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Am J Physiol Renal Physiol
2013 Jul 01;3051:F31-41. doi: 10.1152/ajprenal.00652.2012.
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WNK4 inhibition of ENaC is independent of Nedd4-2-mediated ENaC ubiquitination.
Yu L
,
Cai H
,
Yue Q
,
Alli AA
,
Wang D
,
Al-Khalili O
,
Bao HF
,
Eaton DC
.
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A serine-threonine protein kinase, WNK4, reduces Na⁺ reabsorption and K⁺ secretion in the distal convoluted tubule by reducing trafficking of the thiazide-sensitive Na-Cl cotransporter to and enhancing renal outer medullary potassium channel retrieval from the apical membrane. Epithelial sodium channels (ENaC) in the distal nephron also play a role in regulating Na⁺ reabsorption and are also regulated by WNK4, but the mechanism is unclear. In A6 distal nephron cells, transepithelial current measurement and single channel recording show that WNK4 inhibits ENaC activity. Analysis of the number of channel per patch shows that WNK4 reduces channel number but has no effect on channel open probability. Western blots of apical and total ENaC provide additional evidence that WNK4 reduces apical as well as total ENaC expression. WNK4 enhances ENaC internalization independent of Nedd4-2-mediated ENaC ubiquitination. WNK4 also reduced the amount of ENaC available for recycling but has no effect on the rate of transepithelial current increase to forskolin. In contrast, Nedd4-2 not only reduced ENaC in the recycling pool but also decreased the rate of increase of current after forskolin. WNK4 associates with wild-type as well as Liddle's mutated ENaC, and WNK4 reduces both wild-type and mutated ENaC expressed in HEK293 cells.
Ahlstrom,
Characterization of the kinase activity of a WNK4 protein complex.
2009, Pubmed
Ahlstrom,
Characterization of the kinase activity of a WNK4 protein complex.
2009,
Pubmed
Bertog,
Aldosterone responsiveness of the epithelial sodium channel (ENaC) in colon is increased in a mouse model for Liddle's syndrome.
2008,
Pubmed
Butterworth,
Acute ENaC stimulation by cAMP in a kidney cell line is mediated by exocytic insertion from a recycling channel pool.
2005,
Pubmed
Cai,
WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells.
2006,
Pubmed
,
Xenbase
Canessa,
Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.
1994,
Pubmed
,
Xenbase
Carattino,
Proteolytic processing of the epithelial sodium channel gamma subunit has a dominant role in channel activation.
2008,
Pubmed
,
Xenbase
Castañeda-Bueno,
Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process.
2012,
Pubmed
,
Xenbase
Chen,
Beta-adrenergic regulation of amiloride-sensitive lung sodium channels.
2002,
Pubmed
Chen,
Regulation of a third conserved phosphorylation site in SGK1.
2009,
Pubmed
Coupaye-Gerard,
Differential effects of brefeldin A on hormonally regulated Na+ transport in a model renal epithelial cell line.
1994,
Pubmed
,
Xenbase
Dahlmann,
Mineralocorticoid regulation of epithelial Na+ channels is maintained in a mouse model of Liddle's syndrome.
2003,
Pubmed
Debonneville,
Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression.
2001,
Pubmed
,
Xenbase
Firsov,
Mutational analysis of cysteine-rich domains of the epithelium sodium channel (ENaC). Identification of cysteines essential for channel expression at the cell surface.
1999,
Pubmed
,
Xenbase
Fisher,
Brefeldin A inhibition of apical Na+ channels in epithelia.
1996,
Pubmed
Frelin,
Amiloride and its analogs as tools to inhibit Na+ transport via the Na+ channel, the Na+/H+ antiport and the Na+/Ca2+ exchanger.
1988,
Pubmed
Furgeson,
Mechanisms of type I and type II pseudohypoaldosteronism.
2010,
Pubmed
Gagnon,
Volume sensitivity of cation-Cl- cotransporters is modulated by the interaction of two kinases: Ste20-related proline-alanine-rich kinase and WNK4.
2006,
Pubmed
,
Xenbase
Garty,
Epithelial sodium channels: function, structure, and regulation.
1997,
Pubmed
Gunthorpe,
Characterisation of a human acid-sensing ion channel (hASIC1a) endogenously expressed in HEK293 cells.
2001,
Pubmed
Haggerty,
Na+/H+ exchanger activity in the pig kidney epithelial cell line, LLC-PK1: inhibition by amiloride and its derivatives.
1985,
Pubmed
Hansson,
Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome.
1995,
Pubmed
,
Xenbase
He,
Intersectin links WNK kinases to endocytosis of ROMK1.
