{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:09:19Z","timestamp":1785431359492,"version":"3.56.0"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007899","name":"Doris Duke Charitable Foundation","doi-asserted-by":"publisher","award":["CDA-2123691-CDA39"],"award-info":[{"award-number":["CDA-2123691-CDA39"]}],"id":[{"id":"10.13039\/100007899","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007899","name":"Doris Duke Charitable Foundation","doi-asserted-by":"publisher","award":["2021263 (4258021\/FUTR1)"],"award-info":[{"award-number":["2021263 (4258021\/FUTR1)"]}],"id":[{"id":"10.13039\/100007899","id-type":"DOI","asserted-by":"publisher"}]},{"award":["CDA-2123691-CDA39"],"award-info":[{"award-number":["CDA-2123691-CDA39"]}],"id":[{"id":"https:\/\/ror.org\/04n65rp89","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2021263 (4258021\/FUTR1)"],"award-info":[{"award-number":["2021263 (4258021\/FUTR1)"]}],"id":[{"id":"https:\/\/ror.org\/04n65rp89","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Australian Government Research Training Program Scholarship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Primary aldosteronism (PA) is the most common cause of secondary hypertension and accounts for 5\u201315% of hypertensive patients. Familial hyperaldosteronism, a monogenic cause of PA, accounts for ~1\u20135% of cases. Familial hyperaldosteronism type III results from mutations in the KCNJ5 gene, which lead to excessive aldosterone production and hypertension due to dysfunction of the GIRK4 channel in the adrenal gland. Despite the importance of KCNJ5 in PA pathogenesis, little is known about the molecular mechanisms underlying germline KCNJ5 mutations and their functional consequences. This study explored the structural changes in KCNJ5 pathogenic variant c.452G&gt;A (p.Gly151Glu or GIRK4G151E). Homology modeling and molecular dynamics simulations of the mutant GIRK4 channel showed that structural rearrangements occur in GIRK4G151E when compared to GIRK4WT, displaying higher RMSD and SASA, which may be attributed to differences in residue fluctuations in the cytosolic and extracellular domains, and ligands may bind with a stronger affinity to GIRK4G151E. Given that the mutation is located within or proximal to the selectivity filter of GIRK4, we expect that the primary mechanism of dysfunction involves altered ion selectivity, leading to membrane depolarization. Our novel findings highlight the importance of understanding the molecular mechanisms underlying KCNJ5 mutations in PA and hypertension pathogenesis. This knowledge could inform the development of more targeted and effective treatments for this condition.<\/jats:p>","DOI":"10.3390\/molecules31111842","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T11:03:27Z","timestamp":1779879807000},"page":"1842","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanism of Mutation in G Protein-Gated Inwardly Rectifying K+ Channel in Familial Hyperaldosteronism-Type III: Residue Fluctuations and Conformational Instability"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5093-3405","authenticated-orcid":false,"given":"Asmaa S.","family":"AbuMaziad","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Nephrology, University of Arizona College of Medicine, Tucson, AZ 85724, USA"},{"name":"Thomas W. Keating Bioresearch Building, BIO5 Institute, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3031-3169","authenticated-orcid":false,"given":"Julia J.","family":"Liang","sequence":"additional","affiliation":[{"name":"EpiMed Centre, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia"},{"name":"Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Melbourne, VIC 3086, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex N. O.","family":"Logothetis","sequence":"additional","affiliation":[{"name":"EpiMed Centre, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia"},{"name":"Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Pitsillou","sequence":"additional","affiliation":[{"name":"EpiMed Centre, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia"},{"name":"School of Science, STEM College, RMIT University, Melbourne, VIC 3001, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3569-2951","authenticated-orcid":false,"given":"Andrew","family":"Hung","sequence":"additional","affiliation":[{"name":"School of Science, STEM College, RMIT University, Melbourne, VIC 3001, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Beck","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Nephrology, University of Arizona College of Medicine, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rissa","family":"Zudekoff","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Nephrology, University of Arizona College of Medicine, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Autri","family":"Hafezi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Nephrology, University of Arizona College of Medicine, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Chy","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Nephrology, University of Arizona College of Medicine, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Slack","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Nephrology, University of Arizona College of Medicine, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"AbdAssalam","family":"Qannus","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, University of Arizona Health Sciences, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7968-7375","authenticated-orcid":false,"given":"Assam","family":"El-Osta","sequence":"additional","affiliation":[{"name":"Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia"},{"name":"Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia"},{"name":"Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China"},{"name":"Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China"},{"name":"Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China"},{"name":"Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC 3010, Australia"},{"name":"Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9967-1546","authenticated-orcid":false,"given":"Tom C.","family":"Karagiannis","sequence":"additional","affiliation":[{"name":"EpiMed Centre, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia"},{"name":"Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Melbourne, VIC 3086, Australia"},{"name":"Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia"},{"name":"Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC 3010, Australia"},{"name":"Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1111\/j.1440-1681.1994.tb02519.x","article-title":"High incidence of primary aldosteronism in 199 patients referred with hypertension","volume":"21","author":"Gordon","year":"1994","journal-title":"Clin. 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