Structure and function of the cystic fibrosis transmembrane conductance regulator

Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). Mutatio ns in the CFTR gene may result in a defective processing of its protein and alter the function and regulation of this channel. Mutations are associate d with different symptoms, including pancreatic insufficiency, bile duct ob struction, infertility in males, high sweat Cl-, intestinal obstruction, na sal polyp formation, chronic sinusitis, mucus dehydration, and chronic Pseu domonas aeruginosa and Staphylococcus aureus lung infection, responsible fo r 90% of the mortality of CF patients. The gene responsible for the cellula r defect in CF was cloned in 1989 and its protein product CFTR is activated by an increase of intracellular cAMP. The CFTR contains two membrane domai ns, each with six transmembrane domain segments, two nucleotide-binding dom ains (NBDs), and a cytoplasmic domain. In this review we discuss the studie s that have correlated the role of each CFTR domain in the protein function as a chloride channel and as a regulator of the outwardly rectifying Cl- c hannels (ORCCs).