Fig. 1.
Effect of inhibitors on CFTR-dependent currents. Compounds acting as inhibitors of CFTR gating (left) equally reduce CFTR-dependent current at all membrane potentials. The current–voltage (I–V) relationship remains linear even in the presence of the inhibitor (e.g. CFTRinh-172). In contrast, compounds acting as open channel blockers (center and right) interact with the CFTR pore. They can reach the pore from the extracellular side or the intracellular side. If they are electrically charged, their block is affected by membrane potential. For low-affinity CFTR blockers (e.g. NPPB, DPC, and niflumic acid), which are negatively charged and act from the inside, negative membrane potentials make the block stronger, thus changing I–V relationship from linear to outwardly rectifying. For compounds like GlyH-101, which acts from the outside, the effect of membrane potential is opposite and the I–V relationship becomes inwardly rectifying