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Cardiovascular Research 2002 53(1):6-8; doi:10.1016/S0008-6363(01)00518-1
© 2002 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

An ion channel ‘addicted’ to ether, alcohol and cocaine: the HERG potassium channel

Christoph A Karle* and Johann Kiehn

Department of Cardiology, University of Heidelberg Medical School, Bergheimerstraße 58, D-69115 Heidelberg, Germany

* Corresponding author. Tel.: +49-6221-568-682; fax: +49-6221-565-515 christoph.karle{at}gmx.de

Received 26 October 2001; accepted 26 October 2001

See article by O'Leary [25] (pages 59–67) in this issue.

In cardiomyocytes, the rapid component of the delayed rectifier K+ current, IKr [1,2], plays an important role in repolarization. During the plateau phase, IKr has only a small amplitude; this function of IKr supports the formation of the plateau potential and is a consequence of its inwardly rectifying properties. As repolarization proceeds, a transient increase in IKr outward current occurs, due to fast recovery from inactivation and slow deactivation, which effectively repolarizes the cardiac cell [3].

On the molecular level, IKr is encoded by the ‘human ether-a-go-go related gene’ (HERG). This has been demonstrated in macroscopic current measurements [4,5] and single channel recordings [6,7]. Many class III antiarrhythmic drugs prolong the cardiac action potential and thereby the refractory period by blocking IKr. Likewise, block of HERG channels by various drugs has been previously investigated, i.e. azimilide [8], amiodarone [9], RP 58866 or terikalant [10], dofetilide [9], clofilium and its tertiary analog LY97241 [11], haloperidol [12], terfenadine racemate and enantiomers [13] and carvedilol [14].

Like other K+ channels, HERG channels are associated with β-subunits: MiRP1 [15], MiRP2 [16] and MinK [17]. MiRP1 shifts the HERG activation curve to more positive potentials, accelerates deactivation and decreases single channel conductance, thereby forming a current very similar to the native IKr in cardiomyocytes. Coexpression of MiRP2 and HERG, though, has been reported to drastically suppress HERG currents [16]. Binding of MinK to HERG increases current amplitude, shifts the HERG activation curve to more negative potentials and increases steady-state inactivation.

One congenital form of the Long QT-syndrome (LQT2) has mutations in HERG, which leads to a reduction of IKr. This prolongs the cardiac action potential. An extreme action potential lengthening can induce early afterdepolarizations, an increased tendency to heart arrhythmia and the occurrence of ‘torsade de pointes’ ventricular tachycardias, eventually leading to ventricular fibrillation and sudden death [18]. A different form of Long QT-syndrome involving HERG is characterized by a mutation in the β-subunit MiRP1 [15].

IKr and its underlying gene HERG are regulated by protein kinase A dependent second messenger pathways [19–21], presumably via β1-adrenergic activation [22]. This regulation can possibly explain the proarrhythmic effect of physical and emotional stress, especially in patients with LQT2.

A unique characteristic of HERG K+ channels is that it is affected by inhalants and various substances of abuse. The funny name HERG, or written out ‘human ether-a-go-go related gene’, is derived from the similarity between this gene and the EAG (‘ether-a-go-go’) locus of the fruitfly Drosophila melanogaster. Some D. melanogaster with a mutation in the EAG exhibit leg-shaking behavior during ether anesthesia, just like go-go dancers in a theater or discotheque [23]. Interestingly, nicotine, a main constituent of tobacco smoke, may be responsible for some cases of sudden coronary death, since a block of the HERG K+ channel by nicotine has been shown by Wang et al. [24].

In the current issue of Cardiovascular Research, Michael E. O'Leary [25] has investigated the role of cocaine and ethanol in arrhythmogenesis. He found that cocaine, alcohol and cocaethylene, a metabolite of cocaine and alcohol, significantly block the HERG potassium channel, thereby potentially inducing cardiac arrhythmias. Cocaine is a widely abused drug, known to increase heart rate and blood pressure [26,27]. Its use has been linked to a high incidence of cardiac arrhythmias and sudden death [28]. This proarrhythmic effect of cocaine might be attributed to its ability to inhibit the HERG K+ channel [29]. Statistics show that more than half of the people who consume cocaine also report simultaneous consumption of alcohol [30,31]. Likewise, the cardiovascular effects are amplified when cocaine is consumed with alcohol [32], and this drug combination is more cardiotoxic [33] and significantly increases the risk of sudden cardiac death than either substance alone [34]. O'Leary investigated the effect of cocaethylene, a metabolite of cocaine and ethanol, on the HERG K+ channel in an interesting and well-performed pharmacological study. HERG currents were measured with the patch-clamp technique in tsA201 cells, where HERG channels were transiently expressed. His findings are in agreement with whole animal-studies, where cocaethylene increased the QT intervals and caused ‘torsades de pointes’ ventricular dysrhythmias [35]. The prolongation of the QT-interval fits well to the shown effect on HERG K+ currents. In the study by Michael E. O'Leary, cocaethylene inhibited open HERG channels, voltage- and concentration-dependently with an IC50 of 4.0 µM. Cocaethylene accelerated inactivation of HERG current without affecting recovery from inactivation. Tail current experiments demonstrated that cocaethylene significantly slowed deactivation, indicating that drug-modified channels close slowly at hyperpolarized voltages. The blocking mechanism is an ‘open channel block’, and binding may prevent channel closing by a ‘foot in the door’ mechanism similar to that proposed for quaternary ammonium compounds. The study by O'Leary has a high physiological impact, since realistic plasma concentrations of either drug have been used. HERG K+ channels have also been found in neurocytes, putatively contributing to the neuropsychological behavior of individuals in contact with alcohol and cocaine.

Many questions of molecular electrophysiology and arrhythmogenesis have not yet been answered. The mechanistic link between effects on the HERG potassium channel with consecutive QT-prolongation and the resulting ventricular arrhythmias appears to be partially understood. Early afterdepolarizations caused by a calcium overload of cardiac cells and the reduced counterbalancing HERG-current are the crucial pathophysiological conditions that cause ‘torsade de pointes’ ventricular arrhythmias. Additionally, factors like the coupling of potassium channels to the adrenergic system or its regulation by second messenger systems may come into play. Moreover, these pathophysiological factors are affected by Ca2+-channel blocking agents, which successfully reduce the occurrence of ‘torsade de pointes’ ventricular tachycardias. However, insights into the pathogenesis of the relatively rare ‘torsade de pointes’ ventricular arrhythmias, involving HERG-channel regulation, might not suffice to explain other forms of ventricular arrhythmia, which occur in most cases of patients with coronary artery disease or dilated cardiomyopathy. In any case, the HERG K+ channel, exhibiting features of classical delayed and inwardly rectifying potassium channels, plays an important role in arrhythmogenesis, as a target of many different substances, e.g. antiarrhythmics, ether, ethanol, cocaine and cocaethylene, as shown by Michael E. O'Leary.


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