Titre
The Antidiabetic Drug Metformin Regulates Voltage-Gated Sodium Channel Na<sub>V</sub>1.7 via the Ubiquitin-Ligase NEDD4-2.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Deftu, A.F.
Auteure/Auteur
Chu Sin Chung, P.
Auteure/Auteur
Laedermann, C.J.
Auteure/Auteur
Gillet, L.
Auteure/Auteur
Pertin, M.
Auteure/Auteur
Kirschmann, G.
Auteure/Auteur
Decosterd, I.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
2373-2822
Statut éditorial
Publié
Date de publication
2022
Volume
9
Numéro
2
Première page
0409
Dernière page/numéro d’article
21.2022 1-14
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Publication Status: epublish
Résumé
The antidiabetic drug metformin has been shown to reduce pain hypersensitivity in preclinical models of chronic pain and in neuropathic pain in humans. Multiple intracellular pathways have been described as metformin targets. Among them, metformin is an activator of the adenosine 5'-monophosphate protein kinase that can in turn modulate the activity of the E3 ubiquitin ligase NEDD4-2 and thus post-translational expression of voltage-gated sodium channels (Na <sub>V</sub> s). In this study, we found that the bulk of the effect of metformin on Na1.7 is dependent on NEDD4-2. In HEK cells, the expression of Na <sub>V</sub> 1.7 at the membrane fraction, obtained by a biotinylation approach, is only reduced by metformin when cotransfected with NEDD4-2. Similarly, in voltage-clamp recordings, metformin significantly reduced Na <sub>V</sub> 1.7 current density when cotransfected with NEDD4-2. In mouse dorsal root ganglion (DRG) neurons, without changing the biophysical properties of Na <sub>V</sub> 1.7, metformin significantly decreased Na <sub>V</sub> 1.7 current densities, but not in Nedd4L knock-out mice (SNS-Nedd4L <sup>-/-</sup> ). In addition, metformin induced a significant reduction in NEDD4-2 phosphorylation at the serine-328 residue in DRG neurons, an inhibitory phosphorylation site of NEDD4-2. In current-clamp recordings, metformin reduced the number of action potentials elicited by DRG neurons from Nedd4L <sup>fl/fl</sup> , with a partial decrease also present in SNS-Nedd4L <sup>-/-</sup> mice, suggesting that metformin can also change neuronal excitability in an NEDD4-2-independent manner. We suggest that NEDD4-2 is a critical player for the effect of metformin on the excitability of nociceptive neurons; this action may contribute to the relief of neuropathic pain.
Sujets
PID Serval
serval:BIB_D9129D3F0190
PMID
Open Access
Oui
Date de création
2022-02-12T13:41:23.002Z
Date de création dans IRIS
2025-05-21T01:34:12Z
Fichier(s)![Vignette d'image]()
En cours de chargement...
Nom
35131865_BIB_D9129D3F0190.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by/4.0
Taille
2.11 MB
Format
Adobe PDF
PID Serval
serval:BIB_D9129D3F0190.P001
URN
urn:nbn:ch:serval-BIB_D9129D3F01902
Somme de contrôle
(MD5):917d04cfd8974a7c8a0c5e7e0ade5d3d