HERG Potassium Channels in Drug Discovery and Development

Abstract

Potassium (K+) channels play a central role in the electrical activity of excitable cells. Although there are variety of potassium channels, scientists have developed immense interest in human ether-a-go-go-related gene (hERG) potassium channels due to their involvement in life-threatening cardiac arrhythmia. hERG is a gene that encodes the pore-forming α-subunit of a voltage-gated potassium channel expressed in nervous and cardiac tissue including atrium, ventricles, purkinje fiber, SA node and AV node. Potassium flow through hERG channel plays an important role in action potential repolarization, particularly in ventricular muscle. Blockade of hERG potassium channel via pharmacological interventions or hereditary mutations of genes encoding the channel is associated with a prolongation of cardiac ventricular repolarization, that is long QT syndrome (LQTS), a disorder that predisposesindividuals to life-threatening arrhythmias and substantial risk of sudden death. Inherited or drug-induced mutations in hERG channel lead to disruption of delayed rectifier potassium current (IKr), increase in cardiac excitability subsequently torsades de pointes and sudden death. A large number of putative disease-causing mutations in hERG have been identified in affected families so far, yet mechanism behind these mutations is unspecified and undistinguished. Therefore, entire paradigm of drug discovery has shifted towards the safety of the new molecules to screen for potential cardiac arrhythmogenic effects. Non-clinical assays are not sensitive enough to accurately predict QT prolongation liabilities in humans. For this reason, International Conference on Harmonization (ICH) safety pharmacology S7B guidelines were proposed for new chemical entities. According to these guidelines, thorough studies (in vitro and in vivo) on QT are required for virtually all newly developed pharmaceutical agents. In this article, an overview on hERG channels, their functions and dysfunctions, therapeutic agents modulating these channels and associated QT prolongation, and assay have been discussed.