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Papers of the Week

Papers: 21 Nov 2020 - 27 Nov 2020

Animal Studies

2020 Nov 25

Eur J Neurosci

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


Wang S, Qi S, Kogure Y, Kanda H, Tian L, Yamamoto S, Noguchi K, Dai Y
Eur J Neurosci. 2020 Nov 25.
PMID: 33236491.


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.