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Functional coupling of V-ATPase and CLC-5
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 ex...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Baishideng Publishing Group Inc
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215204/ https://www.ncbi.nlm.nih.gov/pubmed/28101447 http://dx.doi.org/10.5527/wjn.v6.i1.14 |
Sumario: | 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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