Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine
- Wuhan University, China
- China Pharmaceutical University, China
- Nanjing University of Chinese Medicine, China
- CNRS UMR8246, INSERM U1130, UPMC UM119, France
Abstract
The multimodal sensory channel transient receptor potential vanilloid-3 (TRPV3) is expressed in epidermal keratinocytes and implicated in chronic pruritus, allergy, and inflammation-related skin disorders. Gain-of-function mutations of TRPV3 cause hair growth disorders in mice and Olmsted Syndrome in human. We here report that mouse and human TRPV3 channel is targeted by the clinical medication dyclonine that exerts a potent inhibitory effect. Accordingly, dyclonine rescued cell death caused by gain-of-function TRPV3 mutations and suppressed pruritus symptoms in vivo in mouse model. At the single-channel level, dyclonine inhibited TRPV3 open probability but not the unitary conductance. By molecular simulations and mutagenesis, we further uncovered key residues in TRPV3 pore region that could toggle the inhibitory efficiency of dyclonine. The functional and mechanistic insights obtained on dyclonine-TRPV3 interaction will help to conceive updated therapeutics for skin inflammation.
Data availability
All the data for Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine have been deposited in Dyrad with DOI https://doi.org/10.5061/dryad.7d7wm37sq.
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Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonineDryad Digital Repository, doi:10.5061/dryad.7d7wm37sq.
Article and author information
Author details
Funding
National Natural Science Foundation of China (31830031)
- Jing Yao
National Natural Science Foundation of China (31929003)
- Jing Yao
National Natural Science Foundation of China (31871174)
- Jing Yao
National Natural Science Foundation of China (31671209)
- Jing Yao
National Natural Science Foundation of China (31601864)
- Jing Yao
Natural Science Foundation of Hubei Province (2017CFA063)
- Jing Yao
Natural Science Foundation of Hubei Province (2018CFA016)
- Jing Yao
Natural Science Foundation of Jiangsu Province (BK20202002)
- Ye Yu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Kenton J Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States
Ethics
Animal experimentation: All mice were housed in the specific pathogen-free animal facility at Wuhan University and all animal experiments were in accordance with protocols were adhered to the Chinese National Laboratory Animal-Guideline for Ethical Review of Animal Welfare and approved by the Institutional Animal Care and Use Committee of Wuhan University (NO. WDSKY0201804). The mice were euthanatized with CO2 followed by various studies.
Version history
- Received: March 5, 2021
- Accepted: April 19, 2021
- Accepted Manuscript published: April 20, 2021 (version 1)
- Version of Record published: May 11, 2021 (version 2)
- Version of Record updated: May 13, 2021 (version 3)
Copyright
© 2021, Liu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine
eLife 10:e68128.
https://doi.org/10.7554/eLife.68128
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