Referenced in: none

Automatically associated channels: ClC4 , ClCK1 , Kir1.1

Title: Barttin increases surface expression and changes current properties of ClC-K channels.

Authors: Siegfried Waldegger, Nikola Jeck, Petra Barth, Melanie Peters, Helga Vitzthum, Konrad Wolf, Armin Kurtz, Martin Konrad, Hannsjörg W Seyberth

Journal, date & volume: Pflugers Arch., 2002 Jun , 444, 411-8

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/12111250

Abstract
The term Bartter syndrome encompasses a heterogeneous group of autosomal recessive salt-losing nephropathies that are caused by disturbed transepithelial sodium chloride reabsorption in the distal nephron. Mutations have been identified in the NKCC2 (Na(+)-K(+)-2Cl(-)) cotransporter and ROMK potassium channel, which cooperate in the process of apical sodium chloride uptake, and ClC-Kb chloride channels, which mediate basolateral chloride release. Recently, mutations in barttin, a protein not related to any known ion transporter or channel, were described in BSND, a variant of Bartter syndrome associated with sensorineural deafness. Here we show that barttin functions as an activator of ClC-K chloride channels. Expression of barttin together with ClC-K in Xenopus oocytes increased ClC-K current amplitude, changed ClC-K biophysical properties, and enhanced ClC-K abundance in the cell membrane. Co-immunoprecipitation revealed a direct interaction of barttin with ClC-K. We performed in situ hybridization on rat kidney slices and RT-PCR analysis on microdissected nephron segments to prove co-expression of barttin, ClC-K1 and ClC-K2 along the distal nephron. Functional analysis of BSND-associated point mutations revealed impaired ClC-K activation by barttin. The results demonstrate regulation of a CLC chloride channel by an accessory protein and indicate that ClC-K activation by barttin is required for adequate tubular salt reabsorption.