Cystic fibrosis regulatory

CFTR has a single-channel conductance of about 8 pS. It is present in the apical membranes of many epithelia. Its mutation leads to the potentially lethal disease cystic fibrosis. In addition to acting as a chloride channel, CFTR is also thought to regulate, e.g., the epithelial sodium channel ENaC, a molecularly unknown outwardly-rectifying chloride channel, and possibly also potassium channels and water channels. Some of these potential regulatory processes, however, are controversial. CFTR also acts as a receptor for bacteria. 

Figure 41-17. Diagram of the structure of the CFTR protein (not to scale). The protein contains twelve transmembrane segments (probably helical), two nucleotide-binding folds or domains (NBFl and NBF2), and one regulatory (R) domain. NBFl and NBF2 probably bind ATP and couple its hydrolysis to transport of Cl . Phe 508, the major locus of mutations in cystic fibrosis, is located in NBFl.

The hypothesis that Pgp regulates volume-activated chloride channels was developed by the observation that Pgp was highly related to the cystic fibrosis transmembrane regulator protein (CFTR). CFTR belongs, like Pgp, to the ABC superfamily of transporters and is a plasma membrane chloride channel that is dysfunctional in cystic fibrosis (50). However, the role of Pgp in volume-regulatory processes has been controversial, and a current hypothesis is that Pgp does not have channel activity itself, but it may regulate swelling-induced anion channels (57). 

There are other diseases whose incidence is likely to remain static. Cystic fibrosis is the most common genetic disorder in Caucasian populations. It afflicts between one in 1600 and one in 8000. In the UK, about 400 infants per year are bom with the disorder and less than 25% would be expected to live until their thirties. The population of sufferers depends on survival rates but, with a United States incidence of one in 3800, a figure of the order of 10 000 is probable, well within the orphan drag Umit. Recombinant DNase, Pulmozyme (doraase alpha) is an orphan drug that breaks down the thick mucous secretions associated with the disease. It gained regulatory approval in 1994 but the cost per patient is about 10 000 per year. °... 

Poulsen JH, Fischer H, Illek B, Machen TE. Bicarbonate conductance and pH regulatory capability of cystic fibrosis transmembrane conductance regulator. E roc Natl Acad Sci USA 1994 91 5340. 

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