{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T05:23:45Z","timestamp":1778909025076,"version":"3.51.4"},"reference-count":49,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2015,7,30]],"date-time":"2015-07-30T00:00:00Z","timestamp":1438214400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft DFG","award":["SFB699"],"award-info":[{"award-number":["SFB699"]}]},{"name":"Bavarian State, Sonderforschungsbereich"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2015,10]]},"abstract":"<jats:p>Sodium chloride reabsorption in the thick ascending limb of the loop of Henle is mediated by the Na<jats:sup>+<\/jats:sup>\u2010K<jats:sup>+<\/jats:sup>\u20102Cl<jats:sup>\u2212<\/jats:sup> cotransporter (<jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>2). The loop diuretic furosemide is a potent inhibitor of <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>2. However, less is known about the mechanism regulating the electrolyte transporter. Considering the well\u2010established effects of nitric oxide on <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>2 activity, c<jats:styled-content style=\"fixed-case\">GMP<\/jats:styled-content> is likely involved in this regulation. c<jats:styled-content style=\"fixed-case\">GMP<\/jats:styled-content>\u2010dependent protein kinase I (c<jats:styled-content style=\"fixed-case\">GKI<\/jats:styled-content>;<jats:styled-content style=\"fixed-case\"> PKGI<\/jats:styled-content>) is a c<jats:styled-content style=\"fixed-case\">GMP<\/jats:styled-content> target protein that phosphorylates different substrates after activation through c<jats:styled-content style=\"fixed-case\">GMP<\/jats:styled-content>. We investigated the potential correlation between the c<jats:styled-content style=\"fixed-case\">GMP<\/jats:styled-content>\/c<jats:styled-content style=\"fixed-case\">GKI<\/jats:styled-content> pathway and <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>2 regulation. We treated wild\u2010type (wt) and c<jats:styled-content style=\"fixed-case\">GKI<\/jats:styled-content>\u03b1\u2010rescue mice with furosemide. c<jats:styled-content style=\"fixed-case\">GKI<\/jats:styled-content>\u03b1\u2010rescue mice expressed c<jats:styled-content style=\"fixed-case\">GKI<\/jats:styled-content>\u03b1 only under the control of the smooth muscle\u2010specific transgelin (<jats:styled-content style=\"fixed-case\">SM<\/jats:styled-content>22) promoter in a c<jats:styled-content style=\"fixed-case\">GKI<\/jats:styled-content> deficient background. Furosemide treatment increased the urine excretion of sodium and chloride in c<jats:styled-content style=\"fixed-case\">GKI<\/jats:styled-content>\u03b1\u2010rescue mice compared to that in wt mice. We analyzed the phosphorylation of <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>2 by western blotting and immunostaining using the phosphospecific antibody R5. The administration of furosemide significantly increased the phosphorylated <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>2 signal in wt but not in c<jats:styled-content style=\"fixed-case\">GKI<\/jats:styled-content>\u03b1\u2010rescue mice. <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>2 activation led to its phosphorylation and membrane translocation. To examine whether c<jats:styled-content style=\"fixed-case\">GKI<\/jats:styled-content> was involved in this process, we analyzed vasodilator\u2010stimulated phosphoprotein, which is phosphorylated by c<jats:styled-content style=\"fixed-case\">GKI<\/jats:styled-content>. Furosemide injection resulted in increased vasodilator\u2010stimulated phosphoprotein phosphorylation in wt mice. We hypothesize that furosemide administration activated c<jats:styled-content style=\"fixed-case\">GKI<\/jats:styled-content>, leading to <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>2 phosphorylation and membrane translocation. This c<jats:styled-content style=\"fixed-case\">GKI<\/jats:styled-content>\u2010mediated pathway could be a mechanism to compensate for the inhibitory effect of furosemide on <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>2.<\/jats:p>","DOI":"10.1111\/febs.13376","type":"journal-article","created":{"date-parts":[[2015,7,16]],"date-time":"2015-07-16T14:34:49Z","timestamp":1437057289000},"page":"3786-3798","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Regulation of the Na<sup>+<\/sup>\u2010K<sup>+<\/sup>\u20102Cl<sup>\u2212<\/sup> cotransporter by c<scp>GMP<\/scp>\/c<scp>GMP<\/scp>\u2010dependent protein kinase I after furosemide administration"],"prefix":"10.1111","volume":"282","author":[{"given":"Franziska","family":"Limmer","sequence":"first","affiliation":[{"name":"Pharmacology and Toxicology Institute of Pharmacy University of Regensburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"Schinner","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology Institute of Pharmacy University of Regensburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hayo","family":"Castrop","sequence":"additional","affiliation":[{"name":"Institute of Physiology University of Regensburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helga","family":"Vitzthum","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology University Medical Centre Hamburg\u2010Eppendorf Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franz","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Pharmakologisches Institut, Technische Universit\u00e4t M\u00fcnchen 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