Functional coupling of V-ATPase and CLC-5

Abstract

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.

Keywords: CLC-5; Dent’s disease; E211Q; Endocytosis; Endosomal acidification; Gating glutamate; V-ATPase.

Figure 1

Effects of CLC-5 inactivation on endosomal acidification and endocytosis. A: In CLC-5 knockout mice, both endosomal acidification and endocytosis are impaired, resulting in a Dent’s disease-like phenotype; B: E211A, an artificial mutation of the gating glutamate of CLC-5, converts its function from a 2Cl^-/H⁺ antiporter into a pure Cl^- conductance. E211A knock-in mice exhibit defective endocytosis and manifestations similar to those observed in Dent’s disease manifestations but retain normal endosomal acidification.

Figure 2

Potential roles of CLC-5 in endosomes. A: In this model, Cl^- accumulation by CLC-5 is critical for normal endocytosis; B: In contrast, 2Cl^-/H⁺ exchange mode of CLC-5 activates V-ATPase which is required for maximal endosomal acidification.