000149744 001__ 149744
000149744 005__ 20250127155744.0
000149744 0247_ $$2doi$$a10.1073/pnas.050830310
000149744 0248_ $$2sideral$$a55611
000149744 037__ $$aART-2005-55611
000149744 041__ $$aeng
000149744 100__ $$aRinehart, J
000149744 245__ $$aWnk3 Kinase Is a Positive Regulator of Nkcc2 and Ncc, Renal Cation-Cl- Cotransporters Required for Normal Blood Pressure Homeostasis
000149744 260__ $$c2005
000149744 5203_ $$aWNK1 and WNK4 [WNK, with no lysine (K)] are serine-threonine kinases that function as molecular switches, eliciting coordinated effects on diverse ion transport pathways to maintain homeostasis during physiological perturbation. Gain-of-function mutations in either of these genes cause an inherited syndrome featuring hypertension and hyperkalemia due to increased renal NaCl reabsorption and decreased K+ secretion. Here, we reveal unique biochemical and functional properties of WNK3, a related member of the WNK kinase family. Unlike WNK1 and WNK4, WNK3 is expressed throughout the nephron, predominantly at intercellular junctions. Because WNK4 is a potent inhibitor of members of the cation-cotransporter SLC12A family, we used coexpression studies in Xenopus oocytes to investigate the effect of WNK3 on NCC and NKCC2, related kidney-specific transporters that mediate apical NaCl reabsorption in the thick ascending limb and distal convoluted tubule, respectively. In contrast to WNK4's inhibitory activity, kinase-active WNK3 is a potent activator of both NKCC2 and NCC-mediated transport. Conversely, in its kinase-inactive state, WNK3 is a potent inhibitor of NKCC2 and NCC activity. WNK3 regulates the activity of these transporters by altering their expression at the plasma membrane. Wild-type WNK3 increases and kinase-inactive WNK3 decreases NKCC2 phosphorylation at Thr-184 and Thr-189, sites required for the vasopressin-mediated plasmalemmal translocation and activation of NKCC2 in vivo. The effects of WNK3 on these transporters and their coexpression in renal epithelia implicate WNK3 in NaCl, water, and blood pressure homeostasis, perhaps via signaling downstream of vasopressin.
000149744 540__ $$9info:eu-repo/semantics/closedAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000149744 590__ $$a10.231$$b2005
000149744 591__ $$aMULTIDISCIPLINARY SCIENCES$$b3 / 48 = 0.062$$c2005$$dQ1$$eT1
000149744 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000149744 700__ $$aKahle, K.T
000149744 700__ $$aHeros, P.De Los
000149744 700__ $$aVazquez, N
000149744 700__ $$0(orcid)0000-0002-3587-6622$$aMeade, P$$uUniversidad de Zaragoza
000149744 700__ $$aWilson, F.H
000149744 700__ $$aHebertt, S.C
000149744 700__ $$0(orcid)0000-0002-6043-4869$$aGimenez, I$$uUniversidad de Zaragoza
000149744 700__ $$aGamba, G
000149744 700__ $$aLifton, R.P.
000149744 7102_ $$11005$$2410$$aUniversidad de Zaragoza$$bDpto. Farmacología y Fisiolog.$$cÁrea Fisiología
000149744 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000149744 773__ $$g102, 46 (2005), 16777-16782$$pProc. Natl. Acad. Sci.$$tProceedings of the National Academy of Sciences of the United States of America$$x0027-8424
000149744 8564_ $$s361165$$uhttps://zaguan.unizar.es/record/149744/files/texto_completo.pdf$$yVersión publicada
000149744 8564_ $$s3979645$$uhttps://zaguan.unizar.es/record/149744/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000149744 909CO $$ooai:zaguan.unizar.es:149744$$particulos$$pdriver
000149744 951__ $$a2025-01-27-14:42:27
000149744 980__ $$aARTICLE