The cystic fibrosis transmembrane conductance regulator and its function in epithelial transport.

CF is a well characterized disease affecting a variety of epithelial tissues. Impaired function of the cAMP activated CFTR Cl- channel appears to be the basic defect detectable in epithelial and non-epithelial cells derived from CF patients. Apart from cAMP-dependent Cl- channels also Ca2+ and volume activated Cl- currents may be changed in the presence of CFTR mutations. This is supported by recent additional findings showing that different intracellular messengers converge on the CFTR Cl- channel. Analysis of the ion transport in CF airways and intestinal epithelium identified additional defects in Na+ transport. It became clear recently that mutations of CFTR may also affect the activity of other membrane conductances including epithelial Na+ channels, KvLQT-1 K+ channels and aquaporins (Fig. 7). Several additional, initially unexpected effects of CFTR on cellular functions, such as exocytosis, mucin secretion and regulation of the intracellular pH were reported during the past. Taken together, these results clearly indicate that CFTR not only acts as a cAMP regulated Cl- channel, but may fulfill several other cellular functions, particularly by regulating other membrane conductances. Failure in CFTR dependent regulation of these membrane conductances is likely to contribute to the defects observed in CF. Currently, no general concept is available that can explain how CFTR controls this variety of cellular functions. Further studies will have to verify whether direct protein interaction, specific effects on membrane turnover, changes of the intracellular ion concentration or additional proteins are involved in these regulatory loops. At the end of this review one cannot share the provocative and reassuring title "CFTR!" of a review written a few years ago [114]. Today one might rather finish with the statement "CFTR?".