Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis

Cystic fibrosis (CF) is a disease caused by mutations in the cystic fibrosi s transmembrane conductance regulator (CFTR). Initially, Cl- conductance in the sweat duct was discovered to be impaired in CF1, a finding that has be en extended to all CFTR-expressing cells(2-4). Subsequent cloning of the ge ne(5,6) showed that CFTR functions as a cyclic-AMP-regulated Cl- channel(7) ; and some CF-causing mutations inhibit CFTR Cl- channel activity(2-4,8). T he identification of additional C-causing mutants with normal Cl- channel a ctivity indicates, however, that other CFTR-dependent processes contribute to the disease. Indeed, CFTR regulates other transporters(3,4), including C l- -coupled HCO3- transport(9,10). Alkaline fluids are secreted by normal t issues, whereas acidic fluids are secreted by mutant CFTR-expressing tissue s(11), indicating the importance of this activity. HCO3- and pH affect muci n viscosity(12,13) and bacterial binding(14,15). We have examined Cl- -coup led HCO3- transport by CFTR mutants that retain substantial or normal Cl- c hannel activity. Here we show that mutants reported to be associated with C F with pancreatic insufficiency do not support HCO3- transport, and those a ssociated with pancreatic sufficiency show reduced HCO3- transport. Our fin dings demonstrate the importance of HCO3- transport in the function of secr etory epithelia and in CF.