Cellular hERG Assays - hERG Ion Channel Cell Lines
hERG ion channel cell lines for cardiac safety screening
Despite their effectiveness in blocking target ion channels, all drugs must avoid blocking one channel: a cardiac K channel termed hERG (Human Ether-á-go-go-Related-Gene). Because only patch-clamp assays provide the data required by ICH guidelines, drug discovery requires assays that are rapid and reliable. Invitrogen now provides hERG-expressing cell lines for safety screening assays.
The hERG potassium channel is expressed in the mammalian heart and is crucial for repolarization and relaxation of cardiac muscle during every heartbeat. Potassium efflux occurs when the channel is open and the cardiac myocyte membrane potential is positive to the equilibrium potential for potassium; roughly –90 mV.
Human mutations of this gene increase susceptibility to QT-interval prolongation on an electrocardiogram. This prolonged interval can lead to lethal ventricular arrhythmias. Carriers may be asymptomatic until a sudden startle stimulus (e.g., an alarm or an unexpected telephone call) causes fainting (if awake) or sudden onset of ventricular arrhythmia. Mutations typically decrease the amount of protein expressed on the cell surface; i.e., they encode trafficking-deficient proteins. A diversity of drugs from widely-differing chemical scaffolds block this channel. Patients admitted for QT-interval prolongation or ventricular arrhythmia are typically screened for medications; therapeutically-relevant levels of prescription drugs have been shown to block hERG channels expressed in recombinant cell lines in patch-clamp assays. Such findings have led to the withdrawal of 10–20 marketed drugs, and a recommendation from the ICH that all Investigational New Drugs be tested in such patch-clamp assays to assess hERG block liability before they are administered to humans.
We offer two cell lines utilizing Invitrogen’s proprietary inducible expression technology, T-REx™, where there is little or no expression of hERG current until doxycyline is added. Twenty-four to forty-eight hours after addition of doxycyline, large currents are obtained from a majority of the cells examined in traditional patch-clamp assays.