Bestrophin‐mediated Ca2+ activated Cl‐ conductance of the airway epithelium

Cystic fibrosis, CF, occurs due to the loss of the epithelial, cAMP‐mediated Cl − channel, CFTR. Airway epithelia also contain a second pathway for Cl − secretion, referred to as the calcium activated Cl − conductance (CaCC). Several members of a recently identified gene family (Bestrophin) have been shown to function as Ca 2+ activated Cl − channels. Bestrophin isoforms from a variety of species have been identified and mutations in the hBestrophin1 gene product are associated with vitelliform macular dystrophy‐type 2 (VMD2), also known as “Best’s disease”. We hypothesize that mBestrophin2 mediates the CaCC activity of the murine airway apical membrane. mBestrophin2 is i) expressed in both whole lung and cultured murine tracheal epithelial cells (MTE’s), and ii) absent in the murine intestinal epithelium (a tissue source that lacks CaCC activity). No other murine Bestrophin demonstrates this expression profile. Furthermore, we have shown CaCC activity following expression of mBestrophin2 in ambystoma oocytes and Fischer Rat Thyroid (FRT) cell monolayers. Moreover, function of mBest2 can be regulated by co‐expression with P 2 Y 2 and inhibited by the Cl − channel blocker, niflumic acid. Interestingly, our expression studies of the human airway suggest that hBestrophin3 is the predominant Bestrophin responsible for CaCC activity in this tissue, with no apparent expression of hBestrophin2. Studies examining the functional differences between mBestrophin2 and hBestrophin3 may provide insight into the apparent lack of a CF airway phenotype in the CF mouse model. (supported by NIH [HL62564] and the CFF).