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In this study, we have shown that aminoglycosides also inhibit the activity of Kir4.1 channels. Aminoglycosides inhibit Kir4.1 channels by a pore\u2010blocking mechanism, plugging the central vestibule of the channel.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Patch\u2010clamp recordings were made in HEK\u2010293 cells transiently expressing Kir4.1 channels to analyse the effects of gentamicin, neomycin and kanamycin. <jats:italic>In silico<\/jats:italic> modelling followed by mutagenesis were realized to identify the residues critical for aminoglycosides binding to Kir4.1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Aminoglycoside antibiotics block Kir4.1 channels in a concentration\u2010 and voltage\u2010dependent manner, getting access to the protein from the intracellular side of the plasma membrane. Aminoglycosides block Ki4.1 with a rank order of potency as follows: gentamicin \u02c3 neomycin \u02c3 kanamycin. The residues T128 and principally E158, facing the central cavity of Kir4.1, are important structural determinants for aminoglycosides binding to the channel, as determined by our <jats:italic>in silico<\/jats:italic> modelling and confirmed by mutagenesis experiments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Kir4.1 channels are also target of aminoglycoside antibiotics, which could affect potassium transport in several tissues.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15214","type":"journal-article","created":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T18:33:50Z","timestamp":1596047630000},"page":"4548-4560","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["<i>In vitro<\/i> and <i>in silico<\/i> characterization of the inhibition of Kir4.1 channels by aminoglycoside antibiotics"],"prefix":"10.1111","volume":"177","author":[{"given":"Rita","family":"Mor\u00e1n\u2010Zendejas","sequence":"first","affiliation":[{"name":"Departamento de Fisiolog\u00eda y Biof\u00edsica, Facultad de Medicina Universidad Aut\u00f3noma de San Luis Potos\u00ed  San Luis Potos\u00ed Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayra","family":"Delgado\u2010Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda y Biof\u00edsica, Facultad de Medicina Universidad Aut\u00f3noma de San Luis Potos\u00ed  San Luis Potos\u00ed Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Xu","sequence":"additional","affiliation":[{"name":"Jiangsu Province Key Laboratory of Anesthesiology Xuzhou Medical University  Xuzhou China"},{"name":"Department of Pharmaceutical Sciences Northeastern University  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belkis","family":"Vald\u00e9s\u2010Abad\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda y Biof\u00edsica, Facultad de Medicina Universidad Aut\u00f3noma de San Luis Potos\u00ed  San Luis Potos\u00ed Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iv\u00e1n A.","family":"Ar\u00e9chiga\u2010Figueroa","sequence":"additional","affiliation":[{"name":"CONACyT, Facultad de Medicina Universidad Aut\u00f3noma de San Luis Potos\u00ed  San Luis Potos\u00ed Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Northeastern University  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7501-8836","authenticated-orcid":false,"given":"Aldo A.","family":"Rodr\u00edguez\u2010Menchaca","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda y Biof\u00edsica, Facultad de Medicina Universidad Aut\u00f3noma de San Luis Potos\u00ed  San Luis Potos\u00ed Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,8,17]]},"reference":[{"issue":"1","key":"e_1_2_11_2_1","first-page":"S142","article-title":"The concise guide to pharmacology 2019\/20: Ion channels","volume":"176","author":"Alexander S. 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