title: A molecular mechanism for aberrant CFTR-dependent HCO(3)(-) transport in cystic fibrosis.
abstract: 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 > or =2. SLC26A6 activity is voltage regulated and occurred at HCO(3)(-)/Cl(-) > or =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.
authors.affiliation: Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shigeru B H
authors.initials: SB
authors.lastname: Ko
authors.forename: Nikolay
authors.initials: N
authors.lastname: Shcheynikov
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Choi
authors.forename: Xiang
authors.initials: X
authors.lastname: Luo
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishibashi
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Thomas
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.forename: Satoru
authors.initials: S
authors.lastname: Naruse
authors.forename: Shmuel
authors.initials: S
authors.lastname: Muallem
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001639:Bicarbonates / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D017931:DNA Primers; D007150:Immunohistochemistry; D017136:Ion Transport; D051379:Mice; D008969:Molecular Sequence Data; D051381:Rats
chemical_list: D001639:Bicarbonates; D002712:Chlorides; D017931:DNA Primers; D019005:Cystic Fibrosis Transmembrane Conductance Regulator