TY - JOUR TI - Cystic fibrosis drug ivacaftor stimulates CFTR channels at picomolar concentrations AU - Csanády, László AU - Töröcsik, Beáta A2 - Islas, Leon D A2 - Aldrich, Richard A2 - Islas, Leon D A2 - Simon, Sidney VL - 8 PY - 2019 DA - 2019/06/17 SP - e46450 C1 - eLife 2019;8:e46450 DO - 10.7554/eLife.46450 UR - https://doi.org/10.7554/eLife.46450 AB - The devastating inherited disease cystic fibrosis (CF) is caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel. The recent approval of the CFTR potentiator drug ivacaftor (Vx-770) for the treatment of CF patients has marked the advent of causative CF therapy. Currently, thousands of patients are being treated with the drug, and its molecular mechanism of action is under intensive investigation. Here we determine the solubility profile and true stimulatory potency of Vx-770 towards wild-type (WT) and mutant human CFTR channels in cell-free patches of membrane. We find that its aqueous solubility is ~200 fold lower (~60 nanomolar), whereas the potency of its stimulatory effect is >100 fold higher, than reported, and is unexpectedly fully reversible. Strong, but greatly delayed, channel activation by picomolar Vx-770 identifies multiple sequential slow steps in the activation pathway. These findings provide solid guidelines for the design of in vitro studies using Vx-770. KW - cystic fibrosis KW - potentiator drug KW - F508del KW - G551D KW - Vx-770 KW - solubility JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -