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

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.

• Authors: Siegfried Waldegger, Nikola Jeck, Petra Barth, Melanie Peters, Helga Vitzthum, Konrad Wolf, Armin Kurtz, Martin Konrad, Hannsjörg W Seyberth
• Journal: Pflugers Archiv : European journal of physiology (Pflugers Arch) Vol. 444 Issue 3 Pg. 411-8 (Jun 2002) ISSN: 0031-6768 [Print] Germany
• PMID: 12111250 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anion Transport Proteins
• BSND protein, human
• CLCNKA protein, human
• Chloride Channels
• Clcnkb protein, rat
• Membrane Proteins
• RNA, Messenger
• Xenopus Proteins
• bsnd protein, rat
• clcnka protein, Xenopus

Topics

• Animals
• Anion Transport Proteins
• Bartter Syndrome (genetics, metabolism)
• Cell Line
• Chloride Channels (genetics, metabolism)
• Membrane Potentials (physiology)
• Membrane Proteins (genetics, metabolism)
• Nephrons (metabolism)
• Oocytes (physiology)
• Patch-Clamp Techniques
• Point Mutation
• RNA, Messenger (analysis)
• Xenopus Proteins
• Xenopus laevis