The CLC-5 2Cl−/H+ exchange transporter in endosomal function and Dent's disease

Jonathan D Lippiat,Andrew J Smith

doi:10.3389/fphys.2012.00449

Abstract

CLC-5 plays a critical role in the process of endocytosis in the proximal tubule of the kidney and mutations that alter protein function are the cause of Dent's I disease. In this X-linked disorder impaired reabsorption results in the wasting of calcium and low molecular weight protein to the urine, kidney stones, and progressive renal failure. Several different ion-transporting and protein clustering roles have been proposed as the physiological function of CLC-5 in endosomal membranes. At the time of its discovery, nearly 20 years ago, it was understandably assumed to be a chloride channel similar to known members of the CLC family, such as CLC-1, suggesting that chloride transport by CLC-5 was critical for endosomal function. Since then CLC-5 was found instead to be a 2Cl−/H+ exchange transporter with voltage-dependent activity. Recent studies have determined that it is this coupled exchange of protons for chloride, and not just chloride transport, which is critical for endosomal and kidney function. This review discusses the recent ideas that describe how CLC-5 might function in endosomal membranes, the aspects that we still do not understand, and where controversies remain.

Highlights

Like several other proteins that mediate the movement of Cl− ions across membranes, CLC-5 was identified as a protein defective in human disease
CLC-5 is a member of the CLC family of Cl− channels and 2Cl−/H+ transporters, still known today as the voltagegated chloride channel family, and have 9 human members
This classification was based on the functional properties of CLC-1, a plasma membrane Cl− channel that is involved in skeletal muscle excitability

Summary

INTRODUCTION

Like several other proteins that mediate the movement of Cl− ions across membranes, CLC-5 was identified as a protein defective in human disease In this case, the search for genes underlying Dent’s disease, an inherited kidney disorder, identified the CLCN5 gene and sequence variations in Dent’s patients (Fisher et al, 1995; Lloyd et al, 1996). CLC-5 to subapical endosomes in proximal tubule epithelia, colocalizing with H+-ATPase (Gunther et al, 1998) These ideas were supported by studies on mice lacking CLC-5, which exhibit several of the features characteristic of Dent’s disease, where loss of CLC-5 was linked to defective endosomal acidification and receptor-mediated endocytosis (Piwon et al, 2000; Wang et al, 2000; Silva et al, 2003). It is important for the process of endosomal maturation and enzyme activation along the www.frontiersin.org

Lippiat and Smith

SUMMARY AND PROSPECTIVE