Calcium homeostasis is abnormal in cystic fibrosis airway epithelial cells but is normalized after rescue of F508del-CFTR

Abstract Retention of F508del-CFTR proteins in the endoplasmic reticulum (ER) is dependent upon chaperone proteins, many of which require Ca2+ for optimal activity. Here, we show in human tracheal gland CF-KM4 cells, that after correction of F508del-CFTR trafficking by miglustat ( N -butyldeoxynojirimycin) or low temperature (27 °C), the Ca2+ mobilization is decreased compared to uncorrected cells and becomes identical to the Ca2+ response observed in non-CF MM39 cells. In CF-KM4 and human nasal epithelial CF15 cells, we also show that inhibiting vesicular trafficking by nocodazole prevents not only the rescue of F508del-CFTR but also the Ca2+ mobilization decrease. Finally, experiments using the CFTR inhibitor CFTRinh -172 showed that the presence but not the channel activity of F508del-CFTR at the plasma membrane is required to decrease the Ca2+ mobilization in corrected CF cells. These findings show that correction of the abnormal trafficking of F508del-CFTR proteins might have profound consequences on cellular homeostasis such as the control of intracellular Ca2+ level.