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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-04-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/68128 |
| _version_ | 1818019099585806336 |
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| author | Qiang Liu Jin Wang Xin Wei Juan Hu Conghui Ping Yue Gao Chang Xie Peiyu Wang Peng Cao Zhengyu Cao Ye Yu Dongdong Li Jing Yao |
| author_facet | Qiang Liu Jin Wang Xin Wei Juan Hu Conghui Ping Yue Gao Chang Xie Peiyu Wang Peng Cao Zhengyu Cao Ye Yu Dongdong Li Jing Yao |
| author_sort | Qiang Liu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-14T07:47:47Z |
| format | Article |
| id | doaj.art-4762a5c2c8eb48cfa6f33ecd4d878ac0 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:47:47Z |
| publishDate | 2021-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-4762a5c2c8eb48cfa6f33ecd4d878ac02022-12-22T02:05:17ZengeLife Sciences Publications LtdeLife2050-084X2021-04-011010.7554/eLife.68128Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonineQiang Liu0Jin Wang1Xin Wei2Juan Hu3Conghui Ping4Yue Gao5Chang Xie6Peiyu Wang7Peng Cao8Zhengyu Cao9Ye Yu10Dongdong Li11https://orcid.org/0000-0002-6731-4771Jing Yao12https://orcid.org/0000-0003-1844-3988State Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, ChinaSchool of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, ChinaState Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, ChinaState Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, ChinaState Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, ChinaState Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, ChinaState Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, ChinaState Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, ChinaHospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaState Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, ChinaSchool of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, ChinaSorbonne Université, Institute of Biology Paris Seine, Neuroscience Paris Seine, CNRS UMR8246, Inserm U1130, Paris, FranceState Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, ChinaThe 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.https://elifesciences.org/articles/68128TRPV3dycloninecell deathpruritusskin inflammation |
| spellingShingle | Qiang Liu Jin Wang Xin Wei Juan Hu Conghui Ping Yue Gao Chang Xie Peiyu Wang Peng Cao Zhengyu Cao Ye Yu Dongdong Li Jing Yao Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine eLife TRPV3 dyclonine cell death pruritus skin inflammation |
| 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 | TRPV3 dyclonine cell death pruritus skin inflammation |
| url | https://elifesciences.org/articles/68128 |
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