The gene that is defective in patients with cystic fibrosis (CF) encodes a protein termed the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a member of a superfamily of transmembrane proteins known as the ATP Binding Cassette (ABC) Transporters. It is clear that CFTR functions as a cAMP dependent protein kinase A stimulated chloride (CI-) channel. Although abnormal CI- channel activity, specifically cAMP- dependent protein kinase A (PKA) stimulation of CI- secretion, is a predominant feature of CF- affected epithelial cells and believed to be a direct result of the dysfunctional CFTR protein, there are a number of other ion transport abnormalities that are characteristic of CF- affected epithelial cells. There is increasing evidence that CFTR can interact with other channel proteins and act as a channel regulator as do a number of the ABC transporters. Our hypothesis is the CFTR is a bifunctional peptide that acts as a regulator of ion channels and transporters as well as a regulated CI- channel. Furthermore it is likely that the ability to act as a channel regulator depends on domains that are common to many members of the ABC transporter superfamily. The studies proposed in this application will examine how CFTR acts as a channel regulator. Voltage clamp and patch clamp techniques will be used to dissect the mechanisms that control CFTR's interactions with ion channels and identify which domains of CFTR participate in these interactions. The ultimate goal of this project is to apply insights gained from these basic science studies of CFTR function to improve the clinical management of cystic fibrosis patients.
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