The CFTR chloride channel of mammalian heart.

Abstract

Cystic fibrosis (CF), the most prevalent fatal genetic disease among Cauca­ sians, is caused by alterations in the single gene encoding the cystic fibrosis transmembrane conductance regulator (CFfR; 114). The gene alterations result in defective epithelial Cltransport and, consequently, a disruption of fluid secretion in respiratory, intestinal, and reproductive epithelia, and of salt reab­ sorption in sweat glands (109), A single mutation, deletion of the three nucleic acids that code for phenylalanine 508, accounts for two thirds of all diagnosed cases of CF (136), but over 300 other disease-causing mutations have been identified so far. CFfR is now known to be a Clion channel, although, as its name implies, this was not at all clear from the deduced amino acid sequence (1 14). CFfR's predicted topology (Figure 1; 114) of two similar halves, each comprising six putative transmembrane stretches followed by an intracellular nucleotide-bind­ ing domain (NBD), linked by a large intracellular regulatory (R) domain containing mUltiple sites for phosphorylation by protein kinase A (PKA) and protein kinase C (PKC), placed it in the large family of A TP-binding cassette (ABC) tfansport proteins (71). The ABC family includes numerous bacterial peri plasmic transporters as well as eukaryotic members such as the exporter (STE6) of the yeast a-factor mating pheromone, and the mammalian P-glyco-