{"doi":"10.1085/jgp.202112915","title":"The distinct role of the four voltage sensors of the skeletal CaV1.1 channel in voltage-dependent activation","abstract":"Initiation of skeletal muscle contraction is triggered by rapid activation of RYR1 channels in response to sarcolemmal depolarization. RYR1 is intracellular and has no voltage-sensing structures, but it is coupled with the voltage-sensing apparatus of CaV1.1 channels to inherit voltage sensitivity. Using an opto-electrophysiological approach, we resolved the excitation-driven molecular events controlling both CaV1.1 and RYR1 activations, reported as fluorescence changes. We discovered that each of the four human CaV1.1 voltage-sensing domains (VSDs) exhibits unique biophysical properties: VSD-I time-dependent properties were similar to ionic current activation kinetics, suggesting a critical role of this voltage sensor in CaV1.1 activation; VSD-II, VSD-III, and VSD-IV displayed faster activation, compatible with kinetics of sarcoplasmic reticulum Ca2+ release. The prominent role of VSD-I in governing CaV1.1 activation was also confirmed using a naturally occurring, charge-neutralizing mutation in VSD-I (R174W). This mutation abolished CaV1.1 current at physiological membrane potentials by impairing VSD-I activation without affecting the other VSDs. Using a structurally relevant allosteric model of CaV activation, which accounted for both time- and voltage-dependent properties of CaV1.1, to predict VSD-pore coupling energies, we found that VSD-I contributed the most energy (~75 meV or ∼3 kT) toward the stabilization of the open states of the channel, with smaller (VSD-IV) or negligible (VSDs II and III) energetic contribution from the other voltage sensors (<25 meV or ∼1 kT). This study settles the longstanding question of how CaV1.1, a slowly activating channel, can trigger RYR1 rapid activation, and reveals a new mechanism for voltage-dependent activation in ion channels, whereby pore opening of human CaV1.1 channels is primarily driven by the activation of one voltage sensor, a mechanism distinct from that of all other voltage-gated channels.","journal":"The Journal of General Physiology","year":2021,"id":165476,"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":36,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.95,"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":689111,"name":"Marina Angelini","orcid":"0000-0003-4621-3784","position":1,"is_corresponding":false},{"id":690007,"name":"Federica Steccanella","orcid":null,"position":2,"is_corresponding":false},{"id":689112,"name":"Julian Wier","orcid":"0000-0001-7142-604X","position":3,"is_corresponding":false},{"id":690008,"name":"Fenfen Wu","orcid":null,"position":4,"is_corresponding":false},{"id":689113,"name":"Marbella Quiñonez","orcid":"0000-0002-0684-9705","position":5,"is_corresponding":false},{"id":689114,"name":"Marino DiFranco","orcid":"0000-0002-9315-9429","position":6,"is_corresponding":false},{"id":689115,"name":"Alan Neely","orcid":"0000-0002-6007-2159","position":7,"is_corresponding":false},{"id":523474,"name":"Stephen C. Cannon","orcid":"0000-0001-8428-3690","position":8,"is_corresponding":false},{"id":444321,"name":"Riccardo Olcese","orcid":"0000-0003-4225-9814","position":9,"is_corresponding":false},{"id":689110,"name":"Nicoletta Savalli","orcid":"0000-0001-7267-9655","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-18T23:45:40.838485Z","pmid":"34546289","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":[]}