Expression of deltaF508 CFTR Results in Depletion of Endoplasmic Reticulum (ER) Ca2+ levels

Cystic fibrosis (CF) is predominately associated with inheritance in the homologous configuration of the delta508 mutation in the ABC transporter cystic fibrosis transmembrane conductance regulator(CFTR). The underlying basis for the CF pathology has generally been attributed to an absence of Cl‐ secretion through CFTR. The importance of other mechanisms creating the CF lung pathology is beginning to receive considerable attention. To investigate whether deltaF508 CFTR elicits a cellular stress response, we used Ca2+ imaging in transfected HEK293 cells. We demonstrated that deltaF508 CFTR leads to store depletion and elevation of resting cytosolic Ca2+ levels. Store operated Ca2+ influx was not altered by deltaF508 CFTR expression. Western blot analysis indicated that SERCA2b expression is reduced in deltaF508 CFTR expressing cells, which may correspond to a defect in refilling the ER with Ca2+. Our data indicate the deltaF508 CFTR may alter ER Ca2+ handling, potentially through modulation of the SR/ER Ca2+ ATPase (SERCA). Given that depletion of ER Ca2+ stores and elevation of resting cytosolic Ca2+ levels may lead to cellular stress response that activates the transcription factor NF‐kappaB, we propose that a underlying mechanism of CF pathology may consist of reduction of ER Ca2+ levels and subsequent activation of a cellular stress response (Supported by the Cystic Fibrosis Foundation).