ClC-5: Physiological role and biophysical mechanisms

Pusch, Michael; Zifarelli, Giovanni

doi:10.1016/j.ceca.2014.09.007

Cited by 24 publications

(21 citation statements)

References 131 publications

(168 reference statements)

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“…[7][8][9][10] In the PTCs, ClC-5 plays an important role during receptormediated endocytosis of albumin and LMW proteins that make it through the glomerulus and colocalizes with vacuolar H + -ATPase (V-ATPase). 11,12 There ClC-5 contributes to the acidic pH within the endosomes important for ligand:receptor dissociation and subsequent recycling of the receptor to the apical membrane and degradation of the ligand within endosomes 13,14 (Figure 1).…”

Section: Localization and Function Of Clc-5mentioning

confidence: 99%

Dent disease: A window into calcium and phosphate transport

Anglani

Gianesello

Beara-Lasić

et al. 2019

J Cellular Molecular Medi

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This review examines calcium and phosphate transport in the kidney through the lens of the rare X‐linked genetic disorder Dent disease. Dent disease type 1 (DD1) is caused by mutations in the CLCN5 gene encoding ClC‐5, a Cl−/H+ antiporter localized to early endosomes of the proximal tubule (PT). Phenotypic features commonly include low molecular weight proteinuria (LMWP), hypercalciuria, focal global sclerosis and chronic kidney disease; calcium nephrolithiasis, nephrocalcinosis and hypophosphatemic rickets are less commonly observed. Although it is not surprising that abnormal endosomal function and recycling in the PT could result in LMWP, it is less clear how ClC‐5 dysfunction disturbs calcium and phosphate metabolism. It is known that the majority of calcium and phosphate transport occurs in PT cells, and PT endocytosis is essential for calcium and phosphorus reabsorption in this nephron segment. Evidence from ClC‐5 KO models suggests that ClC‐5 mediates parathormone endocytosis from tubular fluid. In addition, ClC‐5 dysfunction alters expression of the sodium/proton exchanger NHE3 on the PT apical surface thus altering transcellular sodium movement and hence paracellular calcium reabsorption. A potential role for NHE3 dysfunction in the DD1 phenotype has never been investigated, either in DD models or in patients with DD1, even though patients with DD1 exhibit renal sodium and potassium wasting, especially when exposed to even a low dose of thiazide diuretic. Thus, insights from the rare disease DD1 may inform possible underlying mechanisms for the phenotype of hypercalciuria and idiopathic calcium stones.

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Section: Localization and Function Of Clc-5mentioning

confidence: 99%

Dent disease: A window into calcium and phosphate transport

Anglani

Gianesello

Beara-Lasić

et al. 2019

J Cellular Molecular Medi

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“…After the identification of ClC-5 mutations as the cause of Dent’s disease (Lloyd et al, 1997), more than 100 such mutations were described (Pusch and Zifarelli, 2015). Most mutations in ClC-5 are missense and non-sense mutations, with many of them located at or near the subunit’s interface, resulting in non-functional truncated proteins (Wu et al, 2003; Stauber et al, 2012).…”

Section: Mammalian Clcs and Human Disordersmentioning

confidence: 99%

ClC Channels and Transporters: Structure, Physiological Functions, and Implications in Human Chloride Channelopathies

2017

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The discovery of ClC proteins at the beginning of the 1990s was important for the development of the Cl- transport research field. ClCs form a large family of proteins that mediate voltage-dependent transport of Cl- ions across cell membranes. They are expressed in both plasma and intracellular membranes of cells from almost all living organisms. ClC proteins form transmembrane dimers, in which each monomer displays independent ion conductance. Eukaryotic members also possess a large cytoplasmic domain containing two CBS domains, which are involved in transport modulation. ClC proteins function as either Cl- channels or Cl-/H+ exchangers, although all ClC proteins share the same basic architecture. ClC channels have two gating mechanisms: a relatively well-studied fast gating mechanism, and a slow gating mechanism, which is poorly defined. ClCs are involved in a wide range of physiological processes, including regulation of resting membrane potential in skeletal muscle, facilitation of transepithelial Cl- reabsorption in kidneys, and control of pH and Cl- concentration in intracellular compartments through coupled Cl-/H+ exchange mechanisms. Several inherited diseases result from C1C gene mutations, including myotonia congenita, Bartter’s syndrome (types 3 and 4), Dent’s disease, osteopetrosis, retinal degeneration, and lysosomal storage diseases. This review summarizes general features, known or suspected, of ClC structure, gating and physiological functions. We also discuss biophysical properties of mammalian ClCs that are directly involved in the pathophysiology of several human inherited disorders, or that induce interesting phenotypes in animal models.

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“…In the kidney, CLC-5 expression is highest in proximal tubules and intercalated cells of the collecting ducts[18]. Especially in proximal tubules, a major site for urinary LMW protein reabsorption via receptor-mediated endocytosis[17,19], CLC-5 is predominantly located in early endosomes, colocalizing with V-ATPase[4,20]. Additionally, CLC-5 is also found to an extent in the apical membrane of proximal tubules, as suggested by its robust plasma membrane expression in HEK293 cells as well as in Xenopus laevis oocytes following heterologous overexpression[4,18].…”

Section: Tissue and Subcellular Distribution Of Clc-5mentioning

confidence: 99%

Functional coupling of V-ATPase and CLC-5

Satoh

Suzuki

Nakamura

et al. 2017

WJN

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Dent’s disease is an X-linked renal tubulopathy characterized by low molecular weight proteinuria, hypercalciuria and progressive renal failure. Disease aetiology is associated with mutations in the CLCN5 gene coding for the electrogenic 2Cl-/H+ antiporter chloride channel 5 (CLC-5), which is expressed in the apical endosomes of renal proximal tubules with the vacuolar type H+-ATPase (V-ATPase). Initially identified as a member of the CLC family of Cl- channels, CLC-5 was presumed to provide Cl- shunt into the endosomal lumen to dissipate H+ accumulation by V-ATPase, thereby facilitating efficient endosomal acidification. However, recent findings showing that CLC-5 is in fact not a Cl- channel but a 2Cl-/H+ antiporter challenged this classical shunt model, leading to a renewed and intense debate on its physiological roles. Cl- accumulation via CLC-5 is predicted to play a critical role in endocytosis, as illustrated in mice carrying an artificial Cl- channel mutation E211A that developed defective endocytosis but normal endosomal acidification. Conversely, a recent functional analysis of a newly identified disease-causing Cl- channel mutation E211Q in a patient with typical Dent’s disease confirmed the functional coupling between V-ATPase and CLC-5 in endosomal acidification, lending support to the classical shunt model. In this editorial, we will address the current recognition of the physiological role of CLC-5 with a specific focus on the functional coupling of V-ATPase and CLC-5.

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ClC-5: Physiological role and biophysical mechanisms

Cited by 24 publications

References 131 publications

Dent disease: A window into calcium and phosphate transport

Dent disease: A window into calcium and phosphate transport

ClC Channels and Transporters: Structure, Physiological Functions, and Implications in Human Chloride Channelopathies

Functional coupling of V-ATPase and CLC-5

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