Poster Presentation 2014 International Biophysics Congress

Modulation of hERG gating kinetics via binding of the N-terminal tail  (#433)

Stefan A. Mann 1 , Peter Tan 1 , Arash Sadrieh 1 , Matthew Perry 1 , Jamie Vandenberg 1 , Adam P. Hill 1
  1. Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia

The human ether-a-gogo gene (hERG) encodes the Kv11.1 potassium channel, which is the pore forming subunit of the rapidly activating delayed rectifier K+ channel. Reduction in Kv11.1 activity results in prolongation of the QT interval on the surface ECG and increased risk of arrhythmias and sudden cardiac death – the so-called Long QT syndrome (LQTS). Kv11.1 channels are tetrameric with each subunit containing cytoplasmic N- and C-terminal domains and six transmembrane domains. The fifth and sixth transmembrane domains surround the ion-conducting pore. The cytoplasmic N-terminus of each subunit contains a Per-Arnt-Sim (PAS) domain and an N-terminal tail that have been shown to regulate channel gating.

Deletions of the PAS domain or the N-terminal tail affect the rate of deactivation. Many LQTS2 mutants cluster in this region and the associated acceleration of deactivation is thought to contribute to reduced IKr current and pathogenesis in the disease causing mutants. So far, attempts to reproduce these gating phenotypes in-silico to investigate arrhythmogenesis have shifted the measured half maximal voltage of the activation / deactivation equilibrium to more positive potentials. This does result in acceleration of deactivation at given membrane potentials, but also reduces the IKr current by reducing the amount of activation, an effect that is not seen in in-vitro characterisation of such mutants. This approach is therefore potentially misrepresenting the primary disease causing mechanism.

In this study we show N-terminal tail binding to the activated voltage sensor causes slowing of the rate of deactivation (with no change in the voltage dependence of activation) and a slowing of the recovery from inactivation. Mutations that disrupt this tail binding, rather than accelerating deactivation as previously reported, prevent the associated slowing of this gating process. 

We propose a model of Kv11.1 gating that reproduces this gating effect in both wildtype and mutant channels.