IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-63767-7.html
   My bibliography  Save this article

Calmodulin binding is required for calcium mediated TRPA1 desensitization

Author

Listed:
  • Justin H. Sanders

    (Yale University)

  • Camila Garcia

    (Yale University)

  • Kehinde M. Taiwo

    (Yale University)

  • Gregory Quevedo

    (Yale University)

  • Glory A. Adekanye

    (Yale University)

  • Avnika Bali

    (Yale University)

  • Candice E. Paulsen

    (Yale University)

Abstract

TRPA1 is an essential calcium (Ca2+)-permeable channel involved in nociception and inflammation. It exhibits complex and mechanistically elusive Ca2+ regulation with initial potentiation then rapid desensitization. We find that the universal Ca2+ sensor Calmodulin (CaM) binds TRPA1 in cells at rest and suppresses channel activity. Combining biochemical, biophysical, modeling, NMR spectroscopy, and functional approaches, we identify an evolutionarily conserved, high-affinity Ca2+/CaM binding element in the TRPA1 distal C-terminus. Genetic or biochemical perturbation of Ca2+/CaM binding to this site yields hyperactive channels that exhibit drastic slowing of desensitization with minor effect on potentiation. Higher extracellular Ca2+ partially rescues slowed desensitization. Our results identify a critical regulatory element in an unstructured TRPA1 region highlighting the importance of these domains, they reveal Ca2+/CaM is an essential TRPA1 auxiliary subunit required for proper channel function, and they suggest that Ca2+/CaM binding at this distal site stabilizes a long-range allosteric mechanism to drive rapid desensitization.

Suggested Citation

  • Justin H. Sanders & Camila Garcia & Kehinde M. Taiwo & Gregory Quevedo & Glory A. Adekanye & Avnika Bali & Candice E. Paulsen, 2025. "Calmodulin binding is required for calcium mediated TRPA1 desensitization," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63767-7
    DOI: 10.1038/s41467-025-63767-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-63767-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-63767-7?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
    ---><---

    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:16:y:2025:i:1:d:10.1038_s41467-025-63767-7. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.