Herg Cardiac Potassium Channel Structure, Function And Long Qt Syndrome

Since being identified in 1995 as a major culprit in congenital and acquired forms of long QT syndrome, the fundamental importance of hERG (the human ether- -go-go-related gene) has been recognized by academic scientists, regulatory authorities dealing with new drug registration and pharmaceutical companies alike. This has coincided with an explosion in the molecular, structural and detection techniques available to researchers studying ion channel structure and function. hERG encodes the pore-forming subunit of the rapid component of the delayed rectifier potassium current in cardiac mycoytes, IKr. Physiologically, it is one of several ion channels involved in the normal action potential repolarization in cardiac myocytes. Pharmacologically, it is the target for class III antiarrhythmic agents, e.g. quinidine, amiodarone and dofetilide. Toxicologically, it is considered to demonstrate promiscuous binding to a wide range of structurally diverse compounds leading to prolongation of the QT interval. This drug-induced QT interval prolongation, leading to risk of ventricular tachyarrhythmia, Torsade de Pointes and mortality, has precipitated the withdrawal of medicines from the market, particularly amongst certain therapeutic classes including antihistamines, gastrointestinal prokinetics, antipsychotics and antibiotics. This book draws together contributions from basic, pharmaceutical and clinical sciences and regulatory authority perspectives aimed at a better understanding of the structure and function of hERG, the molecular basis for compound binding and preferred preclinical test systems. Topics include hERG channel gating, regulation of functional expression, pharmacological properties of hERG/ IKr channels, drug-induced long QT syndrome and preclinical evaluation and regulatory recommendations for assessing QT prolongation risks. It is hoped that a better understanding of the role of the hERG channel in drug-induced cardiac arrhythmias will lead to the development of new and safer medicines.Novartis Foundation Symposium Staff is the author of 'Herg Cardiac Potassium Channel Structure, Function And Long Qt Syndrome', published 2005 under ISBN 9780470021408 and ISBN 0470021403.