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Irritant-evoked activation and calcium modulation of the TRPA1 receptor

Author

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  • Jianhua Zhao

    (University of California, San Francisco)

  • John V. Lin King

    (University of California, San Francisco
    University of California, San Francisco)

  • Candice E. Paulsen

    (University of California, San Francisco
    Yale School of Medicine)

  • Yifan Cheng

    (University of California, San Francisco)

  • David Julius

    (University of California, San Francisco)

Abstract

The transient receptor potential ion channel TRPA1 is expressed by primary afferent nerve fibres, in which it functions as a low-threshold sensor for structurally diverse electrophilic irritants, including small volatile environmental toxicants and endogenous algogenic lipids1. TRPA1 is also a ‘receptor-operated’ channel whose activation downstream of metabotropic receptors elicits inflammatory pain or itch, making it an attractive target for novel analgesic therapies2. However, the mechanisms by which TRPA1 recognizes and responds to electrophiles or cytoplasmic second messengers remain unknown. Here we use strutural studies and electrophysiology to show that electrophiles act through a two-step process in which modification of a highly reactive cysteine residue (C621) promotes reorientation of a cytoplasmic loop to enhance nucleophilicity and modification of a nearby cysteine (C665), thereby stabilizing the loop in an activating configuration. These actions modulate two restrictions controlling ion permeation, including widening of the selectivity filter to enhance calcium permeability and opening of a canonical gate at the cytoplasmic end of the pore. We propose a model to explain functional coupling between electrophile action and these control points. We also characterize a calcium-binding pocket that is highly conserved across TRP channel subtypes and accounts for all aspects of calcium-dependent TRPA1 regulation, including potentiation, desensitization and activation by metabotropic receptors. These findings provide a structural framework for understanding how a broad-spectrum irritant receptor is controlled by endogenous and exogenous agents that elicit or exacerbate pain and itch.

Suggested Citation

  • Jianhua Zhao & John V. Lin King & Candice E. Paulsen & Yifan Cheng & David Julius, 2020. "Irritant-evoked activation and calcium modulation of the TRPA1 receptor," Nature, Nature, vol. 585(7823), pages 141-145, September.
  • Handle: RePEc:nat:nature:v:585:y:2020:i:7823:d:10.1038_s41586-020-2480-9
    DOI: 10.1038/s41586-020-2480-9
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    Citations

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    Cited by:

    1. Amy Clarke & Julia Skerjanz & Mathias A. F. Gsell & Patrick Wiedner & Hazel Erkan-Candag & Klaus Groschner & Thomas Stockner & Oleksandra Tiapko, 2024. "PIP2 modulates TRPC3 activity via TRP helix and S4-S5 linker," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Tuo Ji & Lihua Zheng & Jiale Wu & Mei Duan & Qianwen Liu & Peng Liu & Chen Shen & Jinling Liu & Qinyi Ye & Jiangqi Wen & Jiangli Dong & Tao Wang, 2023. "The thioesterase APT1 is a bidirectional-adjustment redox sensor," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Chengyu Yin & Boyu Liu & Zishan Dong & Sai Shi & Chenxing Peng & Yushuang Pan & Xiaochen Bi & Huimin Nie & Yunwen Zhang & Yan Tai & Qimiao Hu & Xuan Wang & Xiaomei Shao & Hailong An & Jianqiao Fang & , 2024. "CXCL5 activates CXCR2 in nociceptive sensory neurons to drive joint pain and inflammation in experimental gouty arthritis," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    4. Jongdae Won & Jinsung Kim & Hyeongseop Jeong & Jinhyeong Kim & Shasha Feng & Byeongseok Jeong & Misun Kwak & Juyeon Ko & Wonpil Im & Insuk So & Hyung Ho Lee, 2023. "Molecular architecture of the Gαi-bound TRPC5 ion channel," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Lavanya Moparthi & Viktor Sinica & Vamsi K. Moparthi & Mohamed Kreir & Thibaut Vignane & Milos R. Filipovic & Viktorie Vlachova & Peter M. Zygmunt, 2022. "The human TRPA1 intrinsic cold and heat sensitivity involves separate channel structures beyond the N-ARD domain," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Avnika Bali & Samantha P. Schaefer & Isabelle Trier & Alice L. Zhang & Lilian Kabeche & Candice E. Paulsen, 2023. "Molecular mechanism of hyperactivation conferred by a truncation of TRPA1," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    7. Marc Duque & Corinne A. Lee-Kubli & Yusuf Tufail & Uri Magaram & Janki Patel & Ahana Chakraborty & Jose Mendoza Lopez & Eric Edsinger & Aditya Vasan & Rani Shiao & Connor Weiss & James Friend & Sreeka, 2022. "Sonogenetic control of mammalian cells using exogenous Transient Receptor Potential A1 channels," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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