Block of Herg by Trapped Drugs Shows a Different Dependency on Extracellular Potassium Compared to Block of Herg by Drugs That are Not Trapped

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, the decrease in block of D540K by bepridil is less with an increase in extracellular cesium compared to an increase in extracellular potassium (PCs/PK = 0.33). Finally, preliminary data indicate that block by bepridil of a number of HERG inactivation deficient mutants does not depend on extracellular potassium. Together 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.1Barrows et al. (2009) Channels: 3(4) :239-248.2 Stork et al. (2007) BJP151:1368-1376.