Beschreibung:
<jats:sec><jats:label /><jats:p>The advent of targeted CFTR therapeutics allows us to assess differences in epithelial Cl<jats:sup>−</jats:sup> and HCO<jats:sup>3−</jats:sup> conductances that might be attributed to unique combinations of CFTR variants (mutations), CFTR modulators (corrector(s) and potentiators) as well as secretory agonists. To address these questions, Fisher rat thyroid cells expressing wt or mutant CFTR were cultured on permeable supports for the measurement of transepithelial conductance (<jats:italic>G</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub>) in defined ionic conditions. Initial experiments demonstrated stepwise reduction in the forskolin (Forsk)+ivacaftor (VX770)‐stimulated change in <jats:italic>G</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub> as bath NaCl was partially replaced isosmotically with mannitol. Subsequent experiments were conducted in buffers containing 100 mEq/l Cl<jats:sup>−</jats:sup> with the addition of either 25 mM alternative anions (Na<jats:sup>+</jats:sup> salts) or 50 mM mannitol. Outcomes showed forskolin‐induced <jats:italic>G</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub> changes consistent with reported CFTR permselectivity: Cl<jats:sup>−</jats:sup> > NO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> ≥ Br<jats:sup>−</jats:sup> > isethionate ≥ gluconate > mannitol. All subsequent experiments were conducted to assess <jats:italic>G</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub> with 100 mEq/l Cl<jats:sup>−</jats:sup> plus either 25 mEq/l HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>, 50 mM mannitol or 25 mEq/l Cl<jats:sup>−</jats:sup>, in a 5% CO<jats:sub>2</jats:sub> atmosphere. Epithelia expressing wtCFTR respond to forskolin with a substantial increase in <jats:italic>G</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub>. The response in HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> was ~75% of that observed with Cl<jats:sup>−</jats:sup>. Exposure to VX770 increased conductance, but a disproportionately lesser change was observed in HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> (vs. Cl<jats:sup>−</jats:sup>), providing an initial suggestion that VX770 promotes differential ion selectivity.</jats:p><jats:p>Exposure of cells expressing F508del CFTR to correctors, either C17 or C18, allowed for forskolin‐induced stimulation of <jats:italic>G</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub> with a modest increment of HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> conductance. In these conditions, VX770 induced additional Cl<jats:sup>−</jats:sup> conductance, but no enhancement of HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> conductance could be detected. Alternatively, cells exposed to the corrector combination (C17+C18) showed a substantial forskolin‐stimulated increase in anion conductance and a modest increase in CFTR‐associated HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> conductance. Thus, the combination of C17 and C18 gives a different outcome regarding F508del‐CFTR HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> conductance than either corrector alone.</jats:p><jats:p>Cells expressing G551D CFTR exhibited little response to forskolin, but substantial responses to VX770. Responses to VX770 in HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> approached the magnitude of the responses observed in Cl<jats:sup>−</jats:sup>.</jats:p><jats:p>Taken together, the results suggest that CFTR correctors and potentiators can enhance CFTR‐mediated anion conductance, but that significant differences in the conductances of HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> relative to Cl<jats:sup>−</jats:sup> are observed between CFTR variants and that responses can be influenced by the correctors employed. Ultimately, these results suggest that CFTR‐associated pH regulation will be impacted by both the patient’s mutation and the CFTR modulator treatment. Furthermore, additional studies are required to evaluate the CFTR modulators for their effects on Cl<jats:sup>−</jats:sup> and HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> conductances on the many CF causing CFTR variants.</jats:p></jats:sec><jats:sec><jats:title>Support or Funding Information</jats:title><jats:p>CFF BRIDGE18XX0; K‐State CVM SMILE</jats:p></jats:sec>