Key Points
- Characterize the functional interactions between the channel subunits HERG and KCNE2 to determine the mechanisms underlying action potential prolongation in long-QT syndrome.
- Assessed electrophysiological changes in ionic current density and gating kinetics following the coexpression of hKCNE2 and HERG in vitro.
- Integrated experimental electrophysiological parameters into a quantitative computational model of the cardiac action potential.
- Coexpression of hKCNE2 with HERG altered both the current density and gating kinetics of the rapid delayed rectifier potassium current (I(K,r)).
- Quantitative action potential modeling demonstrated that variations in current density, rather than changes in gating kinetics, drive action potential repolarization prolongation.
- Modest changes in gating kinetics caused by long-QT syndrome mutations likely represent epiphenomena or influence repolarization via interactions with other potassium channel alpha subunits.
Structured PICO
PPopulationIn vitro and in silico models of HERG and KCNE2 gene products
IInterventionCoexpression of hKCNE2 with HERG
OOutcomeFunctional interactions (kinetics and density of ionic current) and action potential morphology/repolarizationsurrogate
The primary functional consequence of hKCNE2 on action potential morphology is through modulation of I(K,r) density, suggesting mutations causing only modest kinetic changes may be epiphenomena or act via other subunits.