Modulation of HERG potassium channel function by drug action.
Repolarization of cardiomyocytes is mainly performed by the rapid component of the delayed rectifier potassium current, I(Kr), which is encoded by the human ether-a-go-go-related gene (HERG). Inhibition of HERG potassium currents by class III antiarrhythmic drugs causes lengthening of the cardiac action potential, which produces a beneficial antiarrhythmic effect. Conversely, excessive prolongation of the action potential by a wide variety of antiarrhythmic and non-antiarrhythmic drugs may lead to acquired long-QT syndrome, which is associated with a risk for 'torsade de pointes'-arrhythmias and sudden cardiac death. As a result, this undesirable side effect has prompted the withdrawal of several drugs from the market. Recent studies on HERG channel inhibition provide significant insights into the molecular factors that determine state-, voltage-, and use-dependency of HERG current block. In addition, crucial properties of the putative drug binding site in HERG have been identified. The broad diversity in response to pharmacologic treatment among individuals is likely to depend on a combination of multiple factors from the fields of arrhythmia genetics, physiology and pharmacology. In conclusion, the increasing understanding of the molecular mechanisms that underlie HERG channel block by antiarrhythmic and non-antiarrhythmic drugs may improve prevention and treatment of drug-induced long-QT syndrome.
Thomas
Dierk
D
Department of Cardiology, Medical University Hospital Heidelberg, Bergheimerstrasse 58, D-69115 Heidelberg, Germany. dierk_thomas@med.uni-heidelberg.de
Karle
Christoph A
CA
Kiehn
Johann
J
D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008133:Long QT Syndrome / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D020539:Sequence Analysis, Protein
D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated