{"doi":"10.7554/elife.85773","title":"Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues","abstract":"Voltage-gated potassium (K V ) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K V channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore K V channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of K V channel activators with potential applications in the treatment of arrhythmogenic disorders such as long QT syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac I Ks channel – a tetrameric potassium channel complex formed by K V 7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac I Ks channel, and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the I Ks channel by generating modified aromatic head groups designed to probe cation–pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the I Ks channel through cation–pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.","journal":"eLife","year":2023,"id":344568,"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":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9447,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":392128,"name":"Jessica J. Jowais","orcid":"0000-0002-6716-1787","position":1,"is_corresponding":false},{"id":1084032,"name":"Leif Nyberg","orcid":null,"position":2,"is_corresponding":false},{"id":1083389,"name":"Vanessa Olivier-Meo","orcid":"0009-0006-3365-2365","position":3,"is_corresponding":false},{"id":614432,"name":"Valentina Corradi","orcid":"0000-0001-6546-9780","position":4,"is_corresponding":false},{"id":71810,"name":"D. Peter Tieleman","orcid":"0000-0001-5507-0688","position":5,"is_corresponding":false},{"id":392130,"name":"Sara I. Liin","orcid":"0000-0001-8493-0114","position":6,"is_corresponding":false},{"id":305881,"name":"H. Peter Larsson","orcid":"0000-0002-1688-2525","position":7,"is_corresponding":false},{"id":392126,"name":"Briana M Bohannon","orcid":"0000-0002-3720-1477","position":0,"is_corresponding":true}],"reference_count":32,"raw_metadata":null,"created_at":"2026-07-19T01:11:35.133818Z","pmid":"37350568","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":[]}