title: ClC transporters: discoveries and challenges in defining the mechanisms underlying function and regulation of ClC-5.
abstract: The involvement of several members of the chloride channel (ClC) family of membrane proteins in human disease highlights the need to define the mechanisms underlying their function and the consequences of disease-causing mutations. Despite the utility of high-resolution structural models, our understanding of the molecular basis for function of the chloride channels and transporters in the family remains incomplete. In this review, we focus on recent discoveries regarding molecular mechanisms underlying the regulated chloride:proton antiporter activity of ClC-5, the protein mutated in the Dent's disease-a kidney disease presenting with proteinuria and renal failure in severe cases. We discuss the putative role of ClC-5 in receptor-mediated endocytosis and protein uptake by the proximal renal tubule and the possible molecular and cellular consequences of disease-causing mutations. However, validation of these models will require future study of the intrinsic function of this transporter, in situ, in the membranes of recycling endosomes in proximal tubule epithelial cells.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Toronto, and Programme in Molecular Structure and Function, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Leigh
authors.initials: L
authors.lastname: Wellhauser
authors.forename: Christina
authors.initials: C
authors.lastname: D'Antonio
authors.forename: Christine E
authors.initials: CE
authors.lastname: Bear
mesh_terms: D000818:Animals; D053447:Channelopathies / Q000503:physiopathology; D018118:Chloride Channels / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007669:Kidney Calculi / Q000503:physiopathology; D007674:Kidney Diseases / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000503:physiopathology; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D010750:Phosphoproteins / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology
chemical_list: C097503:CLC-5 chloride channel; D018118:Chloride Channels; D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor