Revealing the structural basis of action of hERG potassium channel activators and blockers.

Human ether-á-go-go related gene (hERG) potassium (K(+)) channels play a critical role in cardiac action potential repolarization. This is due, in large part, to the unique gating properties of these channels, which are characterized by relatively slow activation and an unusually fast and voltage-dependent inactivation. A large number of structurally diverse compounds bind to hERG and carry an unacceptably high risk of causing arrhythmias. On the other hand, drugs that increase hERG current may, at least in principle, prove useful for treatment of long QT syndrome. A few blockers have been shown to increase hERG current at potentials close to the threshold for channel activation--a process referred to as facilitation. More recently, a novel group of hERG channel activators have been identified that slow deactivation and/or attenuate inactivation. Structural determinants for the action of two different types of activators have been identified. These compounds bind at sites that are distinct from each other and also separate from the binding site of high affinity blockers. They reveal not only novel ways of chemically manipulating hERG channel function, but also interactions between structural domains that are critical to normal activation and inactivation gating.