1.7) [40]. Among them, the Nav1.7 channel may play a major role in the generation of ectopic discharge [41]. SCN9A was located on chromosome 2. The voltage-gated sodium channel Nav1.7, which encoded tetrodotoxin-sensitive, was overexpressed in sympathetic ganglia and peripheral neurons. SCN9A gene variation could cause painrelated diseases [42,43]. Recently, more and more evidence has shown that mutations in the SCN9A gene are closely related to abnormal pain. Among them, paroxysmal severe pain and primary erythematous limb pain are all due to misintentional mutations in certain positions of the human SCN9A gene sequence encoding Nav1.7 protein [44,45]. DRG neuron Nav1.7 has a high expression in the inflammatory pain model of rats 46), and the SCN9A gene mutation rat of DRG neuron has significantly reduced responsiveness to inflammatory pain [4748]. The cell types Nav1.7 expressed on DRG neurons were further observed by immunofluorescence double standard method. The mRNA and protein expression levels of Nav1.7 in each group was detected by Western-blot method and quantitative PCR, and the expression of CGRP in the dorsal horn of rat spinal cord was detected by immunofluorescence. It was found that compared with the control group, the Nav1.7 mRNA and protein expression level of rats in the model group was significantly increased (P < 0.05). Compared with LV-SC group, the Nav1.7 mRNA and protein expression level of LV-siSCN9A group was significantly decreased [P < 0.05), and the CGRP expression of spinal dorsal horn was significantly decreased. It indicated that the high expression of Nav1. expression of NLRP3, ASIC3 and CaMK2α in the spinal cord of rats with pathological pain, so as to achieve the effect of reducing NP in rats. The experiment was in line with expectations.

Notes

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The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: Human SCN9A / NaV1.7 (UniProt Q15858) — Functional Annotation, Mechanisms, and Translational Status

0) Identity verification (critical)

The target protein is the human voltage‑gated sodium channel NaV1.7 α‑subunit, encoded by SCN9A, and is explicitly linked to UniProt accession Q15858 in a biochemical study analyzing the full-length channel (“full‑length NaV1.7 (SCN9A, Uniprot Q15858)”). (wright2023thecterminalof pages 2-3)

1) Key concepts and current understanding

1.1 Core molecular function (what the gene product does)

NaV1.7 is a voltage-gated sodium (Na+) channel that supports membrane excitability by permitting selective Na+ flux during action potentials; in nociceptors it is strongly implicated in determining excitability near threshold and thereby controlling pain signaling. (toffano2020computationalpipelineto pages 1-2, meents2019theroleof pages 1-2)

Selectivity/substrate specificity: NaV1.7 is selective for Na+ and shares the canonical NaV architecture and DEKA selectivity filter (Asp-Glu-Lys-Ala across DI–DIV) described for eukaryotic NaV α subunits. (toffano2020computationalpipelineto pages 1-2)

1.2 Structural definitions (domain architecture)

The NaV α-subunit is a single ~2,000 amino‑acid polypeptide organized into four homologous domains (DI–DIV); each domain contains six transmembrane helices (S1–S6). S1–S4 form the voltage-sensing domain (VSD) and S5–S6 plus the extracellular P-loop form the pore domain and selectivity filter. (toffano2020computationalpipelineto pages 1-2, wood2025sensoryneuronsodium pages 1-2)

1.3 Cellular and tissue localization (where it acts)

NaV1.7 is a plasma-membrane channel enriched in nociceptive neurons, with high expression reported in dorsal root ganglia (DRG), trigeminal ganglia, and sympathetic ganglia—an expression pattern central to its role in pain pathways. (dormer2023areviewof pages 8-9)

1.4 Human genetic validation (why SCN9A is a flagship pain target)

SCN9A is among the strongest “human-validated” targets in pain biology:
- Gain-of-function (GOF) variants cause painful channelopathies (e.g., inherited erythromelalgia, paroxysmal extreme pain disorder, and subsets of small fiber neuropathy). (baker2020painfulandpainless pages 1-2, meents2019theroleof pages 1-2)
- Loss-of-function (LOF) variants cause congenital insensitivity to pain. (baker2020painfulandpainless pages 1-2, meents2019theroleof pages 1-2)

These genotype–phenotype links provide unusually direct causal evidence connecting a single ion channel to a clinically meaningful sensory modality. (baker2020painfulandpainless pages 1-2, meents2019theroleof pages 1-2)

