TRPV3 is a temperature-sensitive, nonselective cation channel expressed prominently in skin keratinocytes. TRPV3 plays important roles in hair morphogenesis and maintenance of epidermal barrier function. Gain-of-function mutations of TRPV3 have been found in both humans and rodents and are associated with hair loss, pruritus, and dermatitis. Here, we study the mechanisms of acid regulation of TRPV3 by using site-directed mutagenesis, fluorescent intracellular calcium measurement, and whole-cell patch-clamp recording techniques. We show that, whereas extracellular acid inhibits agonist-induced TRPV3 activation through an aspartate residue (D641) in the selectivity filter, intracellular protons sensitize the channel through cytoplasmic C-terminal glutamate and aspartate residues (E682, E689, and D727). Neutralization of the three C-terminal residues presensitizes the channel to agonist stimulation. Molecular dynamic simulations revealed that charge neutralization of the three C-terminal residues stabilized the sensitized channel conformation and enhanced the probability of α-helix formation in the linker between the S6 transmembrane segment and TRP domain. We conclude that acid inhibits TRPV3 function from the extracellular side but facilitates it from the intracellular side. These novel mechanisms of TRPV3 proton sensing can offer new insights into the role of TRPV3 in the regulation of epidermal barrier permeability and skin disorders under conditions of tissue acidosis.
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1 February 2021
Article|
December 15 2020
Mechanisms of proton inhibition and sensitization of the cation channel TRPV3
Haiyuan Wang
,
Haiyuan Wang
1
Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, China
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX
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Pu Yang
,
Pu Yang
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX
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Yungang Lu
,
Yungang Lu
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX
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Jin Wang
,
Jin Wang
3
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
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Jaepyo Jeon
,
Jaepyo Jeon
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX
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Qiaochu Wang
,
Qiaochu Wang
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX
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Jin-Bin Tian
,
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX
Jin-Bin Tian: jin.bin.tian@uth.tmc.edu
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Bin Zang
,
1
Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, China
Bin Zang: zangbin66@aliyun.com
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Ye Yu
,
Ye Yu
3
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
4
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, China
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Michael X. Zhu
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX
Correspondence to Michael X. Zhu: michael.x.zhu@uth.tmc.edu
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Haiyuan Wang
1
Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, China
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX
Pu Yang
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX
Yungang Lu
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX
Jin Wang
3
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
Jaepyo Jeon
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX
Qiaochu Wang
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX
Jin-Bin Tian
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX
Bin Zang
1
Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, China
Ye Yu
3
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
4
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, China
Michael X. Zhu
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX
Correspondence to Michael X. Zhu: michael.x.zhu@uth.tmc.edu
Bin Zang: zangbin66@aliyun.com
Jin-Bin Tian: jin.bin.tian@uth.tmc.edu
Received:
May 18 2020
Revision Received:
October 07 2020
Accepted:
November 17 2020
Online Issn: 1540-7748
Print Issn: 0022-1295
Funding:
National Institutes of Health
(DK081654)
© 2020 Wang et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Gen Physiol (2021) 153 (2): e202012663.
Article history
Received:
May 18 2020
Revision Received:
October 07 2020
Accepted:
November 17 2020
Citation
Haiyuan Wang, Pu Yang, Yungang Lu, Jin Wang, Jaepyo Jeon, Qiaochu Wang, Jin-Bin Tian, Bin Zang, Ye Yu, Michael X. Zhu; Mechanisms of proton inhibition and sensitization of the cation channel TRPV3. J Gen Physiol 1 February 2021; 153 (2): e202012663. doi: https://doi.org/10.1085/jgp.202012663
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