Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins

Scheel, Olaf; Zdebik, Anselm A.; Lourdel, Stéphane; Jentsch, Thomas J.

doi:10.1038/nature03860

Cited by 455 publications

(541 citation statements)

References 26 publications

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“…It is well established that ClC-4 and ClC-5 mediate coupled anion/proton antiport. 15,16 We therefore performed simultaneous voltage-clamp and fluorescence pH measurements in transfected cells, a methodology that we have previously applied to describe ClC-4 and ClC-5 transport. 28,39 Upon depolarization, significant alkalinization was observed in cells expressing ClC-3 13−19A (Figure 2a).…”

Section: ■ Resultsmentioning

confidence: 99%

“…ClC-4 and ClC-5 mediate coupled Cl − /H + exchange across biological membranes. 15,16 For ClC-4 and ClC-5, a sufficient fraction of transporters inserts into the surface membrane allowing the application of standard electrophysiological techniques for functional studies. In contrast, surface expression of ClC-3 is too low 17,18 to allow unambiguous characterization of its transport characteristics.…”

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confidence: 99%

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ClC-3 Is an Intracellular Chloride/Proton Exchanger with Large Voltage-Dependent Nonlinear Capacitance

Guzman

Grieschat

Fahlke

et al. 2013

ACS Chem. Neurosci.

163

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ABSTRACT:The chloride/proton exchangers ClC-3, ClC-4 and ClC-5 are localized in distinct intracellular compartments and regulate their luminal acidity. We used electrophysiology combined with fluorescence pH measurements to compare the functions of these three transporters. Since the expression of WT ClC-3 in the surface membrane was negligible, we removed an N-terminal retention signal for standard electrophysiological characterization of this isoform. This construct (ClC-3 13−19A ) mediated outwardly rectifying coupled Cl − /H + antiport resembling the properties of ClC-4 and ClC-5. In addition, ClC-3 exhibited large electric capacitance, exceeding the nonlinear capacitances of ClC-4 and ClC-5. Mutations of the proton glutamate, a conserved residue at the internal side of the protein, decreased ion transport but increased nonlinear capacitances in all three isoforms. This suggests that nonlinear capacitances in mammalian ClC transporters are regulated in a similar manner. However, the voltage dependence and the amplitudes of these capacitances differed strongly between the investigated isoforms. Our results indicate that ClC-3 is specialized in mainly performing incomplete capacitive nontransporting cycles, that ClC-4 is an effective coupled transporter, and that ClC-5 displays an intermediate phenotype. Mathematical modeling showed that such functional differences would allow differential regulation of luminal acidification and chloride concentration in intracellular compartments.

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Section: ■ Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

ClC-3 Is an Intracellular Chloride/Proton Exchanger with Large Voltage-Dependent Nonlinear Capacitance

Guzman

Grieschat

Fahlke

et al. 2013

ACS Chem. Neurosci.

163

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“…It is expressed in different cell types in vesicles of the endocytotic-lysosomal pathway; in osteoclasts, ClC-7 is localized also in the ruffled border and is involved in the acidification of the resorption lacuna. Recently it has been shown that, as previously suggested by work on bacterial ClC homologues, the ClC-7 protein and other members of the ClC family are not passive chloride ion channels, but rather secondary active chloride/proton antiporters (Accardi & Miller, 2004;Picollo & Pusch, 2005;Scheel et al, 2005;Graves et al, 2008;Zifarelli & Pusch, 2009).…”