2) Recent developments (prioritizing 2023–2024)

2.1 2023: Cryo‑EM “structural pharmacology” map of human NaV1.7 drug binding sites

A major 2023 advance was the publication of high-resolution cryo‑EM structures of human NaV1.7 bound to multiple clinically used drugs and investigational compounds (2.6–3.2 Å). This work mapped multiple druggable binding sites including:
- a site beneath the intracellular gate (“site BIG”) accommodating carbamazepine, bupivacaine, and lacosamide,
- binding in pore fenestrations (e.g., vixotrigine in the IV–I fenestration; vinpocetine and hardwickiic acid at the III–IV fenestration),
- an unexpected second lacosamide molecule plugging into the selectivity filter from the central cavity. (wu2023structuralmappingof pages 1-2)

A figure from this study provides a consolidated schematic of the mapped druggable sites and is useful for functional annotation because it links channel anatomy directly to chemical mechanisms of inhibition/modulation. (wu2023structuralmappingof media a264241d)

2.2 2023: Accessory protein requirement for toxin-mediated NaV1.7 modulation (TMEM233/dispanins)

A 2023 Nature Communications study demonstrated that voltage-gated sodium channels can behave as multiprotein signaling complexes, and identified TMEM233 (a dispanin-family protein) as an essential NaV1.7-interacting accessory protein for the action of the plant-derived knottin toxin Excelsatoxin A (ExTxA). ExTxA inhibits fast inactivation and induces persistent currents in sensory neurons; in human iPSC-derived sensory neurons this persistent current was largely blocked by a selective NaV1.7 blocker (Pn3a 100 nM), implicating NaV1.7 as a major mediator. (jami2023paincausingstingingnettle pages 1-2)

This establishes a contemporary concept: native accessory proteins can be required to reproduce pharmacology observed in sensory neurons, which may help explain discrepancies between heterologous assays and clinical outcomes. (jami2023paincausingstingingnettle pages 1-2)

2.3 2023: Biochemical regulation by ubiquitination (NEDD4L → NaV1.7)

A 2023 ACS Bio & Med Chem Au study provided direct biochemical evidence that the E3 ligase NEDD4L ubiquitinates the cytoplasmic C‑terminus of NaV1.7. The work also documents motifs in the C‑terminus relevant to regulation (including an IQ motif and a NEDD4L-recognized PY motif) and identifies ubiquitinated lysines by mass spectrometry. (wright2023thecterminalof pages 1-2, wright2023thecterminalof pages 2-3)

This supports a functional annotation element often missing from older descriptions: post-translational modification and trafficking/turnover regulation are likely important determinants of NaV1.7 surface density and nociceptor excitability. (wright2023thecterminalof pages 1-2, wright2023thecterminalof pages 2-3)

2.4 2023: Mechanistic structural basis for pain-causing voltage-sensor mutations

A 2023 Journal of General Physiology study used a tractable bacterial NaV homolog (NaVAb) carrying human-analogous inherited erythromelalgia mutations to provide structural explanations for negative shifts in activation (gain-of-function): widening of the gating-charge translocation pathway or altered hydrophobic/phospholipid interactions favoring outward S4 movement. (wisedchaisri2023structuralbasisfor pages 1-2)

2.5 2024: Structure–function dissection of NaV gating states using engineered NaV1.7 mutants

A 2024 PNAS study solved cryo‑EM structures (2.9–3.4 Å) of engineered human NaV1.7 mutants and linked pore-domain contraction to right-shifted activation/static inactivation, refining how structural states map onto electrophysiological behavior. (li2024dissectionofthe pages 1-2)

2.6 2024: New therapeutic modalities—biologics and gene regulation

Two notable 2024 directions go beyond classic small-molecule pore blockers:
- Single-domain antibody (VHH) against human NaV1.7: an Aug 2024 study reported a VHH that binds NaV1.7, slows deactivation, reduces nociceptor action potential firing, and reverses hyperalgesia in rodent models. (martina2024anovelantigen pages 1-2)
- AAV-delivered engineered transcriptional repressors: a Sep 2024 preprint reported zinc-finger repressors achieving ~90% SCN9A repression in human iPSC-derived neurons, up to 70% repression in mouse DRG, and up to 60% repression in nonhuman primate DRG after intrathecal delivery, with short-term tolerability in NHP. (samie2024potentandselective pages 1-3)

