title: Functional interactions of HCO3- with cystic fibrosis transmembrane conductance regulator.
abstract: Disruption of normal cystic fibrosis transmembrane conductance regulator- (CFTR)-mediated Cl(-) transport is associated with cystic fibrosis (CF). CFTR is also required for HCO(3)(-) transport in many tissues such as the lungs, gastro-intestinal tract, and pancreas, although the exact role CFTR plays is uncertain. Given the importance of CFTR in HCO(3)(-) transport by so many CF-affected organ systems, it is perhaps surprising that relatively little is known about the interactions of HCO(3)(-) ions with CFTR. We have used patch clamp recordings from native pancreatic duct cells to study HCO(3)(-) permeation and interaction with CFTR. Ion selectivity studies shows that CFTR is between 3-5 times more selective for Cl(-) over HCO(3)(-). In addition, extracellular HCO(3)(-) has a novel inhibitory effect on cAMP-stimulated CFTR currents carried by Cl(-). The block by HCO(3)(-) was rapid, relatively independent of voltage and occurred over the physiological range of HCO(3)(-) concentrations. These data show that luminal HCO(3)(-) acts as a potent regulator of CFTR, and suggests that inhibition involves an external anion-binding site on the channel. This work has implications not only for elucidating mechanisms of HCO(3)(-) transport in epithelia, but also for approaches used to treat CF.
authors.affiliation: Department of Physiological Sciences, University Medical School, Newcastle upon Tyne, United Kingdom. m.a.gray@ncl.ac.uk
authors.forename: M A
authors.initials: MA
authors.lastname: Gray
authors.forename: C
authors.initials: C
authors.lastname: O'Reilly
authors.forename: J
authors.initials: J
authors.lastname: Winpenny
authors.forename: B
authors.initials: B
authors.lastname: Argent
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D006801:Humans
chemical_list: D001639:Bicarbonates; C505032:CFTR protein, human; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator