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<p>TRPA1 is an essential calcium (Ca<sup>2+</sup>)-permeable channel involved in nociception and inflammation. It exhibits complex and mechanistically elusive Ca<sup>2+</sup> regulation with initial potentiation then rapid desensitization. We find that the universal Ca<sup>2+</sup> 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 Ca<sup>2+</sup>/CaM binding element in the TRPA1 distal C-terminus. Genetic or biochemical perturbation of Ca<sup>2+</sup>/CaM binding to this site yields hyperactive channels that exhibit drastic slowing of desensitization with minor effect on potentiation. Higher extracellular Ca<sup>2+</sup> partially rescues slowed desensitization. Our results identify a critical regulatory element in an unstructured TRPA1 region highlighting the importance of these domains, they reveal Ca<sup>2+</sup>/CaM is an essential TRPA1 auxiliary subunit required for proper channel function, and they suggest that Ca<sup>2+</sup>/CaM binding at this distal site stabilizes a long-range allosteric mechanism to drive rapid desensitization.</p>

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Calmodulin binding is required for calcium mediated TRPA1 desensitization

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月30日

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

摘要

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.