Referenced in: none

Automatically associated channels: ClC4 , ClC5

Title: Intracellular regulation of human ClC-5 by adenine nucleotides.

Authors: Giovanni Zifarelli, Michael Pusch

Journal, date & volume: EMBO Rep., 2009 Oct , 10, 1111-6

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19713962

Abstract
ClC-5, an endosomal Cl(-)/H(+) antiporter that is mutated in Dent disease, is essential for endosomal acidification and re-uptake of small molecular weight proteins in the renal proximal tubule. Eukaryotic chloride channels (CLCs) contain two cytoplasmic CBS domains, motifs present in different proteins, the function of which is still poorly understood. Structural studies have shown that ClC-5 can bind to ATP at the interface between the CBS domains, but so far the potential functional consequences of nucleotide binding to ClC-5 have not been investigated. Here, we show that the direct application of ATP, ADP and AMP in inside-out patch experiments potentiates the current mediated by ClC-5 with similar affinities. The nucleotides increase the probability of ClC-5 to be in an active, transporting state. The residues Tyr 617 and Asp 727, but not Ser 618, are crucial for the potentiation. These results provide a mechanistic and structural framework for the interpretation of nucleotide regulation of a CLC transporter.