{"doi":"10.1101/2025.06.08.658478","title":"Mechanisms of KCNQ1 gating modulation by KCNE1/3 for cell-specific function","abstract":"Abstract KCNQ1 potassium channels are essential for physiological processes such as cardiac rhythm and intestinal chloride secretion. KCNE-family subunits (KCNE1-5) associate with KCNQ1, conferring distinct properties across various tissues. KCNQ1 activation requires membrane depolarization and phosphatidylinositol 4,5-bisphosphate (PIP2) whose cellular levels are controlled by Gαq-coupled GPCR activation. While modulation of KCNQ1’s voltage-dependent activation by KCNE1/3 is well-characterized, their effects on PIP2-dependent gating of KCNQ1 via GPCR signaling remain less understood. Here we resolved structures of KCNQ1–KCNE1 and reassessed reported KCNQ1-KCNE3 structures with and without PIP2. We revealed that KCNQ1–KCNE1/3 complexes feature two PIP2-binding sites, with KCNE1/3 contributing to a previously overlooked, uncharacterized site involving residues critical for voltage sensor and pore domain coupling. Via this site, KCNE1 and KCNE3 distinctly modulate the PIP2-dependent gating, in addition to the voltage sensitivity, of KCNQ1. Consequently, KCNE3 converts KCNQ1 into a voltage-insensitive PIP2-gated channel governed by GPCR signaling to maintain ion homeostasis in non-excitable cells. KCNE1, by significantly enhancing KCNQ1’s PIP2 affinity and resistance to GPCR regulation, forms predominantly voltage-gated channels with KCNQ1 for conducting the slow-delayed rectifier current in excitable cardiac cells. Our study highlights how KCNE1/3 modulates KCNQ1 gating in different cellular contexts, providing insights for tissue-specifically targeting multi-functional channels.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":567750,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9496,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1471999,"name":"Lu Zhao","orcid":"0009-0005-4390-6456","position":1,"is_corresponding":false},{"id":347893,"name":"Ali A. Kermani","orcid":"0000-0002-4994-9730","position":2,"is_corresponding":false},{"id":1472321,"name":"Shuzong Du","orcid":null,"position":3,"is_corresponding":false},{"id":708539,"name":"Tanadet Pipatpolkai","orcid":"0000-0001-5396-4784","position":4,"is_corresponding":false},{"id":1033792,"name":"Meiqin Jiang","orcid":null,"position":5,"is_corresponding":false},{"id":267226,"name":"Sagar Chittori","orcid":"0000-0003-1417-6552","position":6,"is_corresponding":false},{"id":355442,"name":"Yong Zi Tan","orcid":"0000-0001-6656-6320","position":7,"is_corresponding":false},{"id":321392,"name":"Jingyi Shi","orcid":"0009-0009-5119-8540","position":8,"is_corresponding":false},{"id":561638,"name":"Lucie Delemotte","orcid":"0000-0002-0828-3899","position":9,"is_corresponding":false},{"id":321395,"name":"Jianmin Cui","orcid":"0000-0002-9198-6332","position":10,"is_corresponding":false},{"id":7161,"name":"Ji Sun","orcid":"0000-0002-9302-3177","position":11,"is_corresponding":false},{"id":1225407,"name":"Chenxi Cui","orcid":null,"position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-19T02:56:48.183032Z","pmid":"40661515","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":[]}