000149751 001__ 149751
000149751 005__ 20250127155744.0
000149751 0247_ $$2doi$$a10.1073/pnas.0508307102
000149751 0248_ $$2sideral$$a55612
000149751 037__ $$aART-2005-55612
000149751 041__ $$aeng
000149751 100__ $$aKahle, K.T
000149751 245__ $$aWnk3 Modulates of Cl- Transport in and Out of Cells: Implications for Control of Cell Volume and Neuronal Excitability
000149751 260__ $$c2005
000149751 5203_ $$aThe regulation of Cl- transport into and out of cells plays a critical role in the maintenance of intracellular volume and the excitability of GABA responsive neurons. The molecular determinants of these seemingly diverse processes are related ion cotransporters: Cl- influx is mediated by the Na-K-2Cl cotransporter NKCC1 and Cl- efflux via K-Cl cotransporters, KCC1 or KCC2. A Cl-/volume-sensitive kinase has been proposed to coordinately regulate these activities via altered phosphorylation of the transporters; phosphorylation activates NKCC1 while inhibiting KCCs, and dephosphorylation has the opposite effects. We show that WNK3, a member of the WNK family of serine-threonine kinases, colocalizes with NKCC1 and KCC1/2 in diverse Cl--transporting epithelia and in neurons expressing ionotropic GABAA receptors in the hippocampus, cerebellum, cerebral cortex, and reticular activating system. By expression studies in Xenopus oocytes, we show that kinase-active WNK3 increases Cl- influx via NKCC1, and that it inhibits Cl- exit through KCC1 and KCC2; kinase-inactive WNK3 has the opposite effects. WNK3's effects are imparted via altered phosphorylation and surface expression of its downstream targets and bypass the normal requirement of altered tonicity for activation of these transporters. Together, these data indicate that WNK3 can modulate the level of intracellular Cl- via opposing actions on entry and exit pathways. They suggest that WNK3 is part of the Cl-/volume-sensing mechanism necessary for the maintenance of cell volume during osmotic stress and the dynamic modulation of GABA neurotransmission.
000149751 540__ $$9info:eu-repo/semantics/closedAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000149751 590__ $$a10.231$$b2005
000149751 591__ $$aMULTIDISCIPLINARY SCIENCES$$b3 / 48 = 0.062$$c2005$$dQ1$$eT1
000149751 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000149751 700__ $$aRinehart, J
000149751 700__ $$aDe Los Heros, P
000149751 700__ $$aLouvi, A
000149751 700__ $$0(orcid)0000-0002-3587-6622$$aMeade, P$$uUniversidad de Zaragoza
000149751 700__ $$aVazquez, N
000149751 700__ $$aHebert, S.C
000149751 700__ $$aGamba, G
000149751 700__ $$0(orcid)0000-0002-6043-4869$$aGimenez, I$$uUniversidad de Zaragoza
000149751 700__ $$aLifton, R.P.
000149751 7102_ $$11005$$2410$$aUniversidad de Zaragoza$$bDpto. Farmacología y Fisiolog.$$cÁrea Fisiología
000149751 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000149751 773__ $$g102, 46 (2005), 16783-16788$$pProc. Natl. Acad. Sci.$$tProceedings of the National Academy of Sciences of the United States of America$$x0027-8424
000149751 8564_ $$s713884$$uhttps://zaguan.unizar.es/record/149751/files/texto_completo.pdf$$yVersión publicada
000149751 8564_ $$s3949461$$uhttps://zaguan.unizar.es/record/149751/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000149751 909CO $$ooai:zaguan.unizar.es:149751$$particulos$$pdriver
000149751 951__ $$a2025-01-27-14:42:35
000149751 980__ $$aARTICLE