{"doi":"10.1085/jgp.202112969","title":"ML277 regulates KCNQ1 single-channel amplitudes and kinetics, modified by voltage sensor state","abstract":"<jats:p>KCNQ1 is a pore-forming K+ channel subunit critically important to cardiac repolarization at high heart rates. (2R)-N-[4-(4-methoxyphenyl)-2-thiazolyl]-1-[(4-methylphenyl)sulfonyl]-2 piperidinecarboxamide, or ML277, is an activator of this channel that rescues function of pathophysiologically important mutant channel complexes in human induced pluripotent stem cell–derived cardiomyocytes, and that therefore may have therapeutic potential. Here we extend our understanding of ML277 actions through cell-attached single-channel recordings of wild-type and mutant KCNQ1 channels with voltage sensor domains fixed in resting, intermediate, and activated states. ML277 has profound effects on KCNQ1 single-channel kinetics, eliminating the flickering nature of the openings, converting them to discrete opening bursts, and increasing their amplitudes approximately threefold. KCNQ1 single-channel behavior after ML277 treatment most resembles IO state-locked channels (E160R/R231E) rather than AO state channels (E160R/R237E), suggesting that at least during ML277 treatment, KCNQ1 does not frequently visit the AO state. Introduction of KCNE1 subunits reduces the effectiveness of ML277, but some enhancement of single-channel openings is still observed.</jats:p>","journal":"Journal of General Physiology","year":2021,"id":637411,"datarank":0.47670807455219194,"base_score":3.1780538303479458,"endowment":3.1780538303479458,"self_citation_contribution":0.47670807455219194,"citation_network_contribution":0.0,"self_endowment_contribution":0.47670807455219194,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1655062,"name":"Donald A. McAfee","orcid":"0000-0002-4109-9137","position":1,"is_corresponding":false},{"id":1428126,"name":"Ying Dou","orcid":"0000-0001-9037-6420","position":2,"is_corresponding":false},{"id":1655063,"name":"Yundi Wang","orcid":null,"position":3,"is_corresponding":false},{"id":303146,"name":"David Fedida","orcid":"0000-0001-6797-5185","position":4,"is_corresponding":false},{"id":1490318,"name":"Jodene Eldstrom","orcid":"0000-0002-7684-175X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"ML277 regulates KCNQ1 single-channel amplitudes and kinetics, modified by voltage sensor state","abstract":"<jats:p>KCNQ1 is a pore-forming K+ channel subunit critically important to cardiac repolarization at high heart rates. (2R)-N-[4-(4-methoxyphenyl)-2-thiazolyl]-1-[(4-methylphenyl)sulfonyl]-2 piperidinecarboxamide, or ML277, is an activator of this channel that rescues function of pathophysiologically important mutant channel complexes in human induced pluripotent stem cell–derived cardiomyocytes, and that therefore may have therapeutic potential. Here we extend our understanding of ML277 actions through cell-attached single-channel recordings of wild-type and mutant KCNQ1 channels with voltage sensor domains fixed in resting, intermediate, and activated states. ML277 has profound effects on KCNQ1 single-channel kinetics, eliminating the flickering nature of the openings, converting them to discrete opening bursts, and increasing their amplitudes approximately threefold. KCNQ1 single-channel behavior after ML277 treatment most resembles IO state-locked channels (E160R/R231E) rather than AO state channels (E160R/R237E), suggesting that at least during ML277 treatment, KCNQ1 does not frequently visit the AO state. Introduction of KCNE1 subunits reduces the effectiveness of ML277, but some enhancement of single-channel openings is still observed.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"34636894","pmcid":"PMC8515649","openalex_id":null,"authors":[],"funders":[{"funder_name":"Natural Sciences and Engineering Research Council of Canada","grant_id":"RGPIN-2016-05422","title":null},{"funder_name":"Canadian Institutes of Health Research","grant_id":"PJT-156181","title":null},{"funder_name":"Heart and Stroke Foundation of Canada","grant_id":"G17-0018392","title":null},{"funder_name":"Natural Sciences and Engineering Research Council of Canada","grant_id":"unidentified","title":"unidentified"}],"total_grants":4,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":"CC BY NC SA","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8515649","host_type":"repository"},{"url":"https://rupress.org/jgp/article-pdf/doi/10.1085/jgp.202112969/1805086/jgp_202112969.pdf","host_type":"publisher"},{"url":"https://europepmc.org/articles/PMC8515649","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC8515649?pdf=render","host_type":"Europe_PMC"},{"url":"https://doi.org/10.1085/jgp.202112969","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/34636894","host_type":""},{"url":"http://dx.doi.org/10.1085/jgp.202112969","host_type":""},{"url":"https://dx.doi.org/10.1085/jgp.202112969","host_type":""}],"fields_of_study":["0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":["Myocytes, Cardiac","Humans","Tosyl Compounds","Piperidines","Thiazoles","Potassium Channels, Voltage-Gated","Kinetics","KCNQ1 Potassium Channel","Induced Pluripotent Stem Cells"],"keywords":["Induced Pluripotent Stem Cells","Article","Tosyl Compounds","Kinetics","Thiazoles","Piperidines","Potassium Channels, Voltage-Gated","KCNQ1 Potassium Channel","Humans","Myocytes, Cardiac"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T18:53:57.908864Z","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":[]}