CYSTIC FIBROSIS; CFTR AND THE DEFECT IN MEMBRANE TRANSPORT

Karl Kunzelmann, Department of Physiology and Pharmacology, University of Queensland, St. Lucia, QLD 4072. uqkkunze@mailbox.uq.edu.au

Cystic fibrosis is characterized by a chronic pulmonary and intestinal disease and is of high medical relevance. In epithelial tissues of cystic fibrosis patients, the secretory Cl^- transport is impaired, while the absorptive Na⁺ transport is enhanced. The disease causing cystic fibrosis transmembrane conductance regulator (CFTR) is a protein expressed primarily in luminal membranes of secretory and absorptive epithelial cells, along with other proteins in charge of epithelial transport. After initial characterization of CFTR as a cAMP and protein kinase A regulated Cl^- channel, numerous studies reported influences of CFTR on other independent membrane transport proteins, such as epithelial Na⁺ channels, K⁺ and Cl^- channels, as well as electroneutral transporters such as the Na⁺/H⁺ exchanger or the Cl^-/HCO₃^- antiporter. Currently best examined is the regulation of the epithelial Na⁺ channel ENaC by CFTR. The mechanisms for the inhibition of ENaC by CFTR are only slowly emerging. CFTR may control the membrane transport by other proteins not just by a single mechanism. CFTR's first nucleotide binding domain plays a central role, the Cl^- transport by CFTR affects other transport proteins and CFTR is linked to some of these transport proteins via PDZ binding domain proteins, which may be co-localized in small functional membrane micro-domains. Moreover, a direct binding of CFTR to other transport proteins cannot be excluded. Thus, the puzzle around the functional relationship of CFTR, ENaC and other transport proteins, has not yet been solved and the results may not even be the same in each cell type.