IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-38542-1.html
   My bibliography  Save this article

Molecular mechanism of hyperactivation conferred by a truncation of TRPA1

Author

Listed:
  • Avnika Bali

    (Yale University)

  • Samantha P. Schaefer

    (Yale University)

  • Isabelle Trier

    (Yale University
    Yale University)

  • Alice L. Zhang

    (Yale University)

  • Lilian Kabeche

    (Yale University
    Yale University)

  • Candice E. Paulsen

    (Yale University)

Abstract

A drastic TRPA1 mutant (R919*) identified in CRAMPT syndrome patients has not been mechanistically characterized. Here, we show that the R919* mutant confers hyperactivity when co-expressed with wild type (WT) TRPA1. Using functional and biochemical assays, we reveal that the R919* mutant co-assembles with WT TRPA1 subunits into heteromeric channels in heterologous cells that are functional at the plasma membrane. The R919* mutant hyperactivates channels by enhancing agonist sensitivity and calcium permeability, which could account for the observed neuronal hypersensitivity-hyperexcitability symptoms. We postulate that R919* TRPA1 subunits contribute to heteromeric channel sensitization by altering pore architecture and lowering energetic barriers to channel activation contributed by the missing regions. Our results expand the physiological impact of nonsense mutations, reveal a genetically tractable mechanism for selective channel sensitization, uncover insights into the process of TRPA1 gating, and provide an impetus for genetic analysis of patients with CRAMPT or other stochastic pain syndromes.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38542-1
    DOI: 10.1038/s41467-023-38542-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-38542-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-38542-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Elena O. Gracheva & Julio F. Cordero-Morales & José A. González-Carcacía & Nicholas T. Ingolia & Carlo Manno & Carla I. Aranguren & Jonathan S. Weissman & David Julius, 2011. "Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats," Nature, Nature, vol. 476(7358), pages 88-91, August.
    2. Candice E. Paulsen & Jean-Paul Armache & Yuan Gao & Yifan Cheng & David Julius, 2015. "Structure of the TRPA1 ion channel suggests regulatory mechanisms," Nature, Nature, vol. 520(7548), pages 511-517, April.
    3. Sven-Eric Jordt & Diana M. Bautista & Huai-hu Chuang & David D. McKemy & Peter M. Zygmunt & Edward D. Högestätt & Ian D. Meng & David Julius, 2004. "Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1," Nature, Nature, vol. 427(6971), pages 260-265, January.
    4. 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.
    5. Lindsey J. Macpherson & Adrienne E. Dubin & Michael J. Evans & Felix Marr & Peter G. Schultz & Benjamin F. Cravatt & Ardem Patapoutian, 2007. "Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines," Nature, Nature, vol. 445(7127), pages 541-545, February.
    6. Yiming Zhou & Yoshiro Suzuki & Kunitoshi Uchida & Makoto Tominaga, 2013. "Identification of a splice variant of mouse TRPA1 that regulates TRPA1 activity," Nature Communications, Nature, vol. 4(1), pages 1-12, December.
    7. Candice E. Paulsen & Jean-Paul Armache & Yuan Gao & Yifan Cheng & David Julius, 2015. "Erratum: Structure of the TRPA1 ion channel suggests regulatory mechanisms," Nature, Nature, vol. 525(7570), pages 552-552, September.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Xiaoning Wang & Yangyang Sun & Qian Wang & Fengying Liu & Weijie Yang & Xin Sui & Jun Yang & Minmin Zhang & Shuai Wang & Zhenyu Xiao & Yuan Luo & Yongan Wang & Tong Zhu, 2022. "Potential Common Mechanisms of Cytotoxicity Induced by Amide Herbicides via TRPA1 Channel Activation," IJERPH, MDPI, vol. 19(13), pages 1-18, June.
    2. Jianying Zhu & Qi Zhang & Hui Zhang & Zuoqiang Shi & Mingxu Hu & Chenglong Bao, 2023. "A minority of final stacks yields superior amplitude in single-particle cryo-EM," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. A. Catalina Vélez-Ortega & Ruben Stepanyan & Stephanie E. Edelmann & Sara Torres-Gallego & Channy Park & Desislava A. Marinkova & Joshua S. Nowacki & Ghanshyam P. Sinha & Gregory I. Frolenkov, 2023. "TRPA1 activation in non-sensory supporting cells contributes to regulation of cochlear sensitivity after acoustic trauma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Michael A Ha & Gregory J Smith & Joseph A Cichocki & Lu Fan & Yi-Shiuan Liu & Ana I Caceres & Sven Eric Jordt & John B Morris, 2015. "Menthol Attenuates Respiratory Irritation and Elevates Blood Cotinine in Cigarette Smoke Exposed Mice," PLOS ONE, Public Library of Science, vol. 10(2), pages 1-16, February.
    5. Yi-Yu Lin & Yan Lu & Chun-Yun Li & Xue-Fei Ma & Miao-Qing Shao & Yu-Hao Gao & Yu-Qing Zhang & Hai-Ning Jiang & Yan Liu & Yang Yang & Li-Dong Huang & Peng Cao & Heng-Shan Wang & Jin Wang & Ye Yu, 2024. "Finely ordered intracellular domain harbors an allosteric site to modulate physiopathological function of P2X3 receptors," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. 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.
    7. 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.
    8. 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.
    9. Barbara Gordon, 2023. "Nutritional Considerations for Bladder Storage Conditions in Adult Females," IJERPH, MDPI, vol. 20(19), pages 1-15, October.
    10. 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.
    11. 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.
    12. Liying Zhang & Charlotte Simonsen & Lucie Zimova & Kaituo Wang & Lavanya Moparthi & Rachelle Gaudet & Maria Ekoff & Gunnar Nilsson & Ute A. Hellmich & Viktorie Vlachova & Pontus Gourdon & Peter M. Zyg, 2022. "Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    13. Shogo Hori & Michihiro Tateyama & Tsuyoshi Shirai & Yoshihiro Kubo & Osamu Saitoh, 2023. "Two single-point mutations in Ankyrin Repeat one drastically change the threshold temperature of TRPV1," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    14. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38542-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.