Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
A pure chloride channel mutant of CLC-5 causes Dent's disease via insufficient V-ATPase activation.
Satoh N
,
Yamada H
,
Yamazaki O
,
Suzuki M
,
Nakamura M
,
Suzuki A
,
Ashida A
,
Yamamoto D
,
Kaku Y
,
Sekine T
,
Seki G
,
Horita S
.
???displayArticle.abstract???
Dent's disease is characterized by defective endocytosis in renal proximal tubules (PTs) and caused by mutations in the 2Cl(-)/H(+) exchanger, CLC-5. However, the pathological role of endosomal acidification in endocytosis has recently come into question. To clarify the mechanism of pathogenesis for Dent's disease, we examined the effects of a novel gating glutamate mutation, E211Q, on CLC-5 functions and endosomal acidification. In Xenopus oocytes, wild-type (WT) CLC-5 showed outward-rectifying currents that were inhibited by extracellular acidosis, but E211Q and an artificial pure Cl(-) channel mutant, E211A, showed linear currents that were insensitive to extracellular acidosis. Moreover, depolarizing pulse trains induced a robust reduction in the surface pH of oocytes expressing WT CLC-5 but not E211Q or E211A, indicating that the E211Q mutant functions as a pure Cl(-) channel similar to E211A. In HEK293 cells, E211A and E211Q stimulated endosomal acidification and hypotonicity-inducible vacuolar-type H(+)-ATPase (V-ATPase) activation at the plasma membrane. However, the stimulatory effects of these mutants were reduced compared with WT CLC-5. Furthermore, gene silencing experiments confirmed the functional coupling between V-ATPase and CLC-5 at the plasma membrane of isolated mouse PTs. These results reveal for the first time that the conversion of CLC-5 from a 2Cl(-)/H(+) exchanger into a Cl(-) channel induces Dent's disease in humans. In addition, defective endosomal acidification as a result of insufficient V-ATPase activation may still be important in the pathogenesis of Dent's disease.
Accardi,
Ionic currents mediated by a prokaryotic homologue of CLC Cl- channels.
2004, Pubmed
Accardi,
Ionic currents mediated by a prokaryotic homologue of CLC Cl- channels.
2004,
Pubmed
Accardi,
Secondary active transport mediated by a prokaryotic homologue of ClC Cl- channels.
2004,
Pubmed
Amlal,
Activation of H+-ATPase by hypotonicity: a novel regulatory mechanism for H+ secretion in IMCD cells.
1998,
Pubmed
Cao,
V-ATPase promotes transforming growth factor-β-induced epithelial-mesenchymal transition of rat proximal tubular epithelial cells.
2012,
Pubmed
Carraro-Lacroix,
Role of CFTR and ClC-5 in modulating vacuolar H+-ATPase activity in kidney proximal tubule.
2010,
Pubmed
Claverie-Martín,
Dent's disease: clinical features and molecular basis.
2011,
Pubmed
D'Antonio,
Conformational defects underlie proteasomal degradation of Dent's disease-causing mutants of ClC-5.
2013,
Pubmed
DENT,
HYPERCALCURIC RICKETS ASSOCIATED WITH RENAL TUBULAR DAMAGE.
1964,
Pubmed
Devuyst,
Dent's disease.
2010,
Pubmed
Dutzler,
X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity.
2002,
Pubmed
Dutzler,
Gating the selectivity filter in ClC chloride channels.
2003,
Pubmed
,
Xenbase
Gleixner,
V-ATPase/mTOR signaling regulates megalin-mediated apical endocytosis.
2014,
Pubmed
Grand,
Novel CLCN5 mutations in patients with Dent's disease result in altered ion currents or impaired exchanger processing.
2009,
Pubmed
,
Xenbase
Günther,
ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells.
1998,
Pubmed
Günther,
The ClC-5 chloride channel knock-out mouse - an animal model for Dent's disease.
2003,
Pubmed
Hara-Chikuma,
Impaired acidification in early endosomes of ClC-5 deficient proximal tubule.
2005,
Pubmed
Horita,
Functional analysis of NBC1 mutants associated with proximal renal tubular acidosis and ocular abnormalities.
2005,
Pubmed
,
Xenbase
Hurtado-Lorenzo,
V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway.
2006,
Pubmed
Ishida,
A model of lysosomal pH regulation.
2013,
Pubmed
Jentsch,
Primary structure of Torpedo marmorata chloride channel isolated by expression cloning in Xenopus oocytes.
1990,
Pubmed
,
Xenbase
Kondo,
Axial heterogeneity of sodium-bicarbonate cotransport in proximal straight tubule of rabbit kidney.
1987,
Pubmed
Lloyd,
A common molecular basis for three inherited kidney stone diseases.
