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Barttin is a Cl- channel β-subunit crucial for renal Cl- reabsorption and inner ear K+ secretion


Renal salt loss in Bartter's syndrome is caused by impaired transepithelial transport in the loop of Henle. Sodium chloride is taken up apically by the combined activity of NKCC2 (Na+-K--2Cl- cotransporters) and ROMK potassium channels. Chloride ions exit from the cell through basolateral ClC-Kb chloride channels. Mutations in the three corresponding genes have been identified1,2,3 that correspond to Bartter's syndrome types 1–3. The gene4 encoding the integral membrane protein barttin is mutated in a form of Bartter's syndrome that is associated with congenital deafness and renal failure. Here we show that barttin acts as an essential β-subunit for ClC-Ka and ClC-Kb chloride channels, with which it colocalizes in basolateral membranes of renal tubules and of potassium-secreting epithelia of the inner ear. Disease-causing mutations in either ClC-Kb or barttin compromise currents through heteromeric channels. Currents can be stimulated further by mutating a proline-tyrosine (PY) motif on barttin. This work describes the first known β-subunit for CLC chloride channels and reveals that heteromers formed by ClC-K and barttin are crucial for renal salt reabsorption and potassium recycling in the inner ear5.

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Figure 1: Functional characterization of ClC-K/barttin in Xenopus oocytes.
Figure 2: Basic structural and functional features of barttin.
Figure 3: Functional consequences of disease-associated mutations in Xenopus oocytes.
Figure 4: Barttin and ClC-K proteins in murine kidney.
Figure 5: Barttin and ClC-K protein in the inner ear.
Figure 6: Model for renal Cl- reabsorption (a), and for K+ secretion in the stria vascularis5 (b).


  1. Simon, D. B. et al. Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nature Genet. 13, 183–188 (1996).

    Article  ADS  CAS  Google Scholar 

  2. Simon, D. B. et al. Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nature Genet. 14, 152–156 (1996).

    Article  CAS  Google Scholar 

  3. Simon, D. B. et al. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nature Genet. 17, 171–178 (1997).

    Article  CAS  Google Scholar 

  4. Birkenhäger, R. et al. Mutations of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nature Genet. 29, 310–314 (2001).

    Article  Google Scholar 

  5. Jentsch, T. J. Neuronal KCNQ channel: physiology and role in disease. Nature Rev. Neurosci. 1, 21–30 (2000).

    Article  CAS  Google Scholar 

  6. Kieferle, S., Fong, P., Bens, M., Vandewalle, A. & Jentsch, T. J. Two highly homologous members of the ClC chloride channel family in both rat and human kidney. Proc. Natl Acad. Sci. USA 91, 6943–6947 (1994).

    Article  ADS  CAS  Google Scholar 

  7. Vandewalle, A. et al. Localization and induction by dehydration of ClC-K chloride channels in the rat kidney. Am. J. Physiol. 272, F678–F688 (1997).

    CAS  PubMed  Google Scholar 

  8. Kobayashi, K., Uchida, S., Mizutani, S., Sasaki, S. & Marumo, F. Intrarenal and cellular localization of ClC-K2 protein in the mouse kidney. J. Am. Soc. Nephrol. 12, 1327–1334 (2001).

    Article  CAS  Google Scholar 

  9. Uchida, S. et al. Localization and functional characterization of rat kidney-specific chloride channel, ClC-K1. J. Clin. Invest. 95, 104–113 (1995).

    Article  CAS  Google Scholar 

  10. Matsumura, Y. et al. Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel. Nature Genet. 21, 95–98 (1999).

    Article  CAS  Google Scholar 

  11. Uchida, S. et al. Molecular cloning of a chloride channel that is regulated by dehydration and expressed predominantly in kidney medulla. J. Biol. Chem. 268, 3821–3824 (1993); erratum J. Biol. Chem. 269, 19192 (1994).

    Article  CAS  Google Scholar 

  12. Waldegger, S. & Jentsch, T. J. Functional and structural analysis of ClC-K chloride channels involved in renal disease. J. Biol. Chem. 275, 24527–24533 (2000).

    Article  CAS  Google Scholar 

  13. Zerangue, N., Schwappach, B., Jan, Y. N. & Jan, L. Y. A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane KATP channels. Neuron 22, 537–548 (1999).

    Article  CAS  Google Scholar 

  14. Schwake, M., Friedrich, T. & Jentsch, T. J. An internalization signal in ClC-5, an endosomal Cl--channel mutated in Dent's disease. J. Biol. Chem. 276, 12049–12054 (2001).

    Article  CAS  Google Scholar 

  15. Jentsch, T. J., Friedrich, T., Schriever, A. & Yamada, H. The CLC chloride channel family. Pflügers Arch. Eur. J. Physiol. 437, 783–795 (1999).

    Article  CAS  Google Scholar 

  16. Staub, O. et al. WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome. EMBO J. 15, 2371–2380 (1996).

    Article  CAS  Google Scholar 

  17. Schild, L. et al. Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome. EMBO J. 15, 2381–2387 (1996).

    Article  CAS  Google Scholar 

  18. Staub, O. et al. Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. EMBO J. 16, 6325–6336 (1997).

    Article  CAS  Google Scholar 

  19. Konrad, M. et al. Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome. J. Am. Soc. Nephrol. 11, 1449–1459 (2000).

