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The cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel pore is blocked in a voltage-dependent manner by a broad range of anionic substances added to the cytoplasmic side of the membrane. Here we investigate the origin of the voltage dependence of block by intracellular Au(CN)2-, a highly permeant lyotropic anion which also acts as a high-affinity blocker of Cl- permeation. Not only the affinity, but also the voltage dependence of block by intracellular Au(CN)2- ions is strongly dependent on extracellular Cl- concentration; following replacement of most extracellular Cl- by glucose or by impermeant anions, block by Au(CN)2- shows greatly weakened voltage dependence. This suggests that coupled movement of Au(CN)2- and Cl- ions within the pore contributes to the voltage dependence of block. This explanation requires that interactions between different anions take place within the pore, implying simultaneous binding of multiple anions to intrapore sites. Other anions are able to substitute for extracellular Cl- and interact with intracellular Au(CN)2- ions. Analysis of the effects of different extracellular anions on the apparent affinity and voltage dependence of block by intracellular Au(CN)2- ions suggests that extracellular anions do not need to permeate through the channel in order to destabilize Au(CN)2- binding within the pore, implying that this destabilizing effect results from binding to an externally accessible site in the permeation pathway. We propose that multiple anions can bind simultaneously within the CFTR channel pore, and that repulsive interactions between bound anions speeds anion exit from the pore.
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