{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:49:10Z","timestamp":1787168950130,"version":"build-2736575974"},"reference-count":40,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T00:00:00Z","timestamp":1731110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2024,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Inwardly rectifying potassium (Kir) channels play a pivotal role in physiology by establishing, maintaining, and regulating the resting membrane potential of the cells, particularly contributing to the cellular repolarization of many excitable cells. Dysfunction in Kir2.1 channels is implicated in several chronic and debilitating human diseases for which there are currently no effective treatments. Specifically, Kir2.1\u2010R312H and Kir2.1\u2010C154Y mutations are associated with Andersen\u2010Tawil syndrome (ATS) in humans. We have investigated the impact of these two mutants in the trafficking of the channel to the cell membrane and function in\n                    <jats:italic>Xenopus laevis<\/jats:italic>\n                    oocytes. Despite both mutations being trafficked to the cell membrane at different extents and capable of binding PIP\n                    <jats:sub>2<\/jats:sub>\n                    (phosphatidylinositol\u20104,5\u2010bisphosphate), the main modulator for channel activity, they resulted in defective channels that do not display K\n                    <jats:sup>+<\/jats:sup>\n                    current, albeit through different molecular mechanisms. Coexpression studies showed that R312H and C154Y are expressed and associated with the WT subunits. While WT subunits could rescue R312H dysfunction, the presence of a unique C154Y subunit disrupts the function of the entire complex, which is a typical feature of mutations with a dominant\u2010negative effect. Molecular dynamics simulations showed that Kir2.1\u2010C154Y mutation induces a loss in the structural plasticity of the selectivity filter, impairing the K\n                    <jats:sup>+<\/jats:sup>\n                    flow. In addition, the cryo\u2010EM structure of the Kir2.1\u2010R312H mutant has been reconstructed. This study identified the molecular mechanisms by which two ATS\u2010causing mutations impact Kir2.1 channel function and provide valuable insights that can guide potential strategies for the development of future therapeutic interventions for ATS.\n                  <\/jats:p>","DOI":"10.1096\/fj.202401567r","type":"journal-article","created":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T07:39:33Z","timestamp":1731137973000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Biochemical, biophysical, and structural investigations of two mutants (\n                    <scp>C154Y<\/scp>\n                    and\n                    <scp>R312H<\/scp>\n                    ) of the human Kir2.1 channel involved in the Andersen\u2010Tawil syndrome"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5778-3008","authenticated-orcid":false,"given":"Dania","family":"Zuniga","sequence":"first","affiliation":[{"name":"UMR 7590, CNRS, Mus\u00e9um National d'Histoire Naturelle, IRD, Institut de Min\u00e9ralogie, Physique des Mat\u00e9riaux et de Cosmochimie, IMPMC Sorbonne Universit\u00e9  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Zoumpoulakis","sequence":"additional","affiliation":[{"name":"UMR 7590, CNRS, Mus\u00e9um National d'Histoire Naturelle, IRD, Institut de Min\u00e9ralogie, Physique des Mat\u00e9riaux et de Cosmochimie, IMPMC Sorbonne Universit\u00e9  Paris France"},{"name":"Institut Pasteur Universit\u00e9 Paris Cit\u00e9, CNRS UMR 3571, Channel\u2010Receptors Unit  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael F.","family":"Veloso","sequence":"additional","affiliation":[{"name":"UMR 7590, CNRS, Mus\u00e9um National d'Histoire Naturelle, IRD, Institut de Min\u00e9ralogie, Physique des Mat\u00e9riaux et de Cosmochimie, IMPMC Sorbonne Universit\u00e9  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7992-1245","authenticated-orcid":false,"given":"Laurie","family":"Peverini","sequence":"additional","affiliation":[{"name":"Institut Pasteur Universit\u00e9 Paris Cit\u00e9, CNRS UMR 3571, Channel\u2010Receptors Unit  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Shi","sequence":"additional","affiliation":[{"name":"Institut Pasteur Universit\u00e9 Paris Cit\u00e9, CNRS UMR 3571, Channel\u2010Receptors Unit  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3938-2344","authenticated-orcid":false,"given":"Alexandre","family":"Pozza","sequence":"additional","affiliation":[{"name":"CNRS, UMR 7099, Laboratoire de Biochimie des Prot\u00e9ines Membranaires Institut de Biologie Physico\u2010Chimique, Universit\u00e9 Paris Cit\u00e9  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Kugler","sequence":"additional","affiliation":[{"name":"IMPReSs Facility, Biotechnology and Cell Signaling UMR 7242 CNRS\u2013University of Strasbourg  Illkirch Cedex France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1690-1757","authenticated-orcid":false,"given":"Fran\u00e7oise","family":"Bonnet\u00e9","sequence":"additional","affiliation":[{"name":"CNRS, UMR 7099, Laboratoire de Biochimie des Prot\u00e9ines Membranaires Institut de Biologie Physico\u2010Chimique, Universit\u00e9 Paris Cit\u00e9  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahar","family":"Bouceba","sequence":"additional","affiliation":[{"name":"Sorbonne University, CNRS, Institut de Biologie Paris\u2010Seine (IBPS), Protein Engineering Platform, Molecular Interaction Service Sorbonne University  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4249-9853","authenticated-orcid":false,"given":"Renaud","family":"Wagner","sequence":"additional","affiliation":[{"name":"IMPReSs Facility, Biotechnology and Cell Signaling UMR 7242 CNRS\u2013University of Strasbourg  Illkirch Cedex France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4770-430X","authenticated-orcid":false,"given":"Pierre\u2010Jean","family":"Corringer","sequence":"additional","affiliation":[{"name":"Institut Pasteur Universit\u00e9 Paris Cit\u00e9, CNRS UMR 3571, Channel\u2010Receptors Unit  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6515-6872","authenticated-orcid":false,"given":"Carlos A. 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