{"doi":"10.1016/j.jbc.2024.105759","title":"E3 ubiquitin ligase rififylin has yin and yang effects on rabbit cardiac transient outward potassium currents (Ito) and corresponding channel proteins","abstract":"Genome-wide association studies (GWAS) have reported a correlation between a single nucleotide polymorphism of the RING finger E3 ubiquitin protein ligase rififylin (RFFL) and QT interval variability in humans (Newton-Cheh et al., 2009). Previously, we have shown that RFFL down-regulates expression and function of the human-like ether-a-go-go-related gene (hERG) potassium channel and corresponding rapidly activating delayed rectifier potassium current ( I Kr ) in adult rabbit ventricular cardiomyocytes (ARbCMs). Here we report that RFFL also affects the transient outward current ( I to ), but in a peculiar way. RFFL overexpression in ARbCMs significantly decreases the contribution of its fast component ( I to,f ) from 35% to 21%, and increases the contribution of its slow component ( I to,s ) from 65% to 79%. Since I to,f in rabbits is mainly conducted by Kv4.3, we investigated the effect of RFFL on Kv4.3 expressed in HEK293A cells. We found that RFFL overexpression reduced Kv4.3 expression and corresponding I to,f in a RING domain-dependent manner in the presence or absence of its accessory subunit KChIP2. On the other hand, RFFL overexpression in Kv1.4-expressing HEK cells leads to an increase in both Kv1.4 expression level and I to,s , similarly in a RING domain-dependent manner. Our physiologically detailed rabbit ventricular myocyte computational model shows that these yin and yang effects of RFFL overexpression on I to,f, and I to,s affect phase 1 of the action potential waveform and slightly decrease its duration in addition to suppressing I Kr . Thus, RFFL modifies cardiac repolarization reserve via ubiquitination of multiple proteins that differently affect various potassium channels and cardiac action potential duration (APD).","journal":"Journal of Biological Chemistry","year":2024,"id":476340,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9628,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":386573,"name":"Karim Roder","orcid":null,"position":1,"is_corresponding":false},{"id":332045,"name":"Peter Bronk","orcid":"0000-0002-9067-2016","position":2,"is_corresponding":false},{"id":783670,"name":"Nilüfer N. Turan","orcid":"0000-0003-0710-1237","position":3,"is_corresponding":false},{"id":1313890,"name":"Saroj Dhakal","orcid":null,"position":4,"is_corresponding":false},{"id":1262800,"name":"Mingwang Zhong","orcid":"0000-0002-4263-8833","position":5,"is_corresponding":false},{"id":783668,"name":"Yichun Lu","orcid":"0000-0002-8475-8948","position":6,"is_corresponding":false},{"id":1313891,"name":"Zachary A. Zeltzer","orcid":null,"position":7,"is_corresponding":false},{"id":1224447,"name":"Yonatan Najman-Licht","orcid":null,"position":8,"is_corresponding":false},{"id":943453,"name":"Alain Karma","orcid":"0000-0001-7032-9862","position":9,"is_corresponding":false},{"id":332046,"name":"Gideon Koren","orcid":"0000-0002-9234-0875","position":10,"is_corresponding":false},{"id":404960,"name":"Anatoli Y. Kabakov","orcid":"0000-0003-2159-8462","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:06:25.428435Z","pmid":"38367666","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":[]}