{"doi":"10.1101/2021.01.06.425618","title":"Resolving the molecular fingerprint of the distal carboxy tail in modulating Ca <sub>V</sub> 1 calcium dependent inactivation","abstract":"Abstract Ca 2+ /calmodulin-dependent inactivation (CDI) of Ca V channels is a critical regulatory process required for tuning the kinetics of Ca 2+ entry for different cell types and physiologic responses. Calmodulin (CaM) resides on the IQ domain of the Ca V carboxy-tail, such that Ca 2+ binding initiates a reduction in channel open probability, manifesting as CDI. This regulatory process exerts a significant impact on Ca 2+ entry and is tailored by alternative splicing. Ca V 1.3 and Ca V 1.4 feature a long-carboxy-tail splice variant that modulates CDI through a competitive mechanism. In these channels, the distal-carboxy-tail (DCT) harbors an inhibitor of CDI (ICDI) module that competitively displaces CaM from the IQ domain, thereby diminishing CDI. While this overall mechanism is now well-described, the detailed interaction loci for ICDI binding to the IQ domain is yet to be elucidated. Here, we perform alanine-scanning mutagenesis of the IQ and ICDI domains and evaluate the contribution of neighboring regions. We identify multiple critical residues within the IQ domain, ICDI and the nearby A region of the channel, which are required for high affinity IQ/ICDI binding. Importantly, disruption of this interaction commensurately diminishes ICDI function, as seen by the re-emergence of CDI in mutant channels. Furthermore, analysis of the homologous ICDI region of Ca V 1.2 reveals a selective effect of this channel region on Ca V 1.3 channels, implicating a cross-channel modulatory scheme in cells expressing both channel subtypes. In all, these findings provide new insights into a molecular rheostat that fine tunes Ca 2+ entry and supports normal neuronal and cardiac function.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":222880,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9593,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":723434,"name":"Daiana C.O. Vieira","orcid":"0000-0002-9848-276X","position":1,"is_corresponding":false},{"id":723954,"name":"David T. Yue","orcid":null,"position":2,"is_corresponding":false},{"id":484278,"name":"Manu Ben‐Johny","orcid":"0000-0002-5645-0815","position":3,"is_corresponding":false},{"id":723435,"name":"Ivy E. Dick","orcid":"0000-0002-7253-6846","position":4,"is_corresponding":false},{"id":625457,"name":"Lingjie Sang","orcid":"0000-0003-1485-2426","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-18T23:54:07.287704Z","pmid":null,"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":[]}