    Article  CAS  Google Scholar 

  20. Alper, S. L., Natale, J., Lodish, H. F. & Brown, D. Subtypes of intercalated cells in rat kidney collecting duct defined by antibodies against erythroid band 3 and renal vacuolar H+-ATPase. Proc. Natl Acad. Sci. USA 86, 5429–5433 (1989).

    Article  ADS  CAS  Google Scholar 

  21. Nielsen, S., DiGiovanni, S. R., Christensen, E. I., Knepper, M. A. & Harris, H. W. Cellular and subcellular immunolocalization of vasopressin-regulated water channel in rat kidney. Proc. Natl Acad. Sci. USA 90, 11663–11667 (1993).

    Article  ADS  CAS  Google Scholar 

  22. Ando, M. & Takeuchi, S. mRNA encoding ‘ClC-K1, a kidney Cl- channel’ is expressed in marginal cells of the stria vascularis of rat cochlea: its possible contribution to Cl- currents. Neurosci. Lett. 284, 171–174 (2000).

    Article  CAS  Google Scholar 

  23. Baloh, R. W. Vertigo. Lancet 352, 1841–1846 (1998).

    Article  CAS  Google Scholar 

  24. Jeck, N. et al. Hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness. Pediatrics 108, E5 (2001).

    Article  CAS  Google Scholar 

  25. Delpire, E., Lu, J., England, R., Dull, C. & Thorne, T. Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter. Nature Genet. 22, 192–195 (1999).

    Article  CAS  Google Scholar 

  26. Dixon, M. J. et al. Mutation of the Na-K-Cl co-transporter gene Slc12a2 results in deafness in mice. Hum. Mol. Genet. 8, 1579–1584 (1999).

    Article  CAS  Google Scholar 

  27. Neyroud, N. et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nature Genet. 15, 186–189 (1997).

    Article  CAS  Google Scholar 

  28. Schulze-Bahr, E. et al. KCNE1 mutations cause Jervell and Lange-Nielsen syndrome. Nature Genet. 17, 267–268 (1997).

    Article  CAS  Google Scholar 

  29. Dedek, K. & Waldegger, S. Colocalization of KCNQ1/KCNE channel subunits in the mouse gastrointestinal tract. Pflügers Arch. Eur. J. Physiol. 442, 896–902 (2001).

    Article  CAS  Google Scholar 

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We thank S. Alper for the AE1 antibody, M. Knepper for the aquaporin-2 antibody, M. Knipper for advice on inner ear immunohistochemistry, and J. Enderich and M. Kolster for technical assistance. R.E. is a recipient of a Marie Curie Human Potential Fellowship of the European Union, and F.H. is a Heisenberg scholar of the Deutsche Forschungsgemeinschaft (DFG). This work was supported by grants from the DFG, the Fonds der Chemischen Industrie, and the Prix Louis Jeantet de Médecine to T.J.J., and from the Federal State of Baden-Württemberg to F.H.

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Correspondence to Thomas J. Jentsch.

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Supplementary information

Figure A. Functional characterisation of CIC-K/barttin channels expressed in transfected tsA201 cells

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Figure B. Topology of barttin

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The first hydrophobic region of barttin may span the membrane or may act as a cleavable signal peptide. The latter possibility is suggested by the program SMART ( To distinguish between these possibilities, we epitope-tagged barttin at either end. This did not affect its ability to elicit currents with ClC-Ka. When these constructs were expressed in COS cells with or without ClC-Ka (Ka) and analysed by Western blotting using an antibody against the epitope, bands corresponding in size to barttin were stained with comparable intensities irrespective of the position of the epitope (Fig. B). Mock-transfected COS cells (Ctrl) and ClC-Ka transfected COS cells were used as a controls (left two lanes). This argues against an amino-terminal cleavage, and supports a model in which barttin has two transmembrane spanning segments in its amino-terminal end.

Figure C. RT-PCR detection of ClC-K1 and ClC-K2 in the cochlea

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To examine whether ClC-K1 and ClC-K2 is expressed in the cochlea, we performed RT-PCR experiments on RNA obtained from mouse cochlea. The primers used could differentiate between the highly homologous (~90% identity) ClC-K1 and ClC-K2 mRNAs. Using PCR conditions and primers described in reference 24, we observed bands of the correct sizes in samples containing cochlear RNA, but not in controls (Fig. C). Thus, both ClC-K1 and ClC-K2 are expressed in the cochlea. Because immunofluorescence indicates that ClC-K channels are only present in the stria vascularis, this strongly suggests that these cells express both isoforms.

Figure D. Antibodies against barttin

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Estévez, R., Boettger, T., Stein, V. et al. Barttin is a Cl- channel β-subunit crucial for renal Cl- reabsorption and inner ear K+ secretion. Nature 414, 558–561 (2001).

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