{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T10:08:42Z","timestamp":1782122922487,"version":"3.54.5"},"reference-count":55,"publisher":"American Physiological Society","issue":"6","funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["17SDG33661117"],"award-info":[{"award-number":["17SDG33661117"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["14SDG18650010"],"award-info":[{"award-number":["14SDG18650010"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["HL-137004"],"award-info":[{"award-number":["HL-137004"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2020,12,1]]},"abstract":"<jats:p> We have reported that the reduction in plasma membrane cholesterol could decrease cellular Na\/K-ATPase \u03b11-expression through a Src-dependent pathway. However, it is unclear whether cholesterol could regulate other Na\/K-ATPase \u03b1-isoforms and the molecular mechanisms of this regulation are not fully understood. Here we used cells expressing different Na\/K-ATPase \u03b1 isoforms and found that membrane cholesterol reduction by U18666A decreased expression of the \u03b11-isoform but not the \u03b12- or \u03b13-isoform. Imaging analyses showed the cellular redistribution of \u03b11 and \u03b13 but not \u03b12. Moreover, U18666A led to redistribution of \u03b11 to late endosomes\/lysosomes, while the proteasome inhibitor blocked \u03b11-reduction by U18666A. These results suggest that the regulation of the Na\/K-ATPase \u03b1-subunit by cholesterol is isoform specific and \u03b11 is unique in this regulation through the endocytosis-proteasome pathway. Mechanistically, loss-of-Src binding mutation of A425P in \u03b11 lost its capacity for regulation by cholesterol. Meanwhile, gain-of-Src binding mutations in \u03b12 partially restored the regulation. Furthermore, through studies in caveolin-1 knockdown cells, as well as subcellular distribution studies in cell lines with different \u03b1-isoforms, we found that Na\/K-ATPase, Src, and caveolin-1 worked together for the cholesterol regulation. Taken together, these new findings reveal that the putative Src-binding domain and the intact Na\/K-ATPase\/Src\/caveolin-1 complex are indispensable for the isoform-specific regulation of Na\/K-ATPase by cholesterol. <\/jats:p>","DOI":"10.1152\/ajpcell.00083.2020","type":"journal-article","created":{"date-parts":[[2020,9,30]],"date-time":"2020-09-30T19:09:43Z","timestamp":1601492983000},"page":"C1107-C1119","source":"Crossref","is-referenced-by-count":17,"title":["Regulation of Na\/K-ATPase expression by cholesterol: isoform specificity and the molecular mechanism"],"prefix":"10.1152","volume":"319","author":[{"given":"Jue","family":"Zhang","sequence":"first","affiliation":[{"name":"Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia"},{"name":"Blood Research Institute, Versiti, Milwaukee, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Larre","sequence":"additional","affiliation":[{"name":"Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabhatchandra R.","family":"Dube","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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