title: 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 theCLCN5gene 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-accumulationviaCLC-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.
authors.affiliation: Nobuhiko Satoh, Masashi Suzuki, Motonobu Nakamura, Atsushi Suzuki, Shoko Horita, Department of Internal Medicine, Faculty of Medicine, the University of Tokyo Hospital, Tokyo 113-8655, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Satoh
authors.affiliation: Nobuhiko Satoh, Masashi Suzuki, Motonobu Nakamura, Atsushi Suzuki, Shoko Horita, Department of Internal Medicine, Faculty of Medicine, the University of Tokyo Hospital, Tokyo 113-8655, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Nobuhiko Satoh, Masashi Suzuki, Motonobu Nakamura, Atsushi Suzuki, Shoko Horita, Department of Internal Medicine, Faculty of Medicine, the University of Tokyo Hospital, Tokyo 113-8655, Japan.
authors.forename: Motonobu
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Nobuhiko Satoh, Masashi Suzuki, Motonobu Nakamura, Atsushi Suzuki, Shoko Horita, Department of Internal Medicine, Faculty of Medicine, the University of Tokyo Hospital, Tokyo 113-8655, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Nobuhiko Satoh, Masashi Suzuki, Motonobu Nakamura, Atsushi Suzuki, Shoko Horita, Department of Internal Medicine, Faculty of Medicine, the University of Tokyo Hospital, Tokyo 113-8655, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Horita
authors.affiliation: Nobuhiko Satoh, Masashi Suzuki, Motonobu Nakamura, Atsushi Suzuki, Shoko Horita, Department of Internal Medicine, Faculty of Medicine, the University of Tokyo Hospital, Tokyo 113-8655, Japan.
authors.forename: George
authors.initials: G
authors.lastname: Seki
authors.affiliation: Nobuhiko Satoh, Masashi Suzuki, Motonobu Nakamura, Atsushi Suzuki, Shoko Horita, Department of Internal Medicine, Faculty of Medicine, the University of Tokyo Hospital, Tokyo 113-8655, Japan.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Moriya
keywords: CLC-5; Dent’s disease; E211Q; Endocytosis; Endosomal acidification; Gating glutamate; V-ATPase