Calmodulin binding is required for calcium mediated TRPA1 desensitization

Justin H. Sanders, Camila Garcia, Kehinde M. Taiwo, Gregory Quevedo, Glory A. Adekanye, Avnika Bali and Candice E. Paulsen ()
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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

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63767-7

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