DISRUPTION OF MONOLAYER INTEGRITY ENABLES ACTIVATION OF A CYSTIC-FIBROSIS BYPASS CHANNEL IN HUMAN AIRWAY EPITHELIA

Cystic fibrosis (CF) is a genetic disease characterized by marked redu ction in Cl- conductance across many epithelia. Two kinds of Cl- chann els have been associated with CF. One channel, termed the cystic fibro sis transmembrane conductance regulator (CFTR), is directly coded by t he CF gene(1-3). The other channel is an outwardly rectifying depolari zation induced Cl- channel (ORDIC) that is distinguished from other ou twardly rectifying chloride channels (ORCCs) because its activity is i nduced most reliably by patch excision and depolarization(4-7). An iss ue in current CF research is whether ORDIC channels are indirectly act ivated by CFTR to contribute a significant portion of apical membrane Cl- conductance in airway cells(6). We now show that ORDIC channels ar e readily activated in patches excised and depolarized from isolated c ells, but are rarer or refractory to activation in patches from the ap ical membranes of confluent human airway epithelia. These findings hav e important implications for proposed therapies that would bypass the CFTR conductance by activating ORDIC channels.