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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
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