2007,
Pubmed
Heise,
Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members.
2010,
Pubmed
Huang,
Internalization of UT-A1 urea transporter is dynamin dependent and mediated by both caveolae- and clathrin-coated pit pathways.
2010,
Pubmed
Hughey,
Epithelial sodium channels are activated by furin-dependent proteolysis.
2004,
Pubmed
,
Xenbase
Hughey,
Distinct pools of epithelial sodium channels are expressed at the plasma membrane.
2004,
Pubmed
,
Xenbase
Kabra,
Nedd4-2 induces endocytosis and degradation of proteolytically cleaved epithelial Na+ channels.
2008,
Pubmed
Kahle,
Regulation of diverse ion transport pathways by WNK4 kinase: a novel molecular switch.
2005,
Pubmed
Kahle,
WNK kinases: molecular regulators of integrated epithelial ion transport.
2004,
Pubmed
Kellenberger,
Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure.
2002,
Pubmed
Ko,
RasGRP1 stimulation enhances ubiquitination and endocytosis of the sodium-chloride cotransporter.
2010,
Pubmed
LaBelle,
Reconstituted amiloride-inhibited sodium transporter from rabbit kidney medulla is responsible for Na+-H+ exchange.
1984,
Pubmed
Lalioti,
Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule.
2006,
Pubmed
Lalo,
Spontaneous autocrine release of protons activates ASIC-mediated currents in HEK293 cells.
2007,
Pubmed
Lu,
The PY motif of ENaC, mutated in Liddle syndrome, regulates channel internalization, sorting and mobilization from subapical pool.
2007,
Pubmed
Ma,
Regulation of the epithelial sodium channel by phosphatidylinositides: experiments, implications, and speculations.
2007,
Pubmed
Marunaka,
Effects of vasopressin and cAMP on single amiloride-blockable Na channels.
1991,
Pubmed
Meltzer,
Heteromeric assembly of acid-sensitive ion channel and epithelial sodium channel subunits.
2007,
Pubmed
Ohta,
Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure.
2009,
Pubmed
Pelham,
Recycling of proteins between the endoplasmic reticulum and Golgi complex.
1991,
Pubmed
Pochynyuk,
Physiologic regulation of the epithelial sodium channel by phosphatidylinositides.
2008,
Pubmed
Pochynyuk,
Dietary Na+ inhibits the open probability of the epithelial sodium channel in the kidney by enhancing apical P2Y2-receptor tone.
2010,
Pubmed
Renard,
Biochemical analysis of the membrane topology of the amiloride-sensitive Na+ channel.
1994,
Pubmed
,
Xenbase
Ring,
WNK4 regulates activity of the epithelial Na+ channel in vitro and in vivo.
2007,
Pubmed
,
Xenbase
Ring,
An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis.
2007,
Pubmed
,
Xenbase
Rokaw,
Carboxylmethylation of the beta subunit of xENaC regulates channel activity.
1998,
Pubmed
San-Cristobal,
Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway.
2009,
Pubmed
,
Xenbase
Sheng,
Functional role of extracellular loop cysteine residues of the epithelial Na+ channel in Na+ self-inhibition.
2007,
Pubmed
,
Xenbase
Shimkets,
Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel.
1994,
Pubmed
Subramanya,
WNK4 diverts the thiazide-sensitive NaCl cotransporter to the lysosome and stimulates AP-3 interaction.
2009,
Pubmed
,
Xenbase
Welling,
Multigene kinase network, kidney transport, and salt in essential hypertension.
2010,
Pubmed
Wilson,
Human hypertension caused by mutations in WNK kinases.
2001,
Pubmed
Xu,
WNK1 activates SGK1 to regulate the epithelial sodium channel.
2005,
Pubmed
Yang,
WNK kinases regulate thiazide-sensitive Na-Cl cotransport.
2003,
Pubmed
,
Xenbase
Yang,
Regulation of apical localization of the thiazide-sensitive NaCl cotransporter by WNK4 in polarized epithelial cells.
2005,
Pubmed
,
Xenbase
Yu,
Effect of divalent heavy metals on epithelial Na+ channels in A6 cells.
2007,
Pubmed
,
Xenbase
Zhou,
Nedd4-2 catalyzes ubiquitination and degradation of cell surface ENaC.
2007,
Pubmed
Zhou,
Hrs controls sorting of the epithelial Na+ channel between endosomal degradation and recycling pathways.
2010,
Pubmed
Zhuang,
WNK4 kinase inhibits Maxi K channel activity by a kinase-dependent mechanism.
2011,
Pubmed
