{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:35:09Z","timestamp":1791275709664,"version":"4.1.0"},"reference-count":26,"publisher":"National Academy of Sciences","issue":"10","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,3,6]]},"abstract":"<jats:p>\n                    Homeostasis of intravascular volume, Na\n                    <jats:sup>+<\/jats:sup>\n                    , Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    , and K\n                    <jats:sup>+<\/jats:sup>\n                    is interdependent and determined by the coordinated activities of structurally diverse mediators in the distal nephron and the distal colon. The behavior of these flux pathways is regulated by the renin\u2013angiotensin\u2013aldosterone system; however, the mechanisms that allow independent modulation of individual elements have been obscure. Previous work has shown that mutations in\n                    <jats:italic>WNK4<\/jats:italic>\n                    cause pseudohypoaldosteronism type II (PHAII), a disease featuring hypertension with hyperkalemia, due to altered activity of specific Na-Cl cotransporters, K\n                    <jats:sup>+<\/jats:sup>\n                    channels, and paracellular Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    flux mediators of the distal nephron. By coexpression studies in\n                    <jats:italic>Xenopus<\/jats:italic>\n                    oocytes, we now demonstrate that WNK4 also inhibits the epithelial Na\n                    <jats:sup>+<\/jats:sup>\n                    channel (ENaC), the major mediator of aldosterone-sensitive Na\n                    <jats:sup>+<\/jats:sup>\n                    (re)absorption, via a mechanism that is independent of WNK4's kinase activity. This inhibition requires intact C termini in ENaC \u03b2- and \u03b3-subunits, which contain PY motifs used to target ENaC for clearance from the plasma membrane. Importantly, PHAII-causing mutations eliminate WNK4's inhibition of ENaC, thereby paralleling other effects of PHAII to increase sodium balance. The relevance of these findings\n                    <jats:italic>in vivo<\/jats:italic>\n                    was studied in mice harboring PHAII-mutant WNK4. The colonic epithelium of these mice demonstrates markedly increased amiloride-sensitive Na\n                    <jats:sup>+<\/jats:sup>\n                    flux compared with wild-type littermates. These studies identify ENaC as a previously unrecognized downstream target of WNK4 and demonstrate a functional role for WNK4 in the regulation of colonic Na\n                    <jats:sup>+<\/jats:sup>\n                    absorption. These findings support a key role for WNK4 in coordinating the activities of diverse flux pathways to achieve integrated fluid and electrolyte homeostasis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0611727104","type":"journal-article","created":{"date-parts":[[2007,2,26]],"date-time":"2007-02-26T20:44:09Z","timestamp":1172522649000},"page":"4020-4024","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":122,"title":["WNK4 regulates activity of the epithelial Na\n                    <sup>+<\/sup>\n                    channel\n                    <i>in vitro<\/i>\n                    and\n                    <i>in vivo<\/i>"],"prefix":"10.1073","volume":"104","author":[{"given":"Aaron M.","family":"Ring","sequence":"first","affiliation":[{"name":"*Departments of Genetics, Medicine, and Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam X.","family":"Cheng","sequence":"additional","affiliation":[{"name":"Departments of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Leng","sequence":"additional","affiliation":[{"name":"Departments of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristopher T.","family":"Kahle","sequence":"additional","affiliation":[{"name":"*Departments of Genetics, Medicine, and Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and"},{"name":"Departments of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse","family":"Rinehart","sequence":"additional","affiliation":[{"name":"*Departments of Genetics, Medicine, and Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria D.","family":"Lalioti","sequence":"additional","affiliation":[{"name":"*Departments of Genetics, Medicine, and Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather M.","family":"Volkman","sequence":"additional","affiliation":[{"name":"*Departments of Genetics, Medicine, and Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick H.","family":"Wilson","sequence":"additional","affiliation":[{"name":"*Departments of Genetics, Medicine, and Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven C.","family":"Hebert","sequence":"additional","affiliation":[{"name":"Departments of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard P.","family":"Lifton","sequence":"additional","affiliation":[{"name":"*Departments of Genetics, Medicine, and Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2007,3,6]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/969"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00026.2001"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00241-0"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1043-2760(01)00439-8"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.00-0191com"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.24.7052"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2005.02.012"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1062844"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.242735399"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI17443"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1271"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0306924101"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0406172101"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1877"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.41.25537"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90250-X"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0995-76"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118606"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb00594.x"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.12.5699"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.25.11495"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308434100"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00364.2003"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611728104"},{"key":"e_1_3_4_25_2","first-page":"G133","volume":"248","author":"Will PC","year":"1985","unstructured":"PC Will, RN Cortright, RG Groseclose, U Hopfer Am J Physiol 248, G133\u2013G141 (1985).","journal-title":"Am J Physiol"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602996103"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0611727104","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T15:06:59Z","timestamp":1649776019000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0611727104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,3,6]]},"references-count":26,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2007,3,6]]}},"alternative-id":["10.1073\/pnas.0611727104"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0611727104","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1068849.521787","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,3,6]]},"assertion":[{"value":"2006-12-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2007-03-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}