{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:42:57Z","timestamp":1781106177743,"version":"3.54.1"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"32","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2004,8,10]]},"abstract":"<jats:p>\n                    Epithelial Na\n                    <jats:sup>+<\/jats:sup>\n                    channels mediate the transport of Na across epithelia in the kidney, gut, and lungs and are required for blood pressure regulation. They are inhibited by ubiquitin protein ligases, such as Nedd4 and Nedd4-2, with loss of this inhibition leading to hypertension. Here, we report that these channels are maintained in the active state by the G protein-coupled receptor kinase, Grk2, which has been previously implicated in the development of essential hypertension. We also show that Grk2 phosphorylates the C terminus of the channel \u03b2 subunit and renders the channels insensitive to inhibition by Nedd4-2. This mechanism has not been previously reported to regulate epithelial Na\n                    <jats:sup>+<\/jats:sup>\n                    channels and provides a potential explanation for the observed association of Grk2 overactivity with hypertension. Here, we report a G protein-coupled receptor kinase regulating a membrane protein other than a receptor and provide a paradigm for understanding how the interaction between membrane proteins and ubiquitin protein ligases is controlled.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0402178101","type":"journal-article","created":{"date-parts":[[2004,7,29]],"date-time":"2004-07-29T20:23:41Z","timestamp":1091132621000},"page":"11886-11890","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":71,"title":["The kinase Grk2 regulates Nedd4\/Nedd4-2-dependent control of epithelial Na\n                    <sup>+<\/sup>\n                    channels"],"prefix":"10.1073","volume":"101","author":[{"given":"Anuwat","family":"Dinudom","sequence":"first","affiliation":[{"name":"Department of Physiology, University of Sydney, Sydney NSW 2006, Australia; Hanson Institute, Institute of Medical and Veterinary Science, Frome Road, Adelaide SA 5000, Australia; Department of Medicine, University of Adelaide, Adelaide SA 5000, Australia; and Departments of Medicine and Biochemistry and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew B.","family":"Fotia","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Sydney, Sydney NSW 2006, Australia; Hanson Institute, Institute of Medical and Veterinary Science, Frome Road, Adelaide SA 5000, Australia; Department of Medicine, University of Adelaide, Adelaide SA 5000, Australia; and Departments of Medicine and Biochemistry and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Lefkowitz","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Sydney, Sydney NSW 2006, Australia; Hanson Institute, Institute of Medical and Veterinary Science, Frome Road, Adelaide SA 5000, Australia; Department of Medicine, University of Adelaide, Adelaide SA 5000, Australia; and Departments of Medicine and Biochemistry and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Sydney, Sydney NSW 2006, Australia; Hanson Institute, Institute of Medical and Veterinary Science, Frome Road, Adelaide SA 5000, Australia; Department of Medicine, University of Adelaide, Adelaide SA 5000, Australia; and Departments of Medicine and Biochemistry and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharad","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Sydney, Sydney NSW 2006, Australia; Hanson Institute, Institute of Medical and Veterinary Science, Frome Road, Adelaide SA 5000, Australia; Department of Medicine, University of Adelaide, Adelaide SA 5000, Australia; and Departments of Medicine and Biochemistry and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David I.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Sydney, Sydney NSW 2006, Australia; Hanson Institute, Institute of Medical and Veterinary Science, Frome Road, Adelaide SA 5000, Australia; Department of Medicine, University of Adelaide, Adelaide SA 5000, Australia; and Departments of Medicine and Biochemistry and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2004,7,29]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.127.6.1907"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.64.082101.143243"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81724-9"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90212-0"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1028"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80284-1"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.4.1732"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.21.11710"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199907153410304"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/367463a0"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb00593.x"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.12.7169"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.00-0191com"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C100623200"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02-0497fje"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C000906200"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI2837"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.21.6325"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.41.25537"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb00594.x"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.6.3301"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00011.2002"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.61.4.707"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1996.4582"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1082348"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.49.34531"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1033.2002.03154.x"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M011273200"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(01)02404-8"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3510095"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0134224100"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)83486-X"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.18.12525"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(00)01538-8"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2002.00525.x"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.35.1.38"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.61.4.749"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.01.150"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(00)01098-X"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M010642200"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.24.7052"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00837-4"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.67.1.653"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0402178101","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T09:20:05Z","timestamp":1649755205000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0402178101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,7,29]]},"references-count":43,"journal-issue":{"issue":"32","published-print":{"date-parts":[[2004,8,10]]}},"alternative-id":["10.1073\/pnas.0402178101"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0402178101","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,7,29]]},"assertion":[{"value":"2004-03-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2004-06-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2004-07-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}