Wnk3 Modulates of Cl- Transport in and Out of Cells: Implications for Control of Cell Volume and Neuronal Excitability

Kahle, K.T ; Rinehart, J ; De Los Heros, P ; Louvi, A ; Meade, P (Universidad de Zaragoza) ; Vazquez, N ; Hebert, S.C ; Gamba, G ; Gimenez, I (Universidad de Zaragoza) ; Lifton, R.P.

Resumen: The 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.

Idioma: Inglés

DOI: 10.1073/pnas.0508307102

Año: 2005

Publicado en: Proceedings of the National Academy of Sciences of the United States of America 102, 46 (2005), 16783-16788
ISSN: 0027-8424

Factor impacto JCR: 10.231 (2005)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 3 / 48 = 0.062 (2005) - Q1 - T1

Tipo y forma: Article (Published version)

Área (Departamento): Área Fisiología (Dpto. Farmacología y Fisiolog.)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)