Block Of The HERG Mutant D540K By Terfenadine Shows The Opposite Dependency On Extracellular Potassium Compared To Block Of WT HERG By Terfenadine

Abstract

Block of the cardiac potassium channel HERG by a number of drugs has been shown by different investigators to depend on the extracellular potassium concentration. This dependency on extracellular potassium can be explained by at least two mechanisms: destabilization of the drug by the permeant ion or differential binding to the inactivated state. We previously reported that block of HERG by terfenadine shows the opposite dependency on extracellular potassium compared to quinidine. Thus HERG block by quinidine is greater in 0 mM K compared to 20 mM K whereas block by terfenadine is greater in 20 mM K compared to 0 mM K. In order to determine the mechanism underlying this difference in potassium dependency we measured block by terfenadine of the HERG mutant D540K which opens with both depolarization and hyperpolarization. Block of D540K by terfenadine showed the opposite dependency on extracellular potassium compared to block of WT HERG by terfenadine. Thus block of D540K by terfenadine is greater in 0 mM K compared to 20 mM K, similar to the extracellular potassium dependency of block of WT HERG by quinidine. Recent experiments indicate that terfenadine is trapped inside the channel after the channel closes, whereas quinidine is not1. In addition we have reported that block of HERG by quinidine shows a better correlation with the permeant ion than with inactivation. 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 indicate a possible role for the activation gate in determining the extracellular potassium dependency of block of HERG.1 Stork et al. (2007) BJP 151:1368-1376.