{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T02:17:17Z","timestamp":1789179437233,"version":"build-2803163510"},"reference-count":29,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2006,2,17]],"date-time":"2006-02-17T00:00:00Z","timestamp":1140134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2006,3]]},"abstract":"<jats:p>The serine\u2013threonine kinase WNK3 modulates Cl<jats:sup>\u2212<\/jats:sup> transport into and out of cells through its regulation of <jats:italic>SLC12A<\/jats:italic> cation\u2013Cl<jats:sup>\u2212<\/jats:sup> cotransporters, implicating it as (one of) the long\u2010sought Cl<jats:sup>\u2212<\/jats:sup>\/volume\u2010sensitive kinase(s). Integrators in homeostatic systems regulate structurally diverse but functionally coupled elements. For example, the related kinase WNK4 regulates the Na<jats:sup>+<\/jats:sup>\u2013Cl<jats:sup>\u2212<\/jats:sup> cotransporter (NCC), paracellular Cl<jats:sup>\u2212<\/jats:sup> flux, and the K<jats:sup>+<\/jats:sup> channel ROMK1 (Kir1.1) to maintain renal NaCl and K<jats:sup>+<\/jats:sup> homeostasis; mutations in <jats:italic>PRKWNK4<\/jats:italic>, encoding WNK4, cause a Mendelian disease featuring hypertension and hyperkalaemia. It is known that WNK3 is expressed in the nephron's distal convoluted tubule (DCT) and stimulates NCC activity. Here, we show that WNK3 is also expressed in cortical and outer medullary collecting duct principal cells. Accordingly, we tested WNK3's effect on the mediators of NaCl and K<jats:sup>+<\/jats:sup> handling in these nephron segments \u2013 the epithelial sodium channel (ENaC), paracellular Cl<jats:sup>\u2212<\/jats:sup> flux, and ROMK1 \u2013 using established model systems. WNK3 did not alter paracellular Cl<jats:sup>\u2212<\/jats:sup> flux in tetracycline\u2010responsive MDCK II cells, nor affect amiloride\u2010sensitive currents when coexpressed with ENaC in <jats:italic>Xenopus laevis<\/jats:italic> oocytes. However, additional coexpression studies in oocytes revealed WNK3 inhibited the renal\u2010specific K<jats:sup>+<\/jats:sup> channel ROMK1 activity greater than 5.5\u2010fold (<jats:italic>P<\/jats:italic> &lt; 0.0001) by altering its plasmalemmal surface expression; WNK3 did not affect ROMK1's conductance or open\/closed probability. In contrast, WNK3 had no effect on the activity of the cardiac long\u2010QT syndrome K<jats:sup>+<\/jats:sup> channel KCNQ1\/KCNE1 when coexpressed in oocytes. Inhibition of ROMK1 is independent of WNK3's catalytic activity and is mediated by WNK3's carboxyl terminus \u2013 a mechanism distinct from its known kinase\u2010dependent activation of NCC. A kinase\u2010inactivating point mutation or a missense mutation homologous to one in WNK4 that causes disease produced a gain\u2010of\u2010function effect, enhancing WNK3's inhibition of ROMK1 greater than 2.5\u2010fold relative to wild\u2010type kinase (<jats:italic>P<\/jats:italic> &lt; 0.0001). The magnitude and specificity of WNK3's effects at both NCC and ROMK1, its coexpression with its targets in the distal nephron, and the established <jats:italic>in vivo<\/jats:italic> effect of WNK4 at these same targets provide evidence that WNK3's action is physiologically relevant. WNK3 is probably a component of one of the mechanisms that determines the balance between renal NaCl reabsorption and K<jats:sup>+<\/jats:sup> secretion.<\/jats:p>","DOI":"10.1113\/jphysiol.2005.102202","type":"journal-article","created":{"date-parts":[[2005,12,16]],"date-time":"2005-12-16T01:14:23Z","timestamp":1134695663000},"page":"275-286","source":"Crossref","is-referenced-by-count":63,"title":["WNK3, a kinase related to genes mutated in hereditary hypertension with hyperkalaemia, regulates the K<sup>+<\/sup> channel ROMK1 (Kir1.1)"],"prefix":"10.1113","volume":"571","author":[{"given":"Qiang","family":"Leng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristopher T.","family":"Kahle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse","family":"Rinehart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon G.","family":"MacGregor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick H.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia M.","family":"Canessa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard P.","family":"Lifton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven C.","family":"Hebert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,2,17]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.242728499"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-002-0993-8"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00037.2005"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000174326.96918.d6"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00051.2003"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308434100"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0406172101"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0508307102"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1271"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00243-4"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M502598200"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00241-0"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2004.04.014"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408146101"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504332102"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0508303102"},{"key":"e_1_2_5_18_1","volume-title":"The 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