Together these illustrate a shift from “block the pore” to modulate gating with biologics or reduce SCN9A expression as potentially more durable analgesic strategies. (martina2024anovelantigen pages 1-2, samie2024potentandselective pages 1-3)

3) Current applications and real-world implementations

3.1 Clinical trials: NaV1.7-targeting small molecules and genotype-guided studies

Real-world implementation is best captured by registered clinical trial protocols:

PF‑05089771 (Pfizer) in painful diabetic peripheral neuropathy (DPN):
- NCT02215252 (Phase 2; randomized, double-blind, parallel; COMPLETED) tested PF‑05089771 150 mg BID as monotherapy and as add-on to pregabalin 150 mg BID (300 mg/day).
- Enrollment: 141 participants.
- Primary endpoint: daily pain numeric rating scale (mean of last 7 days).
- Key secondary endpoints: responder rates (30%/50%), Neuropathic Pain Symptom Inventory, PGIC, sleep interference, rescue medication use. (NCT02215252 chunk 1, NCT02215252 chunk 2)

Genotype-guided NaV1.7 strategy in small fiber neuropathy (SFN):
- NCT01911975 (Phase 3; randomized; quadruple-masked; crossover; COMPLETED) evaluated lacosamide 200 mg BID vs placebo in patients with gain-of-function SCN9A mutations and SFN.
- Enrollment: 25.
- Primary endpoint: mean daily pain intensity recorded twice daily over 33 weeks. (NCT01911975 chunk 1)

Inherited erythromelalgia (IEM) precision trial:
- NCT07262268 (Phase 1b; randomized crossover; quadruple-masked; start 2026) enrolls IEM participants with characterized NaV1.7 gain-of-function SCN9A mutations; enrollment 5; primary outcome uses frequent pain scoring. (NCT07262268 chunk 1)

These protocols show how SCN9A biology is operationalized clinically: either by targeting NaV1.7 pharmacologically (often with mixed efficacy historically) or by selecting subjects with SCN9A GOF variants to increase mechanistic alignment and effect size potential. (dormer2023areviewof pages 4-5, NCT02215252 chunk 1)

3.2 Observational genetics in perioperative care

SCN9A variation is also implemented in prospective genotype–phenotype studies:
- NCT02496455: postoperative pain after cesarean section (n=200) with SCN9A SNP genotyping and outcomes including 24-hour VAS pain and tramadol consumption. (NCT02496455 chunk 1)

4) Expert opinions and authoritative analysis (why translation has been difficult)

A 2024 Pain review analyzing the mismatch between preclinical and clinical testing concludes that despite strong genetic support for NaV1.7, NaV1.7-selective inhibitors have not yet proven effective in clinical trials, and highlights key design mismatches: species/population differences, inflammatory pain models vs neuropathic pain trials, evoked pain endpoints vs average pain intensity, and single-dose preclinical studies vs repeat dosing clinically. ()

A 2023 review focusing on SCN9A/Nav1.7 clinical trials similarly concludes that small-molecule programs have often been inconclusive, motivating exploration of alternative approaches (including gene therapy-like strategies). (dormer2023areviewof pages 8-9, dormer2023areviewof pages 4-5)

5) Relevant statistics and quantitative data (selected)

• Structural resolution: human NaV1.7 drug-bound cryo‑EM structures at 2.6–3.2 Å (2023). (wu2023structuralmappingof pages 1-2)
• Engineered NaV1.7 mutant structures: 2.9–3.4 Å (2024). (li2024dissectionofthe pages 1-2)
• Accessory-protein-dependent pharmacology: ExTxA persistent current in human sensory neurons largely blocked by Pn3a 100 nM (2023). (jami2023paincausingstingingnettle pages 1-2)
• Small fiber neuropathy epidemiology (from clinical review): incidence 12/100,000 and prevalence 53/100,000; approximately 30% of idiopathic SFN attributed to SCN9A variants (review synthesis). (dormer2023areviewof pages 4-5)
• Clinical trial sizes/dosing:
• NCT02215252 (PF‑05089771 DPN): n=141, PF‑05089771 150 mg BID, pregabalin 150 mg BID add-on. (NCT02215252 chunk 1)
• NCT01911975 (lacosamide in SCN9A-GOF SFN): n=25, lacosamide 200 mg BID, 33-week monitoring. (NCT01911975 chunk 1)
• Gene repression magnitudes (preclinical): SCN9A repression of ~90% (human iPSC neurons), up to 70% (mouse DRG), up to 60% (NHP DRG). (samie2024potentandselective pages 1-3)

