Our findings suggest that CAR has potential as a new drug target for treatment of condition with hyperactivity/ hyperfunction of CFTR especially secretory diarrheas.
CF-like disease has been reported in a heterozygous carrier of F508delCFTR and the hyperactive variant p.W493R-SCNN1A of the epithelial sodium channel (ENaC).
These data support the hypothesis that wt CFTR can regulate the whole cell, functional, and surface expression of endogenous ENaC in airway epithelial cells and that absence of this regulation may foster ENaC hyperactivity in CF airway epithelia.
We conclude that a latent path may exist between mutation of this conserved sequence, CK2 hyperactivity and disease pathogenesis that might also explain the heterozygote advantage for the common F508delCFTR mutant.
We propose that the hyper-inflammation found in CF may arise as a consequence of disrupted repression of NF-kappaB signalling which is normally mediated by CFTR.