{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T12:59:16Z","timestamp":1790341156300,"version":"4.1.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      G-proteins areindispensable regulators of cellular signaling, with G-protein-gated inwardly rectifying potassium channels (GIRK) as key effectors.\n                      <jats:italic>GNB1<\/jats:italic>\n                      encephalopathy (GNB1E) is a congenital neurological syndrome resulting from mutations in the GNB1 gene, encoding the G\u03b2\n                      <jats:sub>1<\/jats:sub>\n                      subunit of G-proteins trimer (G\u03b1\u03b2\u03b3). GNB1E manifests as a global developmental delay, accompanied by tonus disturbances, ataxia, and epilepsy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We utilized the\n                      <jats:italic>Xenopus laevis<\/jats:italic>\n                      oocyte heterologous expression system to investigate the impact of the L95P mutation in G\u03b2\n                      <jats:sub>1<\/jats:sub>\n                      (G\u03b2\n                      <jats:sub>1<\/jats:sub>\n                      -L95P) on the activation of neuronal GIRK channels GIRK2 and GIRK1\/2. Mutant and wild-type (WT) G\u03b2\n                      <jats:sub>1<\/jats:sub>\n                      RNAs were co-injected with RNAs encoding the G\u03b3\n                      <jats:sub>2<\/jats:sub>\n                      and GIRK channel subunits. The expression levels of both G\u03b2\n                      <jats:sub>1<\/jats:sub>\n                      and the channel proteins, as well as the channel activity, were systematically monitored. Additionally, rigid-body docking was used to model the GIRK1\/2\u2013G\u03b2\u03b3 complex, evaluating L95P\u2019s effect on channel\u2013G\u03b2\u03b3 interaction, G\u03b2\u03b3 stability, and G\u03b2\u03b3\u2013effector affinity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      . G\u03b2\n                      <jats:sub>1<\/jats:sub>\n                      -L95P exhibited reduced protein expression compared to WT. Even after RNA adjustments to restore comparable membrane localization, the mutant failed to effectively activate GIRK2 and GIRK1\/2. Structural analysis revealed that L95 was not consistent in the G\u03b2\u03b3\u2013effector interface. Thermodynamic calculations suggested that the mutation primarily destabilized G\u03b2\n                      <jats:sub>1<\/jats:sub>\n                      and G\u03b2\n                      <jats:sub>1<\/jats:sub>\n                      \u2013effector complex.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      G\u03b2\n                      <jats:sub>1<\/jats:sub>\n                      -L95P leads to both reduced protein expression and impaired function in the GIRK\u2013G\u03b2\u03b3 interaction system. The later effect can be attributed to the changes associated with protein misfolding.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1592012","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T01:36:57Z","timestamp":1746754617000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Loss of expression and function of G\u03b2\u03b3 by GNB1 encephalopathy-associated L95P mutation of the G\u03b21 subunit"],"prefix":"10.3389","volume":"16","author":[{"given":"Haritha P.","family":"Reddy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tal","family":"Keren-Raifman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galit","family":"Tabak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Dascal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Yakubovich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"W344","DOI":"10.1093\/nar\/gkw408","article-title":"ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules","volume":"44","author":"Ashkenazy","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"B2","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1002\/ajmg.a.40472","article-title":"Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature","volume":"176","author":"Bassan","year":"2018","journal-title":"Am. 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