Cystic Fibrosis Transmembrane Conductance Regulator: STRUCTURE AND FUNCTION OF AN EPITHELIAL CHLORIDE CHANNEL

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) forms a Cl channel that is an essential component of epithelial Cl transport systems in many organs, including the intestines, pancreas, lungs, sweat glands, and kidneys. In the Cl secretory intestinal epithelium, Cl enters the cells through a Na-K-2Cl cotransporter in the basolateral membrane and exits through CFTR in the apical membrane; water follows osmotically (1). Absorptive epithelia use similar transporters and channels, but their polarized distribution between the apical and basolateral membranes is usually reversed. A major determinant of the transepithelial Cl transport rate is the level of activation of CFTR (2, 3), which depends on the extent to which it is phosphorylated. This is determined by the relative activities of kinases and phosphatases, the activities of which are often hormonally regulated (1). Defects in the gene encoding CFTR that reduce either its Cl transport capacity or its level of cell surface expression cause cystic fibrosis (CF) (4–6) as well as a form of male sterility due to congenital bilateral absence of the vas deferens (7). CF is the most common lethal genetic disease in Caucasians, with about 30,000 CF patients in the United States. In contrast, in intestinal epithelial cells overstimulation of CFTR because of the activation of protein kinases by bacterial enterotoxins causes secretory diarrhea (1, 8). Secretory diarrhea is the second largest cause of infant mortality in the developing world, causing 3 million deaths per year of children under the age of 5. Thus, although CFTR was named because of its association with CF, as a cause of disease, its relationship to secretory diarrhea is a more widespread public health problem. The cloning of CFTR in 1989 (9) has facilitated studies of its structure, function, regulation, biogenesis, and degradation, which will be reviewed in this article. Issues reviewed elsewhere and not discussed here include the mechanisms by which mutations in CFTR cause CF (5, 6) and the possible role of CFTR in regulating the pH within intracellular organelles (10).