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

Abstract

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 cells^2,3,4. Subsequent cloning of the gene^5,6 showed that CFTR functions as a cyclic-AMP-regulated Cl^- channel⁷; and some CF-causing mutations inhibit CFTR Cl^- channel activity^2,3,4,8. 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 transporters^3,4, including Cl^--coupled HCO^-₃ transport^9,10. 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 viscosity^12,13 and bacterial binding^14,15. 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.