Defective regulatory volume decrease in human cystic fibrosis tracheal cells because of altered regulation of intermediate conductance Ca2+-dependentpotassium channels

The cystic fibrosis transmembrane conductance regulator (CFTR) protein has the ability to function as both a chloride channel and a channel regulator. The loss of these functions explains many of the manifestations of the cys tic fibrosis disease (CF), including lung and pancreatic failure, meconium ileus, and male infertility. CFTR has previously been implicated in the cel l regulatory volume decrease (RVD) response after hypotonic shocks in murin e small intestine crypts, an effect associated to the dysfunction of an unk nown swelling-activated potassium conductance. In the present study, we inv estigated the RVD response in human tracheal CF epithelium and the nature o f the volume-sensitive potassium channel affected, Neither the human trache al cell line CFT1, expressing the mutant CFTR-Delta F508 gene, nor the isog enic vector control line CFT1-LC3, engineered to express the beta gal gene, showed RVD, On the other hand, the cell line CFT1-LCFSN, engineered to exp ress the wild-type CFTR gene, presented a full RVD, Patch-clamp studies of swelling-activated potassium currents in the three cell lines revealed that all of them possess a potassium current with the biophysical and pharmacol ogical fingerprints of the intermediate conductance Ca2+-dependent potassiu m channel (IK, also known as KCNN4), However, only CFT1-LCFSN cells showed an increase in IK currents in response to hypotonic challenges. Although th e identification of the molecular mechanism relating CFTR to the hIK channe l remains to be solved, these data offer new evidence on the complex integr ation of CFTR in the cells where it is expressed.