ADENOSINE TRIPHOSPHATE-DEPENDENT ASYMMETRY OF ANION PERMEATION IN THECYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR CHLORIDE CHANNEL

The cystic fibrosis transmembrane conductance regulator (CFTR) forms a tightly regulated channel that mediates the passive diffusion of Cl- ions. Here we show, using macroscopic current recording from excised m embrane patches, that CFTR also shows significant, but highly asymmetr ical, permeability to a broad range of large organic anions. Thus, all large organic anions tested were permeant when present in the intrace llular solution under biionic conditions (P-X/P-Cl = 0.048-0.25), wher eas most were not measurably permeant when present in the extracellula r solution. This asymmetry was not observed for smaller anions. ATPase inhibitors that ''lock'' CFTR channels in the open state (pyrophospha te, 5'-adenylylimidodiphosphate) disrupted the asymmetry of large anio n permeation by allowing their influx from the extracellular solution, which suggests that ATP hydrolysis is required to maintain asymmetric permeability. The ability of CFTR to allow efflux of large organic an ions represents a novel function of CFTR. Loss of this function may co ntribute to the pleiotropic symptoms seen in cystic fibrosis.