Mike A Gray, Catherine A O'Reilly, John Winpenny, Barry Argent
Disruption of normal cystic fibrosis transmembrane conductance regulator- (CFTR)-mediated Cl- transport is associated with cystic fibrosis (CF). CFTR is also required for HCO3 - 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 HCO3 - transport by so many CF-affected organ systems, it is perhaps surprising that relatively little is known about the interactions of HCO3 - ions with CFTR. We have used patch clamp recordings from native pancreatic duct cells to study HCO3 - permeation and interaction with CFTR. Ion selectivity studies shows that CFTR is between 3-5 times more selective for Cl- over HCO3 - . In addition, extracellular HCO3 - has a novel inhibitory effect on cAMP-stimulated CFTR currents carried by Cl- . The block by HCO3 - was rapid, relatively independent of voltage and occurred over the physiological range of HCO3 - concentrations. These data show that luminal HCO3 - 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 HCO3 - transport in epithelia, but also for approaches used to treat CF.
