hERG (KCNH2 or Kv11.1) K+ channels: screening for cardiac arrhythmia risk.
Testing new compounds for pro-arrhythmic potential has focused in recent years on avoiding activity at the hERG K+ channel, as hERG block is a common feature of many pro-arrhythmic compounds associated with Torsades de Pointes in humans. Blockers of hERG are well known to prolong cardiac action potentials and lead to long QT syndrome, and activators, although rarer, can lead to short QT syndrome. The most reliable assays of hERG utilize stable cell lines, and include ligand binding, Rb+ flux and electrophysiology (both automated and manual). These assays can be followed by measurement of activity at other ion channels contributing to cardiac contractility and detailed action potential/repolarization measurements in cardiac tissue. An integrated risk assessment for pro-arrhythmic potential is ultimately required, as the constellation of ion channel activities and potencies, along with the mechanism/kinetics of ion channel block, may ultimately be the best predictor of cardiac risk in vivo.
Bowlby
Mark R
MR
Neuroscience Discovery, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. bowlbym@wyeth.com
Peri
Ravi
R
Zhang
Howard
H
Dunlop
John
J
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000235:genetics*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D011237:Predictive Value of Tests; D011869:Radioligand Assay; D012413:Rubidium / Q000378:metabolism
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D012413:Rubidium