Section: Introductionmentioning

confidence: 81%

Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations

et al. 2010

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ABSTRACT:The "Osteopetroses" are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts. Three main forms can be distinguished on the basis of severity, age of onset and means of inheritance: the dominant benign, the intermediate and the recessive severe form. While several genes have been involved in the pathogenesis of the different types of osteopetroses, the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes. We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and 2 putative splice site defects. Careful analysis of clinical and molecular data led us to several conclusions. First, intermediate osteopetrosis is not homogeneous, since it can comprise both severe dominant forms with an early onset and recessive ones without central nervous system involvement. Second, the appropriateness of haematopoietic stem cell transplantation in CLCN7-dependent ARO patients has to be carefully evaluated and exhaustive CNS examination is strongly suggested, as transplantation can almost completely cure the disease in situations where no primary neurological symptoms are present. Finally, the analysis of this largest cohort of CLCN7-dependent ARO patients together with some ADO II families allowed us to draw preliminary genotype-phenotype correlations suggesting that haploinsufficiency is not the mechanism causing ADO II. The availability of biochemical assays to characterize ClC-7 function will help to confirm this hypothesis.

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“…Excepting very few cases, the OCRL mutations associated with Dent disease 2 do not overlap with those causing Lowe syndrome. 10,20,24 Missense mutations occur in the middle region of the gene (exons 9-15), whereas truncating mutations are found exclusively in the first 7 exons; the OCRL mutations associated with Lowe syndrome are located instead in the 3 0 region of the gene (exons [9][10][11][12][13][14][15][16][17][18][19][20][21][22] and involve all three functional OCRL1 domains, whereas frameshift and nonsense mutations cluster in exons [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. The different distribution of OCRL mutations in Dent disease 2 and Lowe syndrome suggests a genotype-phenotype correlation that has yet to be thoroughly explored.…”

Section: Resultsmentioning

confidence: 99%

“…[4][5][6] It has recently been demonstrated, however, that ClC-5 functions as a Cl À/H þ antiporter when activated by positive voltages. 7,8 No CLCN5 gene mutations are detected in approximately 40% of patients with the classic symptoms of Dent's disease, suggesting a locus heterogeneity. The OCRL gene located on chromosome Xq26.1, whose mutations cause Lowe syndrome, has recently been found altered in 20% Dent's patients, 9 but about 20% of patients carry neither CLCN5 nor OCRL mutations.…”

Section: Introductionmentioning

confidence: 99%

An atypical Dent’s disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes

et al. 2012

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Dent's disease is an X-linked renal tubulopathy caused by mutations mainly affecting the CLCN5 gene. Defects in the OCRL gene, which is usually mutated in patients with Lowe syndrome, have been shown to lead to a Dent-like phenotype called Dent disease 2. However, about 20% of patients with Dent's disease carry no CLCN5/OCRL mutations. The disease's genetic heterogeneity is accompanied by interfamilial and intrafamilial phenotypic heterogeneity. We report on a case of Dent's disease with a very unusual phenotype (dysmorphic features, ocular abnormalities, growth delay, rickets, mild mental retardation) in which a digenic inheritance was discovered. Two different, novel disease-causing mutations were detected, both inherited from the patient's healthy mother, that is a truncating mutation in the CLCN5 gene (A249fs*20) and a donor splice-site alteration in the OCRL gene (c.388 þ 3A4G). The mRNA analysis of the patient's leukocytes revealed an aberrantly spliced OCRL mRNA caused by in-frame exon 6 skipping, leading to a shorter protein, but keeping intact the central inositol 5-phosphatase domain and the C-terminal side of the ASH-RhoGAP domain. Only wild-type mRNA was observed in the mother's leukocytes due to a completely skewed X inactivation. Our results are the first to reveal the effect of an epistatic second modifier in Dent's disease too, which can modulate its expressivity. We surmise that the severe Dent disease 2 phenotype of our patient might be due to an addictive interaction of the mutations at two different genes.

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Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins

Cited by 455 publications

References 26 publications

ClC-3 Is an Intracellular Chloride/Proton Exchanger with Large Voltage-Dependent Nonlinear Capacitance

ClC-3 Is an Intracellular Chloride/Proton Exchanger with Large Voltage-Dependent Nonlinear Capacitance

Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations

An atypical Dent’s disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes

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