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Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain
Cédric J. Laedermann, … , Hugues Abriel, Isabelle Decosterd
Cédric J. Laedermann, … , Hugues Abriel, Isabelle Decosterd
Published June 17, 2013
Citation Information: J Clin Invest. 2013;123(7):3002-3013. https://doi.org/10.1172/JCI68996.
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Research Article Neuroscience Article has an altmetric score of 27

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

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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 Navs 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 Nav1.7-specific inhibitor, ProTxII, allowed the isolation of Nav1.7-mediated currents. SNI decreased NEDD4-2 expression in DRG cells and increased the amplitude of Nav1.7 and Nav1.8 currents. The redistribution of Nav1.7 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 Nav1.7 and Nav1.8 current amplitudes, but also alleviated SNI-induced mechanical allodynia. These findings demonstrate that NEDD4-2 is a potent posttranslational regulator of Navs and that downregulation of NEDD4-2 leads to the hyperexcitability of DRG neurons and contributes to the genesis of pathological pain.

Authors

Cédric J. Laedermann, Matthieu Cachemaille, Guylène Kirschmann, Marie Pertin, Romain-Daniel Gosselin, Isabelle Chang, Maxime Albesa, Chris Towne, Bernard L. Schneider, Stephan Kellenberger, Hugues Abriel, Isabelle Decosterd

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Figure 6

Delivery of rAAV2/6-NEDD4-2 viral vector decreases functional currents after SNI and alleviates mechanical allodynia.

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Delivery of rAAV2/6-NEDD4-2 viral vector decreases functional currents a...
(A–D) Immunofluorescence of NEDD4-2 in coronal sections of L4 ipsilateral DRG injected with rAAV2/6-NEDD4-2 or saline solution in sham- and SNI-operated mice. Scale bars: 30 μm. (E and F) Scatter dot plots representing Navtotal, Nav1.7, Nav1.8, and NavrTTXs current densities 1 week after SNI in noninfected DRG neurons (NINF), rAAV2/6-NEDD4-2–infected cells (INFNEDD4–2), and in the control group infected with the rAAV2/6-NEDD4-2CS vector (INFNEDD4-2CS). Slow (E, in cyan) and fast (F, in magenta) neurons are shown. Nonparametric 1-way ANOVA (Kruskal-Wallis test) with Dunn’s post-hoc test. See Supplemental Figure 5F for total population, Supplemental Table 5 for biophysical properties and values, and Supplemental Figure 5, A–E. (G) Basal thermal sensitivity showed no difference at 49°C (P = 0.987), 52°C (P = 0.186), or 55°C (P = 0.673) in the hot-plate test between the 2 groups. Student’s t test. (H) An increase in tail-flick latency (P = 0.018 at intensity 7) for high-intensity stimulation in the rAAV2/6-NEDD4-2 group was observed. Mann-Whitney U test. (I) Tail pressure sensitivity was increased in mice infected with rAAV2/6-NEDD4-2. **P = 0.006, Student’s t test. (J) Basal responses to innocuous mechanical stimulation were not different between the 2 strands, but the development of mechanical allodynia was significantly diminished in rAAV2/6-NEDD4-2–infected mice. ***P < 0.001 at day 7 and **P < 0.01 at day 14; 2-way ANOVA on log values with post-hoc Bonferroni’s tests. Data are expressed as the mean ± SEM; n = 12–15 for rAAV2/6-stuffer and rAAV2/6-NEDD4-2.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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