• 1. Brief Review of HERG Research
• 2. HERG Mutations causing congenital LQT2

Notice: The published contents presently include only general HERG information and are of higher educational level. A quick intro for beginners is in preparation and will be added soon. Questions should be addressed to SHCC through our contact channel.

1.1. The HERG at a glance: Today it is believed that IKr is mediated by the potassium channel HERG, which is expressed in the heart but also neural tissue. The biophysical and pharmacological properties of the potassium channel were investigated shortly after the initial discovery in 1994 of the human-eag-related gene (HERG gene) by Warmke and Ganetzky. Early in 1996, the inward rectification mechanism of the HERG channel was described in an elegant work by Paula Smith and colleagues (Smith et al., 1996). In 1997 two additional members (erg-2 and erg-3) of the erg potassium channel gene family were identified (Shi et al., 1997). The structural organization of the alpha subunit of the HERG channel within the membrane is proposed to be similar as that of other voltage-gated ion channels (Roden et al., 1997). The large volume of the inner vestibule, the features of HERG’s S6 sequence as well as the fast C-type inactivation process seem to contribute to the unique properties of the HERG potassium channel (Mitcheson et al., 2000a and 2000b). It has been suggested that additional beta subunits could be associated with HERG to form native IKr channels in cardiac myocytes (Tseng GN, 2001; Vandenberg et al., 2001).

1.2. IKr & LQTS: The rapid delayed rectifier current (IKr) is important for cardiac action potential repolarization. Suppression of IKr function by adverse drug effects can induce long-QT syndrome carrying elevated risk of life-threatening arrhythmias. A large range of therapeutic agents with diverse chemical structures have been reported to induce long QT syndrome. These include antihistamines (e.g. terfenadine), gastrointestinal prokinetic agents (e.g. cisapride), psychoactive substances (e.g. amitryptiline, chlorpromazine, haloperidol, thioridazine) and others. Besides the acquired long-QT syndrome also genetic defects are known to cause the disease (section 2).

1.3. QT Prolongation & APD: The QT interval as recorded in the electrocardiogram (ECG) is a direct measure of the duration of ventricular depolarization and repolarization. Thus, a prolongation of the Action Potential Duration (APD) leads to a prolonged QT interval. If a drug induces a delay of ventricular repolarization and hence prolongation of the QT interval, there is an increased risk for ventricular tachyarrhythmia and Torsades de Pointes. The cardiac action potential is the net result of a concert of cardiac ion channels and transporters. The action potential consists of five sequential phases and is initiated by the fast influx of sodium ions, which depolarizes the cell membrane from -70mV to +20mV:

• Phase 0: The rapid sodium influx through Nav1.5 channels leads to strong depolarization, thus generating the fast upstroke of ventricular action potential.
• Phase 1: Early repolarization after the upstroke is due to sodium channel inactivation and efflux of potassium through Ito potassium channels.
• Phase 2: The plateau of the action potential is the result of calcium influx through Cav1.2 channels (L-type) combined with simultaneous outward repolarizing potassium currents.
• Phase 3: The repolarization phase of ventricular action potential can be ascribed to efflux of potassium ions through HERG channels and KvLQT1/minK channels.
• Phase 4: The inward rectifying IK1 potassium current is responsible for the maintenance of the membrane resting potential.

1.4. Major Target is the HERG: The very majority of drugs so far associated with drug-induced QT prolongation could be shown to excert their unwanted effects through impairment of the repolarization phase of the ventricular action potential via interaction with the HERG potassium channel. Another potential target for cardiac side effects is the KvLQT1/minK channel. However, this potassium channel seems not to be primary locus of action. It could be shown by Mitcheson and coworkers that the HERG channel’s architecture of inner vestibule is larger as compared to other potassium channels, thus offering sufficient space for many drug classes to bind to the HERG ionophore. Download this elegant work as PDF-file.

2.1. Congenital LQT2: The HERG channel is encoded by the gene KCNH2 (chromosomal locus 7q35-q36). More and more, diseases can be attributed to specific defects in ion channels, so-called channelopathies. The mutations in the HERG gene cause LQT2. So far, a total of 8 variants of the Long QT Syndrome (LQTS) can be linked to cardiac ion channel defects (LQT1-8). It is assumed that other genes have to be identified yet since 40% of the LQTS cases cannot be attributed to mutations in the discovered genes.

2.2. HERG Mutations Table: A SHCC reviewed summary table of the known HERG mutations is given below. The presented information is mainly based on the data provided by www.receptors.org. Please notice that SHCC presents both, LQT2 and research mutations (site directed mutagenesis studies). The HERG mutations causing congenital LQT2 are highlighted with asterisks for clarity. The contents of the HERG mutations table have been reviewed and validated by SHCC on September 9, 2006. Only reviewed mutations are published in the HERG mutations table. The citations used for validation are indicated and can be viewed through corresponding weblinks. Completion of table is in progress.