These results begin to indicate that nucleoside triphosphates directly regulate CFTR Cl- channels by interacting with the NBDs. Thus, they may begin to explain why some CF-associated mutations in the NBDs may block Cl- channel function in the epithelia of CF patients. These results also suggest that the intracellular ATP/ADP ratio may be more important than the absolute concentration of ATP in regulating CFTR. Thus, changes in the metabolic state of the cell that alter the ATP-ADP ratio may regulate CFTR Cl- channel activity in vivo. These observations suggest that CFTR might be regulated in the physiologic range of nucleotides. Such a mechanism of regulation could provide a mechanism for coupling the metabolic status of the cell and the activity of the Na-K ATPase with the rate of transepithelial Cl- secretion as regulated by apical membrane CFTR Cl- channels.