Trends in Pharmacological Sciences
ReviewHERG K+ channels: friend and foe
Section snippets
HERG K+ channels
The HERG gene was initially isolated by Warmke and Ganetzky 9 by screening a human hippocampal cDNA library with a mouse homologue of ‘ether-à-go-go’ (eag), a Drosophila K+ channel gene. Shortly thereafter, HERG was identified as the gene involved in chromosome-7-associated long QT syndrome 10 and was found to encode the pore-forming α-subunit of the rapid component of the delayed rectifier current IK(Vr) (Ref. 11). HERG K+ channels have six transmembrane domains (denoted S1–S6), with the S4
Pharmacology of HERG K+ channels
Drug-induced prolongation of repolarization as an antiarrhythmic mechanism was first described 30 years ago (Vaughan Williams Class 3 Action) 24 and is a property of several widely used antiarrhythmic agents, including quinidine, amiodarone and sotalol. More recently, a range of methanesulfonanilide compounds (including dofetilide, E4031 and MK499) have been reported to display very potent Class 3 antiarrhythmic actions as a result of blockade of HERG K+ channels.
Analogous to loss-of-function
Drug-induced long QT syndrome
Drug-induced long QT syndrome has now been reported for a large range of both cardiac and non-cardiac drugs, in which this side-effect is entirely undesired 7, 29. These include antihistamines (e.g. terfenadine), gastrointestinal prokinetic agents (e.g. cisapride), many psychoactive agents (e.g. amitryptiline, chlorpromazine, haloperidol and thioridazine) and some antimicrobials (e.g. macrolide antibiotics, cotrimoxazole and the antimalarial agent halofantrine) 7, 19, 20. Terfenadine and
Structure–function relationships
Given the wide range of chemical structures that can inhibit HERG K+ channels (Fig. 3) and the observation that different compounds appear to bind to different states of the channel (e.g. ketoconazole binds to the closed state 35 whereas methanesulfonanilides require channel opening to bind 36), it is likely that there are multiple distinct binding sites for drugs on HERG K+ channels. In the past few months, however, site-directed mutagenesis in combination with homology modelling has provided
Concluding remarks
HERG K+ channels are important for repolarization of the cardiac action potential and play a specific role in suppressing premature excitation. HERG K+ channel blockers are useful in the treatment of atrial arrhythmias. However, the use of HERG K+ channel blockers, in addition to a large number of non-cardiac drugs that also bind to HERG K+ channels, are associated with an increased risk of torsade de pointes arrhythmias and sudden cardiac death. Drug regulatory authorities have become
Acknowledgements
We gratefully acknowledge helpful comments from and discussions with Pak-Lee Chau, Iwan d'Esch, Gerry Smith, Christopher Huang, Sarah Lummis and Margaret Sunde.
References (51)
- et al.
Molecular genetic insights into cardiovascular disease
Science
(1996) Heart failure: the electrophysiologic connection
J. Cardiovasc. Electrophysiol.
(1999)The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology
Eur. Heart J.
(2000)A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome
Cell
(1995)QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience
Eur. J. Clin. Pharmacol.
(2000)Drug-induced torsade de pointes: from molecular biology to bedside
Jpn. J. Pharmacol.
(2000)- et al.
Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell
Circ. Res.
(1995) Sodium pentobarbital reduces transmural dispersion of repolarization and prevents torsades de pointes in models of acquired and congenital long QT syndrome
J. Cardiovasc. Electrophysiol.
(1999)- et al.
Risk of torsades de pointes with non-cardiac drugs. Doctors need to be aware that many drugs can cause qt prolongation
Br. Med. J.
(2000) Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias
J. Cardiovasc. Electrophysiol.
(2000)
Molecular physiology and pharmacology of HERG. Single-channel currents and block by dofetilide
Circulation
The long QT syndromes: genetic basis and clinical implications
J. Am. Coll. Cardiol.
Genetic and molecular basis of cardiac arrhythmias; impact on clinical management. Study group on molecular basis of arrhythmias of the working group on arrhythmias of the European Society of Cardiology
Eur. Heart J.
Cardiac ionic currents and acute ischemia: from channels to arrhythmias
Physiol. Rev.
Images in clinical medicine. Congenital long-QT syndrome
New Engl. J. Med.
A family of potassium channel genes related to eag in Drosophila and mammals
Proc. Natl. Acad. Sci. USA
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel
Cell.
The inward rectification mechanism of the HERG cardiac potassium channel
Nature
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia
Cell
Cyclic AMP regulates the HERG K(+) channel by dual pathways
Curr. Biol.
A common polymorphism associated with antibiotic-induced cardiac arrhythmia
Proc. Natl. Acad. Sci. USA
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2
Circulation
Analysis of the human KCNH2(HERG) gene: identification and characterization of a novel mutation Y667X associated with long QT syndrome and a non-pathological 9 bp insertion
Hum. Mutat.
Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects
Hum. Mutat.
Cited by (265)
Phytochemistry of the Vepris genus plants: A review and in silico analysis of their ADMET properties
2023, South African Journal of BotanyPhenolic and terpene compounds from Plectranthus amboinicus (Lour.) Spreng act as promising hepatic anticancer agents screened through in silico and in vitro approaches
2022, South African Journal of BotanyCitation Excerpt :hERG (human- ether- a-go-go-related gene) is considered an important model since the inhibition of the hERG potassium channel in human may end in QT interval prolongation and results in severe cardiac side effects, which is a foremost problem in clinical studies of drug (Wang et al., 2012). The hERG potassium channel appears to be the molecular target responsible for the cardiac toxicity of a wide range of therapeutic drugs and is best recognized for its involvement in the electrical activity of the heart that regulates the heart's beating (Vandenberg et al., 2001). Hence, the phytocompounds evaluated on hERG activity possess low to medium risk for hERG-inhibition, thereby reducing the entry of cardiotoxic drugs.
Beneficial effects of carvedilol modulating potassium channels on the control of glucose
2022, Biomedicine and PharmacotherapyMechanisms of torsades de pointes
2022, Torsades de PointesIdentification of New EGFR Inhibitors by Structure-Based Virtual Screening and Biological Evaluation
2024, International Journal of Molecular SciencesIn silico studies of Ruellia tuberosa L. compounds as aldose reductase, dipeptidyl peptidase 4, and α-glucosidase inhibitors against type 2 diabetes mellitus
2024, Journal of Pharmacy and Pharmacognosy Research