HERG1 channelopathies

Abstract

Human ether a go-go-related gene type 1 (hERG1) K+ channels conduct the rapid delayed rectifier K+ current and mediate action potential repolarization in the heart. Mutations in KCNH2 (the gene that encodes hERG1) causes LQT2, one of the most common forms of long QT syndrome, a disorder of cardiac repolarization that predisposes affected subjects to ventricular arrhythmia and increases the risk of sudden cardiac death. Hundreds of LQT2-associated mutations have been described, and most cause a loss of function by disrupting subunit folding, assembly, or trafficking of the channel to the cell surface. Loss-of-function mutations in hERG1 channels have also recently been implicated in epilepsy. A single gain-of-function mutation has been described that causes short QT syndrome and cardiac arrhythmia. In addition, up-regulation of hERG1 channel expression has been demonstrated in specific tumors and has been associated with skeletal muscle atrophy in mice.

Fig. 1

Biophysical properties of hERG1 channel currents. a Voltage clamp protocol (upper panel) and heterologously expressed hERG1 ionic currents (lower panel) recorded from a Xenopus oocyte. Currents were recorded at test potentials that ranged from −70 to +50 mV; deactivating (“tail”) currents were measured at −70 mV. b Current–voltage (I−V) relationship for hERG1 currents measured at the end of test pulses, as indicated by red circle in a. c Voltage dependence of hERG1 current activation. The peak of tail currents measured at −70 mV (indicated by blue square in a) were normalized to the largest value and plotted as a function of the test potential. d Voltage dependence of hERG1 inactivation. Channel availability is decreased at positive potentials, resulting in a decreased magnitude of peak outward currents and the bell-shaped I−V relationship depicted in b

Fig. 2

ECG recording of a sleeping LQT2 subject who was startled awake by the sudden noise from an alarm clock. Note the appearance of several ventricular extrasystoles and the long–short intervals of the QRS complexes immediately before the onset of torsade de pointes. Reproduced with permission from [112]

Fig. 3

Diagram of a single hERG1 subunit, illustrating the widespread distribution in the location of LQT2-associated mutations. The subunit has six transmembrane segments and large intracellular N-terminal and C-terminal domains. Missense mutations are indicated by open circles; other types of mutations (i.e., frameshifts, deletions, splice site) are indicated as filled circles. The size of the symbol reflects the prevalence of a specific mutation (smallest symbol once; largest symbol >5 times). Reproduced with permission from [41]