Question: 

The cystic fibrosis (CF)-associated HCO₃^- secretory defect interferes with mucus clearance, nutrient absorption and fertility. Corrector drug therapy allows the most frequent mutation in CF, the F508del mutant, to partially escape proteasome degradation and reach the apical membrane. But does this restore the HCO₃^- secretory defect? This study aims at finding out whether, and by what molecular mechanism, F508del membrane expression can promote epithelial HCO₃^- secretion in mouse intestine.

Methods: 

Basal and forskolin (FSK) stimulated duodenal HCO₃^- secretion was studied in vivo in luminally perfused (duodenum and colon) anesthetized mice, as well as in vitro in isolated duodenal and colonic mucosa of CFTR KO, F508del mutant, and WT littermates, congenic on FVB/N background. Western blot analysis was performed in isolated brush border membranes (BBM).

Results:

Western blot analysis demonstrated approx 5%, and 0% glycosylated band C CFTR in the intestinal BBM of F508del, and CFTR KO, respectively, compared to WT BBM. The FSK-induced, CFTR dependent Isc response in the F508del mutant intestinal mucosa was also approx. 5–10% of that in WT mucosa, whereas the CFTR-dependent HCO₃^- secretory response in F508del was almost half of the WT response. Similar results were obtained in vivo. This markedly higher HCO₃^- than Isc response in the F508del intestine was completely dependent on the presence of luminal Cl^- both in the duodenal as well as colonic mucosa.

Conclusion: 

The data suggest that even a very low Cl^- membrane conductance significantly enhances apical Cl^-/HCO₃^- exchange. This suggests that F508del corrector therapy has the potential to significantly enhance epithelial HCO₃^- secretion. In vivo studies to further investigate this issue are warranted.