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World J Nephrol. Jan 6, 2017; 6(1): 14-20
Published online Jan 6, 2017. doi: 10.5527/wjn.v6.i1.14
Functional coupling of V-ATPase and CLC-5
Nobuhiko Satoh, Masashi Suzuki, Motonobu Nakamura, Atsushi Suzuki, Shoko Horita, George Seki, Kyoji Moriya
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
George Seki, Department of Endocrinology and Nephrology, Yaizu City Hospital, Shizuoka 425-8505, Japan
Kyoji Moriya, Department of Infection Control and Prevention, the University of Tokyo Hospital, Tokyo 113-8655, Japan
Author contributions: All authors contributed to this paper.
Conflict-of-interest statement: The authors declare no conflict of interest related to this publication.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Nobuhiko Satoh, MD, Department of Internal Medicine, Faculty of Medicine, the University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. nosatou-tky@umin.ac.jp
Telephone: +81-3-38155411 Fax: +81-3-58008806
Received: August 12, 2016
Peer-review started: August 12, 2016
First decision: September 30, 2016
Revised: October 12, 2016
Accepted: November 1, 2016
Article in press: November 2, 2016
Published online: January 6, 2017
Processing time: 138 Days and 7 Hours
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: V-ATPase; CLC-5; Endocytosis; Endosomal acidification; Dent’s disease; Gating glutamate; E211Q

Core tip: Chloride channel 5 (CLC-5) mutations cause Dent’s disease, which is characterized by renal proximal tubulopathy due to defective endocytosis. Recent revelations that CLC-5 is a 2Cl-/H+ antiporter and not a Cl- channel challenged the classical model proposing CLC-5 as a Cl- shunt to facilitate V-ATPase-mediated endosomal acidification. Therefore, physiological roles of CLC-5 and its interaction with V-ATPase in endosomal acidification and/or endocytosis are intensely debated. Recent functional analysis of a novel pure Cl- channel mutant from a Dent’s disease patient indicated a possible functional coupling between V-ATPase and CLC-5 not only in endosomal acidification but also at the plasma membrane.