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A molecular mechanism for aberrantCFTR‐dependent HCO 3 − transport in cystic fibrosis
Author(s) -
Ko Shigeru B.H.,
Shcheynikov Nikolay,
Choi Joo Young,
Luo Xiang,
Ishibashi Kenichi,
Thomas Philip J.,
Kim Joo Young,
Kim Kyung Hwan,
Lee Min Goo,
Naruse Satoru,
Muallem Shmuel
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdf580
Subject(s) - cystic fibrosis transmembrane conductance regulator , cystic fibrosis , chloride channel , cotransporter , pendrin , biology , transporter , δf508 , transport protein , membrane transport , membrane potential , ion transporter , biophysics , biochemistry , microbiology and biotechnology , chemistry , membrane , sodium , genetics , organic chemistry , gene
Aberrant HCO 3 − transport is a hallmark of cystic fibrosis (CF) and is associated with aberrant Cl − ‐dependent HCO 3 − transport by the cystic fibrosis transmembrane conductance regulator (CFTR). We show here that HCO 3 − current by CFTR cannot account for CFTR‐activated HCO 3 − transport and that CFTR does not activate AE1–AE4. In contrast, CFTR markedly activates Cl − and OH − /HCO 3 − transport by members of the SLC26 family DRA, SLC26A6 and pendrin. Most notably, the SLC26s are electrogenic transporters with isoform‐specific stoichiometries. DRA activity occurred at a Cl − /HCO 3 − ratio ≥2. SLC26A6 activity is voltage regulated and occurred at HCO 3 − /Cl − ≥2. The physiological significance of these findings is demonstrated by interaction of CFTR and DRA in the mouse pancreas and an altered activation of DRA by the R117H and G551D mutants of CFTR. These findings provide a molecular mechanism for epithelial HCO 3 − transport (one SLC26 transporter—electrogenic transport; two SLC26 transporters with opposite stoichiometry in the same membrane domain—electroneutral transport), the CF‐associated aberrant HCO 3 − transport, and reveal a new function of CFTR with clinical implications for CF and congenital chloride diarrhea.