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A human TRPV1 genetic variant within the channel gating domain regulates pain sensitivity in rodents
Shufang He, … , Ye Zhang, Eric R. Gross
Shufang He, … , Ye Zhang, Eric R. Gross
Published December 6, 2022
Citation Information: J Clin Invest. 2023;133(3):e163735. https://doi.org/10.1172/JCI163735.
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Research Article Neuroscience Vascular biology

A human TRPV1 genetic variant within the channel gating domain regulates pain sensitivity in rodents

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Abstract

Pain signals are relayed to the brain via a nociceptive system, and in rare cases, this nociceptive system contains genetic variants that can limit the pain response. Here, we questioned whether a human transient receptor potential vanilloid 1 (TRPV1) missense variant causes a resistance to noxious stimuli and, further, whether we could target this region with a cell-permeable peptide as a pain therapeutic. Initially using a computational approach, we identified a human K710N TRPV1 missense variant in an otherwise highly conserved region of mammalian TRPV1. After generating a TRPV1K710N-knockin mouse using CRISPR/Cas9, we discovered that the K710N variant reduced capsaicin-induced calcium influx in dorsal root ganglion neurons. The TRPV1K710N rodents also had less acute behavioral responses to noxious chemical stimuli and less hypersensitivity to nerve injury, while their response to noxious heat remained intact. Furthermore, blocking this K710 region in WT rodents using a cell-penetrating peptide limited acute behavioral responses to noxious stimuli and returned pain hypersensitivity induced by nerve injury to baseline levels. These findings identify K710 TRPV1 as a discrete site that is crucial for the control of nociception and provide insights into how to leverage rare genetic variants in humans to uncover fresh strategies for developing pain therapeutics.

Authors

Shufang He, Vanessa O. Zambelli, Pritam Sinharoy, Laura Brabenec, Yang Bian, Freeborn Rwere, Rafaela C.R. Hell, Beatriz Stein Neto, Barbara Hung, Xuan Yu, Meng Zhao, Zhaofei Luo, Chao Wu, Lijun Xu, Katrin J. Svensson, Stacy L. McAllister, Creed M. Stary, Nana-Maria Wagner, Ye Zhang, Eric R. Gross

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Figure 8

Effect of V1-cal or TAT47–57 on DRG neurons.

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Effect of V1-cal or TAT47–57 on DRG neurons.
(A and B) WT DRG neurons we...
(A and B) WT DRG neurons were treated with TAT47–57 or V1-cal, with and without capsaicin. (C) AUC (total amount of calcium influx) and (D) percentage of maximal change in Fura-2AM following capsaicin-stimulated calcium influx relative to TAT47–57. n = 16–18 DRG cells from 3 independent experiments. (E) Immunostaining for SP and CGRP in DRG tissues following capsaicin or vehicle injection in the presence of V1-cal or TAT47–57. Scale bars: 50 μm. Quantitative analysis of (F) CGRP intensity and (G) SP intensity in each group. n = 6/group. Significance was determined by 2-way ANOVA followed by Tukey’s post hoc test (C, D, F, and G). n = 6/group.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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