Human ether-a-go-go related gene (hERG) K+ channels: Function and dysfunction

Abstract

The human Ether-a-go-go Related Gene (hERG) potassium channel plays a central role in regulating cardiac excitability and maintenance of normal cardiac rhythm. Mutations in hERG cause a third of all cases of congenital long QT syndrome, a disorder of cardiac repolarisation characterised by prolongation of the QT interval on the surface electrocardiogram, abnormal T waves, and a risk of sudden cardiac death due to ventricular arrhythmias. Additionally, the hERG channel protein is the molecular target for almost all drugs that cause the acquired form of long QT syndrome. Advances in understanding the structural basis of hERG gating, its traffic to the cell surface, and the molecular architecture involved in drug-block of hERG, are providing the foundation for rational treatment and prevention of hERG associated long QT syndrome. This review summarises the current knowledge of hERG function and dysfunction, and the areas of ongoing research.

Activation of human ether-a-go-go related gene (hERG) potassium channels by small molecules

“…In hERG, the PAS domain modulates the deactivation of the channel following membrane depolarization. The C-terminus of the channel contains a cyclic nucleotide binding domain (CNBD), which has been linked to mutations affecting trafficking [5] .…”

“…Although the overall structure of hERG is homologous to that of other potassium channels, its kinetic behavior is quite distinct and is characterized by comparatively slow activation and deactivation kinetics (on the order of hundreds of ms to s) but very rapid, voltage-dependent inactivation kinetics (on the order of ms to tens of ms) [5,6] . The unusual kinetics of hERG are compatible with its function in cardiac repolarization.…”

“…As the membrane repolarizes, hERG channels recover from inactivation much faster than they deactivate, thereby generating an outward current that peaks at about -40 mV. This outward current through hERG is the key determinant for termination of the plateau phase of the action potential [5] (Figure 2). Due to the importance and uniqueness of hERG gating kinetics, much of the recent work on hERG has focused on understanding the molecular rearrangements of the channel protein during the cardiac action potential.…”

“…The second is C-type, which involves a slower change in channel conformation at the extracellular mouth. There is evidence that inactivation of hERG is similar to C-type and shows voltage-dependency, even though hERG inactivation is several orders of magnitude faster than C-type inactivation in Shaker K + channels [3,5,11] . Some studies have shown that this fast inactivation limits K + efflux during depolarization, allowing hERG to function as an inward rectifier of potassium concentration [11] .…”

“…It is generally believed that the PXP domain "kinks" this helix to reduce the volume of the pore cavity, and its absence in hERG has been suggested to play a role in promiscuous drug interactions as well. Finally, the hERG channel has a large "S5-P linker" domain between the S5 and P-loop segments that assumes an amphipathic helical arrangement in membrane mimetic sodium dodecyl sulfate (SDS) micelles and is believed to affect channel inactivation [5] . Figure 1.…”