{"doi":"10.1101/2024.02.12.579964","title":"Proteolytic Cleavage of the ENaC γ Subunit – Impact Upon Na <sup>+</sup> and K <sup>+</sup> Handling","abstract":"ABSTRACT The ENaC gamma subunit is essential for homeostasis of Na + , K + , and body fluid. Dual subunit cleavage before and after a short inhibitory tract allows dissociation of this tract, increasing channel open probability (P O ), in vitro . Cleavage proximal to the tract occurs at a furin recognition sequence ( 143 RKRR 146 in mouse). Loss of furin-mediated cleavage prevents in vitro activation of the channel by proteolysis at distal sites. We hypothesized that 143 RKRR 146 mutation to 143 QQQQ 146 ( Q4 ) in 129/Sv mice would reduce ENaC P O , impair flow-stimulated flux of Na + (J Na ) and K + (J K ) in perfused collecting ducts, reduce colonic amiloride-sensitive short circuit current (I SC ), and impair Na + , K + , and body fluid homeostasis. Immunoblot of Q4/Q4 mouse kidney lysates confirmed loss of a band consistent in size with the furin-cleaved proteolytic fragment. However, Q4/Q4 male mice on a low Na + diet did not exhibit altered ENaC P O or flow-induced J Na , though flow-induced J K modestly decreased. Colonic amiloride-sensitive I SC in Q4/Q4 mice was not altered. Q4/Q4 males, but not females, exhibited mildly impaired fluid volume conservation when challenged with a low Na + diet. Blood Na + and K + were unchanged on a regular, low Na + , or high K + diet. These findings suggest that biochemical evidence of gamma subunit cleavage should not be used in isolation to evaluate ENaC activity. Further, factors independent of gamma subunit cleavage modulate channel P O and the influence of ENaC on Na + , K + , and fluid volume homeostasis in 129/Sv mice, in vivo .","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":494460,"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":0.9505,"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":520970,"name":"Andrew J. Nickerson","orcid":"0000-0001-7604-2344","position":1,"is_corresponding":false},{"id":356412,"name":"Shaohu Sheng","orcid":"0000-0002-7198-1702","position":2,"is_corresponding":false},{"id":356408,"name":"Rolando Carrisoza‐Gaytan","orcid":"0000-0001-8771-9269","position":3,"is_corresponding":false},{"id":1002007,"name":"Tracey Lam","orcid":null,"position":4,"is_corresponding":false},{"id":357576,"name":"Allison L. Marciszyn","orcid":null,"position":5,"is_corresponding":false},{"id":1129952,"name":"Lei Zhang","orcid":"0000-0003-4462-8572","position":6,"is_corresponding":false},{"id":1341229,"name":"Alexa Jordahl","orcid":null,"position":7,"is_corresponding":false},{"id":1341230,"name":"Chunming Bi","orcid":null,"position":8,"is_corresponding":false},{"id":812753,"name":"Aaliyah Winfrey","orcid":null,"position":9,"is_corresponding":false},{"id":1341231,"name":"Zhaohui Kou","orcid":null,"position":10,"is_corresponding":false},{"id":526579,"name":"Sébastien Gingras","orcid":"0000-0003-2607-8642","position":11,"is_corresponding":false},{"id":265986,"name":"Annet Kirabo","orcid":"0000-0001-8580-9359","position":12,"is_corresponding":false},{"id":356417,"name":"Lisa M. Satlin","orcid":"0000-0002-1744-1748","position":13,"is_corresponding":false},{"id":356418,"name":"Thomas R. Kleyman","orcid":"0000-0002-2413-5415","position":14,"is_corresponding":false},{"id":351626,"name":"Evan C. Ray","orcid":"0000-0003-1491-4869","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:09:11.736910Z","pmid":"38405735","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":[]}