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

UBIQUITIN ligases; UBIQUITINATION; DORSAL root ganglia; ALLODYNIA; SENSORY neurons

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. [ABSTRACT FROM AUTHOR]

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