hERG (human Ether-à-go-go Related Gene, in italics, or KCNH2 in the new nomenclature) is a gene that encodes the pore-forming alpha subunit of a voltage-gated potassium (K+) channel expressed in the heart and in nervous tissue. The term hERG (standard text, new nomenclature is Kv11.1 [Gutman et al., 2005]) is often used to denote the protein or channel derived from the hERG transcript. in the heart hERG makes up a part, if not all, of the channel that conducts the ‘rapid’ component of the delayed rectifier current (IKr; [Sanguinetti et al., 1995; Trudeau et al., 1995]).
How hERG Works
The following animation provides a detailed description of the way in which the hERG K+ channel functions. The animation is accompanied by an audio explanation so you will want to make sure that your sound is turned on. Press the 'Start' button to begin downloading the animation. Depending on what browser you are running, the animation will either start automatically, or after it is finished downloading (3 megabytes), you will have to press the start button again. Then you can use the 'hergchannel.org' and 'Harry J. Witchel' buttons to move between a theoretical two gate inactivating K+ channel, typical C-type inactivation, and hERG.
The Importance of hERG in the Heart
IKr is important in determining the timing of the electrical repolarisation of the action potential (AP) in ventricular myocytes [Keating and Sanguinetti, 2001; Sanguinetti and Tristani-Firouzi, 2006; Witchel and Hancox, 2000]. Genetic mutations in the hERG channel can result in long QT syndrome (LQTS; [Curran et al., 1995]), a disorder in which the patient has a substantial risk of sudden death due to an arrhythmia known as Torsades de pointes (TdP). Typically, an LQTS patient will have no clinical signs except prolongation of the QT interval on the electrocardiogram (ECG), and the patient will appear otherwise healthy, having no other symptoms except some patients will suffer from occasional syncope.
The hERG channel has been shown to be the target of class III antiarrhythmic drugs (e.g., amiodarone, sotalol and dofetilide [Sanguinetti and Jurkiewicz, 1990; Spector et al., 1996; Snyders and Chaudhary, 1996; Lombardi and Terranova, 2006]), which reduce the risk of re-entrant arrhythmias by prolonging the AP duration and the refractory period without slowing conduction velocity in the myocardium. hERG also promiscuously interacts with many other drugs, and it is the inadvertent target of myriad non-cardiac drugs [Crumb and Cavero, 1999], a phenomenon that can under some circumstances lead to side effects including acquired long QT syndrome and its concomitant risk of sudden death (see www.torsades.org). As a result, since the mid-1990’s a wide variety of drugs found to be tainted by this safety issue have been reclassified or withdrawn from the market [Redfern et al., 2003]. Intensive efforts in drug development are continuing in order to root out compounds that might also suffer from this problem.
Crumb W, Cavero I (1999). QT interval prolongation by non-cardiovascular drugs: issues and solutions for novel drug development. Pharm. Sci. Technol. Today 2:270-280.