Changes in luminal anion concentration regulate CFTR channel activity
The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial Cl- channel that plays a key role in regulating salt and fluid secretion in many epithelial tissues. Mutations in this protein cause cystic fibrosis and over activity of CFTR underlie many forms of secretory diarrhoeas. How the ion transport activity of CFTR is controlled is crucial to understanding the molecular mechanism of epithelial secretion in both normal and disease states. Through high resolution patch clamp studies we provided the first evidence that CFTR is regulated by ‘luminal’ signals. We showed that external (luminal) Cl- concentration directly controls the gating of CFTR. This novel form of regulation was specific to Cl- and likely involves an interaction with a non-pore regulatory Cl- -binding site on CFTR itself. The ability of Cl- to control CFTR function is likely to be physiologically important, particularly for those tissues which secrete high concentrations of HCO3-, where luminal Cl- falls as HCO3- levels rise. Together with other work showing that low external Cl- also alter the permeability of CFTR to anions, our observations established the importance of external Cl- as a novel factor governing CFTR function.
O’Reilly CM, Winpenny JP, Argent BE and Gray MA. 2000. Cystic fibrosis transmembrane conductance regulator currents in guinea pig pancreatic duct cells: Inhibition by bicarbonate ions. Gastroenterology 118, 1187-1196.
Wright AM, Gong X, Verdon B, Linsdell P, Mehta A, Riordan JR, Argent BE and Gray MA. 2004. Novel regulation of CFTR channel gating by external chloride. Journal of Biological Chemistry 279, 41658-41663.