6) Visual evidence (structural map)

The following figure (cropped from the primary 2023 cryo‑EM study) summarizes multiple druggable binding sites mapped onto NaV1.7 and supports the structural pharmacology narrative in Sections 2.1 and 5. (wu2023structuralmappingof media a264241d)

7) Consolidated evidence table (artifact)

The table below consolidates key functional annotation points, evidence types, and translational status with DOIs/URLs.

Table: This table summarizes functional annotation, mechanism, genetics, and clinical translation for human SCN9A/Nav1.7 using the most relevant gathered evidence, prioritizing 2023–2024 sources where possible. It is useful as a compact reference linking molecular function to experimental support and translational status.

8) Notes on nomenclature and aliases

UniProt lists historical names such as “neuroendocrine sodium channel,” “PN1,” and “hNE‑Na.” These aliases were not directly encountered in the retrieved primary texts; this report therefore treats them as database-derived synonyms and relies on primary literature for functional claims. The SCN9A ↔ NaV1.7 ↔ UniProt Q15858 mapping is explicitly supported in Wright et al. 2023. (wright2023thecterminalof pages 2-3)

Key references (with publication dates and URLs)

• Wright KM et al. Oct 2023. The C-Terminal of NaV1.7 Is Ubiquitinated by NEDD4L. ACS Bio & Med Chem Au. https://doi.org/10.1021/acsbiomedchemau.3c00031 (wright2023thecterminalof pages 2-3)
• Wu Q et al. Jun 2023. Structural mapping of Nav1.7 antagonists. Nature Communications. https://doi.org/10.1038/s41467-023-38942-3 (wu2023structuralmappingof pages 1-2)
• Jami S et al. Apr 2023. Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function. Nature Communications. https://doi.org/10.1038/s41467-023-37963-2 (jami2023paincausingstingingnettle pages 1-2)
• Li Z et al. Feb 2024. Dissection of the structure–function relationship of Nav channels. PNAS. https://doi.org/10.1073/pnas.2322899121 (li2024dissectionofthe pages 1-2)
• Martina M et al. Aug 2024. Single-domain antibodies targeting Nav1.7 reduce pain in animal models. Advanced Science. https://doi.org/10.1002/advs.202405432 (martina2024anovelantigen pages 1-2)
• Samie M et al. Sep 2024 (preprint). Zinc finger repressors targeting SCN9A. bioRxiv. https://doi.org/10.1101/2024.09.06.609976 (samie2024potentandselective pages 1-3)
• ClinicalTrials.gov: NCT02215252 (PF‑05089771 in DPN). https://clinicaltrials.gov/study/NCT02215252 (NCT02215252 chunk 1)
• ClinicalTrials.gov: NCT01911975 (lacosamide in SCN9A-GOF SFN). https://clinicaltrials.gov/study/NCT01911975 (NCT01911975 chunk 1)
• ClinicalTrials.gov: NCT02496455 (SCN9A polymorphisms and postoperative pain). https://clinicaltrials.gov/study/NCT02496455 (NCT02496455 chunk 1)
• Yang J et al. Oct 2024. Discordance between preclinical and clinical testing of NaV1.7-selective inhibitors for pain. Pain. https://doi.org/10.1097/j.pain.0000000000003425 ()

References

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Citations

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2. toffano2020computationalpipelineto pages 1-2
3. dormer2023areviewof pages 8-9
4. wu2023structuralmappingof pages 1-2
5. jami2023paincausingstingingnettle pages 1-2
6. wisedchaisri2023structuralbasisfor pages 1-2
7. li2024dissectionofthe pages 1-2
8. martina2024anovelantigen pages 1-2
9. samie2024potentandselective pages 1-3
10. dormer2023areviewof pages 4-5
11. meents2019theroleof pages 1-2
12. wood2025sensoryneuronsodium pages 1-2
13. baker2020painfulandpainless pages 1-2
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16. yogi2025preclinicalanimalmodels pages 1-3
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