Cell membranes: The CFTR ion channel

The cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane-bound glycoprotein with a 12-helix architecture comprising two pseudosymmetric transmembrane domains (MSD) and two nucleotide-binding domains (NBD), which bind and hydrolyze ATP. Between both NBD units is a single regulatory domain (R) that consists of many charged amino acids. The CFTR protein is predominantly expressed in the lungs, pancreas, sweat glands, intestine, liver, nasal mucosa, salivary glands, and reproductive tract.

Figure 1 Representation of the CFTR protein channel

Among human ABC proteins, CFTR is thought to be unique in that it has no active transport function, but instead acts as a phosphorylation-regulated, ATP-gated anion channel. Under normal conditions, CFTR works like a gate that is tightly coupled to ATPase cycles. The binding of ATP to the NBDs induces NBD dimerization – this results in the formation of a transmembrane domain cavity that opens towards the extracellular side to allow the selective flow of anions, such as chloride (Cl${}^{-}$‍) and bicarbonate (HCO3${}^{-}$‍). Particularly in the airway, CFTR regulates the local pH by allowing Cl${}^{-}$‍ and HCO3${}^{-}$‍ to flow out of the cell; in addition, it causes the epithelial sodium channel ENaC to transport sodium into the cell.

Cystic fibrosis (CF) is an autosomal recessive, multisystemic, and chronic disease that originates from pathogenic changes in the CFTR gene, located on the long arm of chromosome 7 (locus 7q.31). More than 2000 CFTR variants have been identified in CF patients, but the most common variant is a phenylalanine deletion at position 508 (p.F508del, ∆F508). The pathogenic variants and their effects have been grouped into several classes, as summarized in Table 1.

Table 1 Classification of CFTR gene mutations