{"doi":"10.1101/2024.12.11.627969","title":"Calmodulin binding is required for calcium mediated TRPA1 desensitization","abstract":"Abstract Calcium (Ca 2+ ) ions affect nearly all aspects of biology. Excessive Ca 2+ entry is cytotoxic and Ca 2+ - mobilizing receptors have evolved diverse mechanisms for tight regulation that often include Calmodulin (CaM). TRPA1, an essential Ca 2+ -permeable ion channel involved in pain signaling and inflammation, exhibits complex Ca 2+ regulation with initial channel potentiation followed by rapid desensitization. The molecular mechanisms of TRPA1 Ca 2+ regulation and whether CaM plays a role remain elusive. We find that TRPA1 binds CaM best at basal Ca 2+ concentration, that they co-localize in resting cells, and that CaM suppresses TRPA1 activity. Combining biochemical, biophysical, modeling, NMR spectroscopy, and functional approaches, we identify an evolutionarily conserved, high-affinity CaM binding element in the distal TRPA1 C-terminus (DCTCaMBE). Genetic or biochemical perturbation of Ca 2+ /CaM binding to the TRPA1 DCTCaMBE yields hyperactive channels that exhibit drastic slowing of desensitization with no effect on potentiation. Ca 2+ /CaM TRPA1 regulation does not require the N-lobe, raising the possibility that CaM is not the Ca 2+ sensor, per se . Higher extracellular Ca 2+ can partially rescue slowed desensitization suggesting Ca 2+ /CaM binding to the TRPA1 DCTCaMBE primes an intrinsic TRPA1 Ca 2+ binding site that, upon binding Ca 2+ , triggers rapid desensitization. Collectively, our results identify a critical regulatory element in an unstructured TRPA1 region highlighting the importance of these domains, they reveal Ca 2+ /CaM is an essential TRPA1 auxiliary subunit required for rapid desensitization that establishes proper channel function with implications for all future TRPA1 work, and they uncover a mechanism for receptor regulation by Ca 2+ /CaM that expands the scope of CaM biology.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":489385,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.958,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":465061,"name":"Kehinde M. Taiwo","orcid":"0000-0003-4766-0519","position":1,"is_corresponding":false},{"id":1334281,"name":"Glory A. Adekanye","orcid":"0000-0003-1919-9534","position":2,"is_corresponding":false},{"id":999422,"name":"Avnika Bali","orcid":"0000-0001-6921-8196","position":3,"is_corresponding":false},{"id":865928,"name":"Yuekang Zhang","orcid":"0000-0002-4690-3825","position":4,"is_corresponding":false},{"id":247483,"name":"Candice E. Paulsen","orcid":"0000-0001-5317-773X","position":5,"is_corresponding":false},{"id":337694,"name":"Justin H. Sanders","orcid":"0000-0002-8976-7990","position":0,"is_corresponding":true}],"reference_count":125,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:23.929823Z","pmid":"39713425","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}