TRPV1 SUMOylation regulates nociceptive signaling in models of inflammatory pain

Yan Wang,Yong Li,Yingping Wang,Tian Zhou,Quan Tian,Ruining Ma,Jinke Cheng,Kaidi Mei,Huiqing Liu,Jing Yao,Tian-Le Xu,Yuqiang Ding,Qiang Liu,Yingwei Gao,Qi Deng,Michael X Zhu,Weifang Rong,Yangbo Wang

doi:10.1038/s41467-018-03974-7

Abstract

Although TRPV1 channels represent a key player of noxious heat sensation, the precise mechanisms for thermal hyperalgesia remain unknown. We report here that conditional knockout of deSUMOylation enzyme, SENP1, in mouse dorsal root ganglion (DRG) neurons exacerbated thermal hyperalgesia in both carrageenan- and Complete Freund’s adjuvant-induced inflammation models. TRPV1 is SUMOylated at a C-terminal Lys residue (K822), which specifically enhances the channel sensitivity to stimulation by heat, but not capsaicin, protons or voltage. TRPV1 SUMOylation is decreased by SENP1 but upregulated upon peripheral inflammation. More importantly, the reduced ability of TRPV1 knockout mice to develop inflammatory thermal hyperalgesia was rescued by viral infection of lumbar 3/4 DRG neurons of wild-type TRPV1, but not its SUMOylation-deficient mutant, K822R. These data suggest that TRPV1 SUMOylation is essential for the development of inflammatory thermal hyperalgesia, through a mechanism that involves sensitization of the channel response specifically to thermal stimulation.

Highlights

TRPV1 channels represent a key player of noxious heat sensation, the precise mechanisms for thermal hyperalgesia remain unknown
We further identified a lysine residue at the C-terminus of TRPV1 (K822) to be SUMOylated by SUMO1 and deSUMOylated by SENP1, which when mutated to Arg, failed to exhibit a SUMO1-induced channel sensitization to heat stimulus in vitro and was unable to rescue inflammatory thermal hyperalgesia in vivo when introduced into dorsal root ganglia (DRG) neurons of the TRPV1 knockout mice
To assess a possible involvement of SUMOylation/deSUMOylation in sensory neurons, we first examined whether SUMO1 and SUMO1/SENP1 are expressed in mouse DRG

Summary

Introduction

TRPV1 channels represent a key player of noxious heat sensation, the precise mechanisms for thermal hyperalgesia remain unknown. The reduced ability of TRPV1 knockout mice to develop inflammatory thermal hyperalgesia was rescued by viral infection of lumbar 3/4 DRG neurons of wild-type TRPV1, but not its SUMOylation-deficient mutant, K822R. These data suggest that TRPV1 SUMOylation is essential for the development of inflammatory thermal hyperalgesia, through a mechanism that involves sensitization of the channel response to thermal stimulation. We further identified a lysine residue at the C-terminus of TRPV1 (K822) to be SUMOylated by SUMO1 and deSUMOylated by SENP1, which when mutated to Arg, failed to exhibit a SUMO1-induced channel sensitization to heat stimulus in vitro and was unable to rescue inflammatory thermal hyperalgesia in vivo when introduced into DRG neurons of the TRPV1 knockout mice

Methods

Results

Conclusion