Seminars

March 1 2018

1:00 pm 1100 TLSB

This seminar is sponsored by Mechanisms of Arrhythmia:hERG Channel Biophysics in Cardiac Repolarization

David Jones
Department of Neuroscience
Wisconsin Institutes for Medical Research University of Wisconsin

Summary

Mechanisms of Arrhythmia:hERG Channel Biophysics in Cardiac Repolarization
The human ether-a-go-go related gene (hERG) encodes two subunits, hERG 1a and hERG 1b, that combine in vivo to conduct the rapid delayed rectifier potassium current (IKr). Reduced IKr slows cardiac action potential (AP) repolarization and is an underlying cause of cardiac arrhythmias associated with long QT syndrome (LQTS). hERG 1a contains a long N-terminus that includes a PAS domain that is critical for generating the slow gating behavior of hERG 1a homomeric channels. In contrast, the hERG 1b N-terminus is short and lacks a PAS domain. Heterologous studies have demonstrated that the absence of this PAS domain enhances current magnitude in heteromeric hERG 1a/1b channels compared to hERG 1a homomeric channels. Most recently, using cardiomyocytes derived from human pluripotent stem cells (iPSC-CMs), we demonstrated a causal link between targeted reduction of the hERG 1b subunit and cellular hallmarks of proarrhythmia. These data also demonstrated that the N-terminal PAS domain suppresses hERG current and suggest that the PAS domain is used as a physiological tool to fine tune native IKr and AP morphology. We set to probe the functional consequences of hERG 1a N-terminal disruption by generating two antibody fragments that recognize distinct epitopes within the hERG 1a PAS domain. When administered to heterologously expressed hERG channels, both antibodies disrupted inactivation and increased the current magnitude recorded during a ventricular action potential voltage command. Further, both antibodies increased native IKr and significantly shortened the cardiac action potential recorded in iPSC-CMs. Overall, these molecules constitute a new class of hERG channel activators and establish the hERG 1a PAS domain as a therapeutic target to treat diseases of excitability.