Aberrant CFTR-dependent HCO-3 transport in mutations associated with cystic fibrosis

Cystic fibrosis (CF) is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Initially, Cl- conductance in the sweat duct was discovered to be impaired in CF1, a finding that has been extended to all CFTR-expressing cells2,3,4. Subsequent cloning of the gene5,6 showed that CFTR functions as a cyclic-AMP-regulated Cl- channel7; and some CF-causing mutations inhibit CFTR Cl- channel activity2,3,4,8. The identification of additional CF-causing mutants with normal Cl- channel activity indicates, however, that other CFTR-dependent processes contribute to the disease. Indeed, CFTR regulates other transporters3,4, including Cl--coupled HCO-3 transport9,10. Alkaline fluids are secreted by normal tissues, whereas acidic fluids are secreted by mutant CFTR-expressing tissues11, indicating the importance of this activity. HCO-3 and pH affect mucin viscosity12,13 and bacterial binding14,15. We have examined Cl--coupled HCO-3 transport by CFTR mutants that retain substantial or normal Cl- channel activity. Here we show that mutants reported to be associated with CF with pancreatic insufficiency do not support HCO-3 transport, and those associated with pancreatic sufficiency show reduced HCO-3 transport. Our findings demonstrate the importance of HCO-3 transport in the function of secretory epithelia and in CF.