title: Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain.
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.
authors.affiliation: Pain Center, Department of Anesthesiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: Cédric J
authors.initials: CJ
authors.lastname: Laedermann
authors.forename: Matthieu
authors.initials: M
authors.lastname: Cachemaille
authors.forename: Guylène
authors.initials: G
authors.lastname: Kirschmann
authors.forename: Marie
authors.initials: M
authors.lastname: Pertin
authors.forename: Romain-Daniel
authors.initials: RD
authors.lastname: Gosselin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Chang
authors.forename: Maxime
authors.initials: M
authors.lastname: Albesa
authors.forename: Chris
authors.initials: C
authors.lastname: Towne
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
authors.forename: Stephan
authors.initials: S
authors.lastname: Kellenberger
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Decosterd
mesh_terms: D000200:Action Potentials; D000818:Animals; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000201:enzymology / Q000293:injuries / Q000503:physiopathology*; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism*; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases; D009437:Neuralgia / Q000201:enzymology*; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D059348:Peripheral Nerve Injuries / Q000201:enzymology* / Q000503:physiopathology; D012584:Sciatic Nerve / Q000201:enzymology / Q000293:injuries / Q000503:physiopathology; D013111:Spider Venoms / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; C470626:ProTx-II peptide; C568318:Scn10a protein, mouse; C503479:Scn9a protein, mouse; D013111:Spider Venoms; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases