Interaction non grata between CFTR’s correctors and potentiators

Cystic fibrosis (CF), the most common life-shortening hereditary diseases in people of Caucasian ethnicity, is caused by mutations that render the CF transmembrane conductance regulator (CFTR) chloride channel dysfunctional (1,2). So far, more than 1,900 mutations have been discovered to cause CF (http://www.cftr2.org) (3,4), but approximately 90% of the CF patients are inherited with at least one copy of the ΔF508 mutation, the deletion of a single amino acid residue phenylalanine at position 508. Multiple defects of the CFTR channels have been associated with the ΔF508 mutation. It is now well established that the majority of misfolded ΔF508-CFTR proteins are degraded by the endoplasmic reticulum (ER) quality control machinery (5,6). This defect in protein maturation, which results in an insufficient amount of functional channels reaching the apical membrane of epithelial cells (7), is further exacerbated by the fact that once the ΔF508-CFTR channels do make it to the plasma membrane, their half-life is greatly shortened (7,8). Adding on top of these already intractable pathologies is a disrupted gating, i.e., a much reduced probability of the mutant channel being opened (9-11), for ΔF508 channels that stay long enough in the cell membrane to be recorded by electrophysiological means. The requirement of having drugs to correct all the underlying defects including misfolding, mislocalization, protein instability and malfunction of channel gating in ΔF508-CFTR leaves this most common disease-associated mutant thornier to be contended in our search for targeted CF therapy.