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

rectification. A genetically encoded Eag domain fragment (amino acids 1-135) was shown to restore slow deactivation to N-truncated channels. Our present study sought to further investigate Eag domain contributions to hERG gating kinetics. We coexpressed the genetically encoded Eag domain fragment (N1-135) with hERG channels bearing a deletion of the N-terminus in Xenopus oocytes and measured current with two-electrode voltage-clamp recordings. Here we report that coexpression with the N1-135 peptide led to a reduction in relative outward current and slowed recovery from inactivation resulting in channels with properties similar to those measured in wild-type hERG. Through regulation of deactivation and inactivation gating, the Eag domain determines the physiologically critical resurgent component of hERG current via a non-covalent interaction with the channel.