One of the main problems for many individuals with CF is blockage of the outflow of digestive enzymes from the exocrine pancreas into the small intestine, and the resultant pancreatitis that can lead to the cystic changes in the pancreas previously noted by Dorothy Andersen in 1938.A second major difficulty in CF (and probably the most devastating for the long-term health of the individual) is the accumulation of heavy dehydrated mucus in the airways and the resultant changes in the capability of the lungs to fight infections. A third major change—which leads to the ability to use the sweat chloride test as the standard diagnostic test for the disease—is the abnormally salty sweat of CF patients. A fourth clinical manifestation is sterility in both males and females; this is particularly prevalent in males and may be irreversible. A fifth manifestation, which may be recognized less frequently than some of the others, is abnormal secretion in the small intestine.

Mutations Causing CF
How do the various CF mutations affect the function of the CFTR proteins? The various mutations that have been shown to cause CF have been categorized into four classes:

• Class I mutations cause defective protein production, with a total loss of functional CFTRs. One defect produces a truncated CFTR due to premature stop mutants. This defect may be corrected by certain antibiotics that bypass the shortened protein to make full-length functional CFTR.These antibiotics have restored 25–35% CFTR protein function when only 10% correction appears to be enough for noticeable improvement in patients.
• Class II mutations cause defective protein processing leading to CFTR that is not in its correct location in the cell or that is different from CFTRs in normal individuals (fewer glycoproteins and gangliosides on the cell surface in CF cells). The most common mutation found in 70% of CF patients (the delta F508 deletion) is one of these class II mutations.
• Class III mutations cause defective regulation of channel opening of CFTR by changes in the nucleotide binding fold or R domain of CFTR.
• Class IV mutations cause defective ion conduction through CFTRs. These mutations are in the membrane-spanning domains of the protein and thus affect the pore that normally allows ion fluxes.

Class I and II mutations generally lead to the more serious phenotype of the disease and have accompanying pancreatic insufficiency. Class III and IV mutations generally lead to a less serious phenotype with normal pancreatic function.

Regulation of CFTR
How are CFTRs in normal, healthy people regulated? Various studies of CFTR protein function have shown that, in the absence of phosphorylation of the regulatory (R) domain, the channel is closed and chloride ion transport ceases. Cyclic adenosine monophosphate (cAMP) stimulates protein kinase A to phosphorylate one to four serine residues on the R domain and, depending upon how many sites are phosphorylated, the CFTR may be activated to varying degrees. Sequential phosphorylation of at least three sites increases the likelihood of high-affinity binding of adenosine triphosphate (ATP) to the nucleotide binding fold and enhances the open probability of the channel.When the nucleotide binding folds (NBFs) on CFTR bind ATP, a conformational change occurs.ATP hydrolysis has been shown to be necessary for the conformational change in the pore and may be located in or near the membranespanning portion of the pore.These changes may lead to as many as three different gating states of the pore, including closed, open only briefly, and open for long periods of time. In addition, the open probability and voltage-dependent fast gate of CFTR may be dependent upon tyrosine phosphorylation.

CFTRs are cAMP and protein kinase A-regulated chloride channels that also regulate numerous other ion channels. Recent studies have shown that at least 13 different transporters interact with CFTR by being inhibited or activated, and that a common motif for protein interaction called the PDZ-binding domain is likely involved.5 Evidence indicates that CFTRs play important roles in the transcellular secretion of bicarbonate by serving as the conductive pathway for hydrocarbonate (HCO₃ -) exit across the apical membranes in HCO₃ --secreting cells.