Functional coupling of V-ATPase and CLC-5

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.