{"doi":"10.3389/fphys.2022.903050","title":"Two small-molecule activators share similar effector sites in the KCNQ1 channel pore but have distinct effects on voltage sensor movements","abstract":"ML277 and R-L3 are two small-molecule activators of KCNQ1, the pore-forming subunit of the slowly activating potassium channel I Ks . KCNQ1 loss-of-function mutations prolong cardiac action potential duration and are associated with long QT syndrome, which predispose patients to lethal ventricular arrhythmia. ML277 and R-L3 enhance KCNQ1 current amplitude and slow deactivation. However, the presence of KCNE1, an auxiliary subunit of I Ks channels, renders the channel insensitive to both activators. We found that ML277 effects are dependent on several residues in the KCNQ1 pore domain. Some of these residues are also necessary for R-L3 effects. These residues form a putative hydrophobic pocket located between two adjacent KCNQ1 subunits, where KCNE1 subunits are thought to dwell, thus providing an explanation for how KCNE1 renders the I Ks channel insensitive to these activators. Our experiments showed that the effect of R-L3 on voltage sensor movement during channel deactivation was much more prominent than that of ML277. Simulations using a KCNQ1 kinetic model showed that the effects of ML277 and R-L3 could be reproduced through two different effects on channel gating: ML277 enhances KCNQ1 channel function through a pore-dependent and voltage sensor–independent mechanism, while R-L3 affects both channel pore and voltage sensor.","journal":"Frontiers in Physiology","year":2022,"id":276799,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":947371,"name":"Gary Peng","orcid":"0000-0002-9072-7187","position":1,"is_corresponding":false},{"id":947372,"name":"Thomas W. Comollo","orcid":"0000-0001-5634-2163","position":2,"is_corresponding":false},{"id":947766,"name":"Xinle Zou","orcid":null,"position":3,"is_corresponding":false},{"id":352594,"name":"Kevin J. Sampson","orcid":"0000-0003-3484-8010","position":4,"is_corresponding":false},{"id":305881,"name":"H. Peter Larsson","orcid":"0000-0002-1688-2525","position":5,"is_corresponding":false},{"id":352598,"name":"Robert S. Kass","orcid":"0000-0003-4377-3874","position":6,"is_corresponding":false},{"id":263721,"name":"Lei Chen","orcid":"0000-0002-9327-1621","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-19T00:28:30.709588Z","pmid":"35957984","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":[]}