Abstract

Block of the cardiac potassium channel HERG by a number of drugs has been shown to decrease with an increase in the extracellular potassium concentration. This dependency on extracellular potassium can be explained by at least two mechanisms: 1) destabilization of the drug by the permeant ion 2) differential binding to the inactivated state. We have previously shown that block of HERG by quinidine, a drug that is not trapped after channel deactivation, correlates better with the permeant ion than with inactivation, indicating that quinidine block is destabilized by the permeant ion.1 We show here that block of HERG by terfenadine and bepridil, drugs shown to be trapped in the channel after channel deactivation2, is not altered with an increase in the extracellular potassium concentration. Furthermore block by both terfenadine and bepridil of the HERG mutant D540K, which opens with both depolarization and hyperpolarization, is decreased with increased extracellular potassium, similar to the effect of extracellular potassium on block of WT HERG by quinidine. In addition, block of D540K by bepridil at −120 mV, a voltage at which D540K is open and does not inactivate is similar in 0 mM extracellular K and 20 mM NH4 and reduced in 20 mM extracellular K and 20 mM extracellular Cs. Given that the permeability sequence through HERG is PK>PCs>PNH4, these results suggest that the permeant ion is not able to destabilize a trapped drug but is able to destabilize a drug that is not trapped and suggest a possible role for the activation gate in determining the extracellular potassium dependency of block of HERG by certain compounds.1 Barrows et al. (2009) Channels: 3(4) :239 −248.2 Stork et al. (2007) BJP151:1368-1376.

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