{"doi":"10.1085/jgp.202513817","title":"A critical residue mediates proper assembly and gating of GIRK2 channels","abstract":"G protein-gated inwardly rectifying potassium (GIRK) channels mediate membrane hyperpolarization in response to G protein-coupled receptor activation and are critical for regulating neuronal excitability. The membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) is essential for regulating the large family of inward rectifiers, and disruptions in PIP2 interactions contribute to some neurological diseases. Structural analyses have identified arginine-92 (R92) in GIRK2 as a key amino acid interacting with PIP2 as well as the potentiator cholesteryl hemisuccinate (CHS). Using electrophysiological assays and fluorescent K+ flux measurements, we show that substitutions at R92 (F, Y, or Q) disrupt PIP2 regulation, as well as G protein and alcohol activation. Cryo-EM structures of R92F and R92Q show an unexpected change in the orientation of the slide helix that leads to a \"domain swap\" between adjacent subunits in the cytoplasmic domain, producing a unique arrangement of the alcohol-binding pocket and G protein-interacting domain. These findings indicate that R92 plays a crucial role in how GIRK2 channel subunits assemble for physiological gating, and likely extend to gating of most inward rectifiers due to the high conservation of arginine in that location.","journal":"The Journal of General Physiology","year":2025,"id":537621,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9441,"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":830066,"name":"Jonathan Mount","orcid":"0000-0001-5366-0449","position":1,"is_corresponding":false},{"id":875277,"name":"Keino Hutchinson","orcid":"0000-0001-7492-6365","position":2,"is_corresponding":false},{"id":1423407,"name":"Yihan Zhao","orcid":"0000-0002-7603-0498","position":3,"is_corresponding":false},{"id":1017986,"name":"Yulin Zhao","orcid":"0000-0003-1292-8618","position":4,"is_corresponding":false},{"id":338841,"name":"Ian W. Glaaser","orcid":"0000-0003-2478-6602","position":5,"is_corresponding":false},{"id":506037,"name":"Peng Yuan","orcid":"0000-0002-5660-225X","position":6,"is_corresponding":false},{"id":2333,"name":"Avner Schlessinger","orcid":"0000-0003-4007-7814","position":7,"is_corresponding":false},{"id":244535,"name":"Paul A. Slesinger","orcid":"0000-0002-3868-7528","position":8,"is_corresponding":false},{"id":1380872,"name":"Ha Nguyen","orcid":"0000-0003-0012-8381","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T02:52:12.997494Z","pmid":"41417002","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":[]}