Received for publication March 28, 2008.
Revised March 31, 2008.
Accepted for publication March 31, 2008.

Refining insights into high affinity drug binding to the hERG potassium channel (Relates to article by Myokai, et al., Fast Forward 7 March 2008)

Abstract

hERG (human ether-a-go-go-related gene) potassium (K⁺) channels play a crucial role in electrophysiological activity in the heart, exerting a profound influence on ventricular action potential repolarization and on the duration of the QT interval of the electrocardiogram. hERG channels are strongly implicated in the acquired form of long QT syndrome (LQTS) as they exhibit a unique susceptibility to pharmacological inhibition by therapeutically and chemically diverse drugs. Investigations over a number of years provide compelling evidence that a comparatively large inner cavity and the presence of particular aromatic amino-acid residues (Y652 and F656) on the inner (S6) helices of the channel are important features that allow hERG to accommodate and bind disparate drugs. However, whereas functional hERG channels are comprised of four identical subunits, blocking molecules may not interact equally with aromatic residues from each of the four subunits. In this issue of Molecular Pharmacology, Myokai et al (pgs XXX-XXX) report for the first time the use of tandem dimers incorporating mutations to Y652 and F656 to elucidate asymmetric binding of the high affinity hERG inhibitor cisapride. Not only has this approach provided increased information on spatial arrangements involved in cisapride binding to the channel, but it offers a powerful means of refining the wider understanding of hERG channel structure-function in relation to drug binding.

Key words: Serotonin, Antiarrhythmic drugs, Structure-activity relationships and modeling, Func. analysis receptor/ion channel mutants, Protein targets