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Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine
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 i...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112869/ https://www.ncbi.nlm.nih.gov/pubmed/33876725 http://dx.doi.org/10.7554/eLife.68128 |
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author | Liu, Qiang Wang, Jin Wei, Xin Hu, Juan Ping, Conghui Gao, Yue Xie, Chang Wang, Peiyu Cao, Peng Cao, Zhengyu Yu, Ye Li, Dongdong Yao, Jing |
author_facet | Liu, Qiang Wang, Jin Wei, Xin Hu, Juan Ping, Conghui Gao, Yue Xie, Chang Wang, Peiyu Cao, Peng Cao, Zhengyu Yu, Ye Li, Dongdong Yao, Jing |
author_sort | Liu, Qiang |
collection | PubMed |
description | 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 humans. Nevertheless, whether and how TRPV3 could be therapeutically targeted remains to be elucidated. 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 therapeutics for skin inflammation. |
format | Online Article Text |
id | pubmed-8112869 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-81128692021-05-12 Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine Liu, Qiang Wang, Jin Wei, Xin Hu, Juan Ping, Conghui Gao, Yue Xie, Chang Wang, Peiyu Cao, Peng Cao, Zhengyu Yu, Ye Li, Dongdong Yao, Jing eLife Biochemistry and Chemical Biology 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 humans. Nevertheless, whether and how TRPV3 could be therapeutically targeted remains to be elucidated. 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 therapeutics for skin inflammation. eLife Sciences Publications, Ltd 2021-04-20 /pmc/articles/PMC8112869/ /pubmed/33876725 http://dx.doi.org/10.7554/eLife.68128 Text en © 2021, Liu et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Liu, Qiang Wang, Jin Wei, Xin Hu, Juan Ping, Conghui Gao, Yue Xie, Chang Wang, Peiyu Cao, Peng Cao, Zhengyu Yu, Ye Li, Dongdong Yao, Jing Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine |
title | Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine |
title_full | Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine |
title_fullStr | Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine |
title_full_unstemmed | Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine |
title_short | Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine |
title_sort | therapeutic inhibition of keratinocyte trpv3 sensory channel by local anesthetic dyclonine |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112869/ https://www.ncbi.nlm.nih.gov/pubmed/33876725 http://dx.doi.org/10.7554/eLife.68128 |
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