1996,
Pubmed
,
Xenbase
Lobet,
Ion-binding properties of the ClC chloride selectivity filter.
2006,
Pubmed
Lourdel,
ClC-5 mutations associated with Dent's disease: a major role of the dimer interface.
2012,
Pubmed
Mellman,
Acidification of the endocytic and exocytic pathways.
1986,
Pubmed
Miesenböck,
Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins.
1998,
Pubmed
Nakamura,
Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome.
2015,
Pubmed
Nguitragool,
Uncoupling of a CLC Cl-/H+ exchange transporter by polyatomic anions.
2006,
Pubmed
Novarino,
Endosomal chloride-proton exchange rather than chloride conductance is crucial for renal endocytosis.
2010,
Pubmed
Picollo,
Proton block of the CLC-5 Cl-/H+ exchanger.
2010,
Pubmed
,
Xenbase
Picollo,
Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5.
2005,
Pubmed
Piwon,
ClC-5 Cl- -channel disruption impairs endocytosis in a mouse model for Dent's disease.
2000,
Pubmed
Rahmati,
Slc26a11 is prominently expressed in the brain and functions as a chloride channel: expression in Purkinje cells and stimulation of V H⁺-ATPase.
2013,
Pubmed
Sabolić,
Characteristics of the proton pump in rat renal cortical endocytotic vesicles.
1986,
Pubmed
Sakamoto,
Cellular and subcellular immunolocalization of ClC-5 channel in mouse kidney: colocalization with H+-ATPase.
1999,
Pubmed
Scheel,
Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins.
2005,
Pubmed
,
Xenbase
Schödel,
HIF-prolyl hydroxylases in the rat kidney: physiologic expression patterns and regulation in acute kidney injury.
2009,
Pubmed
Seki,
The chloride/base exchanger in the basolateral cell membrane of rabbit renal proximal tubule S3 segment requires bicarbonate to operate.
1990,
Pubmed
Sekine,
Japanese Dent disease has a wider clinical spectrum than Dent disease in Europe/USA: genetic and clinical studies of 86 unrelated patients with low-molecular-weight proteinuria.
2014,
Pubmed
Shirakabe,
IRBIT, an inositol 1,4,5-trisphosphate receptor-binding protein, specifically binds to and activates pancreas-type Na+/HCO3- cotransporter 1 (pNBC1).
2006,
Pubmed
,
Xenbase
Smith,
Characterization of Dent's disease mutations of CLC-5 reveals a correlation between functional and cell biological consequences and protein structure.
2009,
Pubmed
Smith,
Direct endosomal acidification by the outwardly rectifying CLC-5 Cl(-)/H(+) exchanger.
2010,
Pubmed
Sonawane,
Chloride concentration in endosomes measured using a ratioable fluorescent Cl- indicator: evidence for chloride accumulation during acidification.
2002,
Pubmed
Stauber,
Cell biology and physiology of CLC chloride channels and transporters.
2012,
Pubmed
Stauber,
Chloride in vesicular trafficking and function.
2013,
Pubmed
Steinmeyer,
Cloning and functional expression of rat CLC-5, a chloride channel related to kidney disease.
1995,
Pubmed
,
Xenbase
Suzuki,
Functional analysis of a novel missense NBC1 mutation and of other mutations causing proximal renal tubular acidosis.
2008,
Pubmed
,
Xenbase
Thakker,
Pathogenesis of Dent's disease and related syndromes of X-linked nephrolithiasis.
2000,
Pubmed
Wang,
Mice lacking renal chloride channel, CLC-5, are a model for Dent's disease, a nephrolithiasis disorder associated with defective receptor-mediated endocytosis.
2000,
Pubmed
Weinert,
Lysosomal pathology and osteopetrosis upon loss of H+-driven lysosomal Cl- accumulation.
2010,
Pubmed
Wrong,
Dent's disease; a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure and a marked male predominance.
1994,
Pubmed
Wu,
Modeling study of human renal chloride channel (hCLC-5) mutations suggests a structural-functional relationship.
2003,
Pubmed
Yamazaki,
Functional characterization of nonsynonymous single nucleotide polymorphisms in the electrogenic Na+-HCO3- cotransporter NBCe1A.
2011,
Pubmed
,
Xenbase
Yamazaki,
Identification of dominant negative effect of L522P mutation in the electrogenic Na⁺-HCO₃⁻ cotransporter NBCe1.
2013,
Pubmed
,
Xenbase
Zifarelli,
On the mechanism of gating charge movement of ClC-5, a human Cl(-)/H(+) antiporter.
2012,
Pubmed
Zifarelli,
Conversion of the 2 Cl(-)/1 H+ antiporter ClC-5 in a NO3(-)/H+ antiporter by a single point mutation.
2009,
Pubmed
,
Xenbase
Zoncu,
mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase.
2011,
Pubmed
