Barttin is a Cl- channel beta-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 identified that correspond to Bartter's syndrome types 1-3. The gene 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 beta-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 beta-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 ear.
Estévez
R
R
Zentrum für Molekulare Neurobiologie (ZMNH), Universität Hamburg, Falkenried 94, D-20246 Hamburg, Germany.
Boettger
T
T
Stein
V
V
Birkenhäger
R
R
Otto
E
E
Hildebrandt
F
F
Jentsch
T J
TJ
D000042:Absorption; D000818:Animals; D027321:Anion Transport Proteins; D001477:Bartter Syndrome / Q000378:metabolism; D002460:Cell Line; D018118:Chloride Channels / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D007758:Ear, Inner / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D021122:Protein Subunits; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014981:Xenopus
D027321:Anion Transport Proteins; C440005:BSND protein, human; C412733:CLCNKB protein, human; D018118:Chloride Channels; D002712:Chlorides; D008565:Membrane Proteins; D021122:Protein Subunits; D011994:Recombinant Proteins; D011188:Potassium