The ubiquitin E3 ligase Nedd4-2 relieves mechanical allodynia through the ubiquitination of TRPA1 channel in db/db mice.

Abstract

Neural precursor cell-expressed developmentally downregulated protein 4-2 (Nedd4-2) is a member of the E3 ubiquitin ligase family that is highly expressed in sensory neurons and involved in pain modulation via downregulation of ion channels in excitable membranes. Ubiquitination involving Nedd4-2 is regulated by adenosine monophosphate-activated protein kinase (AMPK), which is impaired in the dorsal root ganglion (DRG) neurons of db/db mice. AMPK negatively regulates the expression of transient receptor potential ankyrin 1 (TRPA1), a recognised pain sensor expressed on the membrane of DRG neurons, consequently relieving mechanical allodynia in db/db mice. Herein, we studied the involvement of Nedd4-2 in painful diabetic neuropathy and observed that Nedd4-2 negatively regulated diabetic mechanical allodynia. Nedd4-2 was co-expressed with TRPA1 in mouse DRG neurons. Nedd4-2 was involved in TRPA1 ubiquitination, this ubiquitination, as well as Nedd4-2-TRPA1 interaction, was decreased in db/db mice. Moreover, Nedd4-2 levels were decreased in db/db mice, while an abnormal intracellular distribution was observed in short-term high glucose-cultured DRG neurons. AMPK activators not only restored Nedd4-2 distribution but also increased Nedd4-2 expression. These findings demonstrate that Nedd4-2 is a potent regulator of TRPA1 and that the abnormal expression of Nedd4-2 in DRG neurons contributes to diabetic neuropathic pain.

• Authors: Shenglan Wang, Simin Qi, Yoko Kogure, Hirosato Kanda, Lin Tian, Satoshi Yamamoto, Koichi Noguchi, Yi Dai
• Journal: The European journal of neuroscience (Eur J Neurosci) Vol. 53 Issue 6 Pg. 1691-1704 (03 2021) ISSN: 1460-9568 [Electronic] France
• PMID: 33236491 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Chemical References

• TRPA1 Cation Channel
• Transient Receptor Potential Channels
• Trpa1 protein, mouse
• Ubiquitin
• Nedd4 Ubiquitin Protein Ligases
• Nedd4l protein, mouse
• Ubiquitin-Protein Ligases

Topics

• Animals
• Hyperalgesia
• Mice
• Nedd4 Ubiquitin Protein Ligases
• TRPA1 Cation Channel
• Transient Receptor Potential Channels
• Ubiquitin
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination