An atomic scale measurement from the voltage sensor in hERG channels using lanthanide-based resonance energy transfer

The cardiac human ether-a-go-go related gene (hERG) channel is a voltage-gated potassium (Kv) channel that plays a fundamental role in cardiac repolarization. The importance of the hERG channel derives from its unusually slow activation (opening) and deactivation (closing) processes. Like other Kv channels, structural reconfigurations of the hERG voltage sensor upon membrane depolarization and repolarization underlie channel activation and deactivation, respectively. However, specific rearrangements of the voltage sensor that may dictate the unique slow activation and deactivation in hERG channels remain unclear. Lanthanide-based resonance transfer (LRET) is a spectroscopic technique that has previously demonstrated an ability to provide quantitative description of voltage sensor dynamics in an archetypal Kv channel. In this report, we outline a rationalized approach to applying LRET to examine hERG channel voltage sensor dynamics that may be of physiological significance. As a result, we report the first distance measurement from voltage sensors across the hERG channel pore.