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 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 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.