HOME

About hERG

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.

How hERG works.

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.

 

References

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.
Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT (1995). A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80:795-803.
Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA, Robertson GA, Rudy B, Sanguinetti MC, Stuhmer W, Wang X (2005). International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol. Rev. 57:473-508.
Keating MT, Sanguinetti MC (2001). Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104:569-580.
Lombardi F, Terranova P (2006). Pharmacological treatment of atrial fibrillation: mechanisms of action and efficacy of class III drugs. Curr. Med. Chem. 13:1635-1653.
Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG (2003). Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58:32-45.
Sanguinetti MC, Jiang C, Curran ME, Keating MT (1995). A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81:299-307.
Sanguinetti MC, Jurkiewicz NK (1990). Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J. Gen. Physiol. 96:195-215.
Sanguinetti MC, Tristani-Firouzi M (2006). hERG potassium channels and cardiac arrhythmia. Nature. 440:463-469.
Snyders DJ, Chaudhary A (1996). High affinity open channel block by dofetilide of HERG expressed in a human cell line. Mol. Pharm. 49:949-955.
Spector PS, Curran ME, Keating MT, Sanguinetti MC (1996). Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides. Circ. Res. 78:499-503.
Trudeau MC, Warmke JW, Ganetzky B, Robertson GA (1995). HERG, a human inward rectifier in the voltage gated potassium channel family. Science 269:92-95.
Witchel HJ, Hancox JC (2000). Familial and acquired Long QT Syndrome and the cardiac rapid delayed rectifier potassium current. Clin. Exp. Pharm. Physiol. 27:753-766.