{"doi":"10.1111/bph.15676","title":"Subtype‐selective positive modulation of K<sub>Ca</sub>2 channels depends on the HA/HB helices","abstract":"Background and Purpose In the activated state of small‐conductance Ca 2+ ‐activated potassium (K Ca 2) channels, calmodulin interacts with the HA/HB helices and the S4‐S5 linker. CyPPA potentiates K Ca 2.2a and K Ca 2.3 channel activity but not the K Ca 2.1 and K Ca 3.1 subtypes. Experimental Approach Site‐directed mutagenesis, patch‐clamp recordings and in silico modelling were utilised to explore the structural determinants for the subtype‐selective modulation of K Ca 2 channels by CyPPA. Key Results Mutating residues in the HA (V420) and HB (K467) helices of K Ca 2.2a channels to their equivalent residues in K Ca 3.1 channels diminished the potency of CyPPA. CyPPA elicited prominent responses on mutant K Ca 3.1 channels with an arginine residue in the HB helix substituted for its equivalent lysine residue in the K Ca 2.2a channels (R355K). K Ca 2.1 channels harbouring a three‐amino‐acid insertion upstream of the cognate R438 residues in the HB helix showed no response to CyPPA, whereas the deletion mutant (K Ca 2.1_ΔA434/Q435/K436) became sensitive to CyPPA. In molecular dynamics simulations, CyPPA docked between calmodulin C‐lobe and the HA/HB helices widens the cytoplasmic gate of K Ca 2.2a channels. Conclusion and Implications Selectivity of CyPPA among K Ca 2 and K Ca 3.1 channel subtypes relies on the HA/HB helices.","journal":"British Journal of Pharmacology","year":2021,"id":189356,"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":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9656,"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":409994,"name":"Meng Cui","orcid":"0000-0002-3895-135X","position":1,"is_corresponding":false},{"id":734100,"name":"Naglaa Salem El‐Sayed","orcid":"0000-0001-8687-2325","position":2,"is_corresponding":false},{"id":409995,"name":"Razan Orfali","orcid":"0000-0002-0584-4013","position":3,"is_corresponding":false},{"id":410758,"name":"Misa Nguyen","orcid":null,"position":4,"is_corresponding":false},{"id":631958,"name":"Grace Yang","orcid":"0000-0001-8346-908X","position":5,"is_corresponding":false},{"id":751927,"name":"Mohammad Asikur Rahman","orcid":"0000-0002-0411-5417","position":6,"is_corresponding":false},{"id":751928,"name":"Judy Lee","orcid":"0000-0001-5808-2983","position":7,"is_corresponding":false},{"id":410000,"name":"Miao Zhang","orcid":"0000-0002-3099-155X","position":8,"is_corresponding":false},{"id":409993,"name":"Youngwoo Nam","orcid":"0000-0001-5936-1124","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-18T23:49:18.604374Z","pmid":"34458981","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":[]}