ArticleThe Journal of clinical investigation2013
Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain.
Article in The Journal of clinical investigation, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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Who cites it
81 citing papers in PubMed, 132 citations in OpenAlex.
- Herpes simplex virus pUL56 abolishes neuronal activity by removing voltage-gated ion channels from the plasma membrane.Science advances · 2026Article
- The Excelsatoxin A-Receptor TMEM233 Modulates Nav1.8.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Palmitic acid aggravates atopic dermatitis by regulating SGK1/NEDD4L-involved cutaneous neuroimmune inflammation through driving TRPV1 and MRGPRB2 S-palmitoylation.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies.Nature communications · 2025Article
- Benchmarking In-Cell Proteomics for Profiling Neuroblastoma Cell Differentiation and the Ubiquitin-Proteasome System.Journal of proteome research · 2025Article
- Arrestin-biased allosteric modulator of neurotensin receptor 1 alleviates acute and chronic pain.Cell · 2025Article
- Pharmacologically enabling the degradation of Na V 1.8 channels to reduce neuropathic pain.Pain · 2025Article
- Preclinical Animal Models to Investigate the Role of NaLife (Basel, Switzerland) · 2025Review
- Small-molecule natural product sophoricoside reduces peripheral neuropathic pain via directly blocking of NaV1.6 in dorsal root ganglion nociceptive neurons.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Small molecule-mediated targeted protein degradation of voltage-gated sodium channels involved in pain.bioRxiv : the preprint server for biology · 2025Article
- Comprehensive Proteomic Profiling of Human Nav1.7-Interacting Proteins Reveals Conserved Regulatory Networks Involved in Nociceptive Signaling.Neuroscience insights · 2025Article
- Kv3.1 Interaction with UBR5 Is Required for Chronic Inflammatory Pain.Molecular neurobiology · 2025Article
- Shared genetic architecture and causality between autism spectrum disorder and irritable bowel syndrome, multisite pain, and fatigue.Translational psychiatry · 2024Article
- A Novel Antigen Design Strategy to Isolate Single-Domain Antibodies that Target Human Nav1.7 and Reduce Pain in Animal Models.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.Molecular systems biology · 2024Article
- Dysfunctional sodium channel kinetics as a novel epilepsy mechanism in chromosome 15q11-q13 duplication syndrome.Epilepsia · 2023Article
- Identification and targeting of a unique NaProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Suberoylanilide Hydroxamic Acid Ameliorates Pain Sensitization in Central Neuropathic Pain After Spinal Cord Injury via the HDAC5/NEDD4/SCN9A Axis.Neurochemical research · 2023Article
- Integrative miRNA-mRNA profiling of human epidermis: unique signature of SCN9A painful neuropathy.Brain : a journal of neurology · 2023Article
- Evolving techniques for reducing phantom limb pain.Experimental biology and medicine (Maywood, N.J.) · 2023Review
21 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of voltage-gated sodium channels (Navs) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying the altered expression of Na(v)s remain unknown. This study investigated the role of the E3 ubiquitin ligase NEDD4-2, which is known to ubiquitylate Navs, in the pathogenesis of neuropathic pain in mice. The spared nerve injury (SNI) model of traumatic nerve injury-induced neuropathic pain was used, and an Na(v)1.7-specific inhibitor, ProTxII, allowed the isolation of Na(v)1.7-mediated currents. SNI decreased NEDD4-2 expression in DRG cells and increased the amplitude of Na(v)1.7 and Na(v)1.8 currents. The redistribution of Na(v)1.7 channels toward peripheral axons was also observed. Similar changes were observed in the nociceptive DRG neurons of Nedd4L knockout mice (SNS-Nedd4L(-/-)). SNS-Nedd4L(-/-) mice exhibited thermal hypersensitivity and an enhanced second pain phase after formalin injection. Restoration of NEDD4-2 expression in DRG neurons using recombinant adenoassociated virus (rAAV2/6) not only reduced Na(v)1.7 and Na(v)1.8 current amplitudes, but also alleviated SNI-induced mechanical allodynia. These findings demonstrate that NEDD4-2 is a potent posttranslational regulator of Na(v)s and that downregulation of NEDD4-2 leads to the hyperexcitability of DRG neurons and contributes to the genesis of pathological pain.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.