Modulation of Herg Potassium Channels by a Novel Small Molecule Activator

KCNH2-encodedhERG1 channels conduct the rapid delayed rectifier potassium current (IKr), which plays a vital role in controlling the duration of cardiac action potentials. Ever since the importance of hERG1 currents in regulating cardiac repolarization was first demonstrated, there has been considerable interest in the pharmacological manipulation of these channels. In their paper, Sale et al. (2017) have characterized the properties of a structurally and functionally novel hERG activator, ITP-2, which dramatically increases hERG1 current amplitudes. Long before hERG1 activators became available, selective hERG1 channel blockers were developed as class III antiarrhythmic drugs to prolong refractory periods and treat re-entrant arrhythmias. However, post-marketing surveillance and then clinical trials revealed that selective hERG1 channel inhibitors could produce excessive prolongation of repolarization and, thereby, be pro-arrhythmic. Subsequent work found that hERG1 channels are also sensitive to pharmacological inhibition by diverse non-cardiac drugs (see Vandenberg et al., 2012), and this is one of the main causes of drug-induced long QT syndrome (LQTS). Genetically inherited loss-of-function hERG1 mutations that reduce hERG1 channel function, through either altered kinetics or impaired trafficking, have also been linked to inherited LQTS (LQTS2) and a greatly increased risk of ventricular fibrillation and sudden death. Gain-of-function hERG1 mutations have also been identified that cause an excessive shortening of QT interval and also carry an increased risk of ventricular fibrillation and sudden death. This has led to the ‘Goldilocks’ principle in which the magnitude and timing of repolarizing hERG currents need to be ‘just right’. The unique and complex gating properties of hERG underlie its crucial role in cardiac action potential repolarization. hERG gating is characterized by a very rapid and voltage-dependent form of inactivation, which unusually is faster than activation gating. During the early part of the action potential, hERG current magnitude is small because the channels activate slowly and most have rapidly inactivated. However, once repolarization starts, the channels quickly recover from inactivation, resulting in a rapid increase in hERG amplitude that plays a central role in timing the end of the plateau phase of the action potential. hERG channels also deactivate slowly ensuring they remain open to contribute to final repolarization and also oppose undesirable premature depolarizations. Inherited LQTS can result not only from mutations to hERG1 but also a variety of other cardiac genes. Seventeen different LQTS-associated genes have been identified – most of which encode ion channel subunits (Campuzano et al., 2015). LQTS is one of the most common genetic diseases and affects an estimated 1 in 5000 to 10 000 people worldwide and is a particularly significant cause of sudden death among young people. hERG1 channel activators (or agonists) are compounds that increase the amplitude of hERG1 currents. At least in principle, hERG1 activators have therapeutic potential for reducing the risk of sudden death in LQTS patients by increasing the amount of repolarizing K current during the cardiac action potential (Grunnet, 2010). The pharmaceutical industry has made tremendous progress in identifying compounds early in development that have the potential to cause the drug-induced form of LQTS. This has been facilitated by the advent of new medium throughput electrophysiology platforms that make it feasible to test large numbers of compounds for their potential to block hERG1 channels. Ironically, the identification of hERG1 activators has predominantly come from efforts to screen out hERG1 blockers. Three main groups of compounds with the ability to increase hERG1 current amplitudes have been described, based primarily on their mechanisms of function and, to a lesser extent, on their putative site of action (Perry et al., 2010). Type 1 activators enhance current primarily by profoundly slowing BJP British Journal of Pharmacology British Journal of Pharmacology (2017) 174 3669–3671 3669