Human ether-a-go-go related gene (hERG) K+ channels: Function and dysfunction

Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia.
Progress in Biophysics and Molecular Biology (Impact Factor: 3.38). 12/2008; 98(2-3):137-48. DOI: 10.1016/j.pbiomolbio.2008.10.006
Source: PubMed

ABSTRACT The human Ether-a-go-go Related Gene (hERG) potassium channel plays a central role in regulating cardiac excitability and maintenance of normal cardiac rhythm. Mutations in hERG cause a third of all cases of congenital long QT syndrome, a disorder of cardiac repolarisation characterised by prolongation of the QT interval on the surface electrocardiogram, abnormal T waves, and a risk of sudden cardiac death due to ventricular arrhythmias. Additionally, the hERG channel protein is the molecular target for almost all drugs that cause the acquired form of long QT syndrome. Advances in understanding the structural basis of hERG gating, its traffic to the cell surface, and the molecular architecture involved in drug-block of hERG, are providing the foundation for rational treatment and prevention of hERG associated long QT syndrome. This review summarises the current knowledge of hERG function and dysfunction, and the areas of ongoing research.

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    • "This cardiac potassium channel is voltage-activated. It has a relatively large inner cavity that allows drug molecules to enter and bind tightly to the channel pore [3] [8] [16]. Aromatic amino acid residues arranged in two rings of four amino acids each within the central cavity enhance interactions with aromatic groups of drugs and thus may lead to channel blockage, prevent potassium conduction, and eventually cause the drug-acquired LQTS [17e21]. "
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    ABSTRACT: The human Ether-a-go-go-Related-Gene (hERG) potassium (K(+)) channel is liable to drug-inducing blockage that prolongs the QT interval of the cardiac action potential, triggers arrhythmia and possibly causes sudden cardiac death. Early prediction of drug liability to hERG K(+) channel is therefore highly important and preferably obligatory at earlier stages of any drug discovery process. In vitro assessment of drug binding affinity to hERG K(+) channel involves substantial expenses, time, and labor; and therefore computational models for predicting liabilities of drug candidates for hERG toxicity is of much importance. In the present study, we apply the Iterative Stochastic Elimination (ISE) algorithm to construct a large number of rule-based models (filters) and exploit their combination for developing the concept of hERG Toxicity Index (ETI). ETI estimates the molecular risk to be a blocker of hERG potassium channel. The area under the curve (AUC) of the attained model is 0.94. The averaged ETI of hERG binders, drugs from CMC, clinical-MDDR, endogenous molecules, ACD and ZINC, were found to be 9.17, 2.53, 3.3, -1.98, -2.49 and -3.86 respectively. Applying the proposed hERG Toxicity Index Model on external test set composed of more than 1300 hERG blockers picked from chEMBL shows excellent performance (Matthews Correlation Coefficient of 0.89). The proposed strategy could be implemented for the evaluation of chemicals in the hit/lead optimization stages of the drug discovery process, improve the selection of drug candidates as well as the development of safe pharmaceutical products.
    European Journal of Medicinal Chemistry 05/2013; 65C:304-314. DOI:10.1016/j.ejmech.2013.04.059 · 3.43 Impact Factor
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    • "It is lined by many unique aromatic residues that are absent in most other K channels. These optimally positioned aromatic residues and the polar residues are an integral part of the unique binding sites for diverse pharmacologic agents [Perry et al. 2010; Perrin et al. 2008; Kannankeril, 2008]. "
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    ABSTRACT: The prolonged QT interval is both widely seen and associated with the potentially deadly rhythm, Torsades de Pointes (TdP). While it can occur spontaneously in the congenital form, there is a wide array of drugs that have been implicated in the prolongation of the QT interval. Some of these drugs have either been restricted or withdrawn from the market due to the increased incidence of fatal polymorphic ventricular tachycardia. The list of drugs that cause QT prolongation continues to grow, and an updated list of specific drugs that prolong the QT interval can be found at This review focuses on the mechanism of drug-induced QT prolongation, risk factors for TdP, culprit drugs, prevention and monitoring of prolonged drug-induced QT prolongation and treatment strategies.
    10/2012; 3:241-253. DOI:10.1177/2042098612454283
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    • "For example, a mutation in CFTR (F508) produces a functional Cl  channel that never reaches the plasma membrane, thus hampering Cl  transport and leading to cystic fibrosis (Skach, 2000). Defects in ether-a-go-go (hERG) channel trafficking lead to long QT syndrome, a cardiac disorder that increases arrhythmias and the risk of sudden cardiac death (Perrin et al., 2008). Members of the transient receptor potential canonical channel family are also regulated by vesicular insertion into the cell membrane after agonist stimulation (Bezzerides et al., 2004; Singh et al., 2004). "
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    ABSTRACT: The egg's competency to activate at fertilization and transition to embryogenesis is dependent on its ability to generate a fertilization-specific Ca(2+) transient. To endow the egg with this capacity, Ca(2+) signals remodel during oocyte maturation, including inactivation of the primary Ca(2+) influx pathway store-operated Ca(2+) entry (SOCE). SOCE inactivation is coupled to internalization of the SOCE channel, Orai1. In this study, we show that Orai1 internalizes during meiosis through a caveolin (Cav)- and dynamin-dependent endocytic pathway. Cav binds to Orai1, and we map a Cav consensus-binding site in the Orai1 N terminus, which is required for Orai1 internalization. Furthermore, at rest, Orai1 actively recycles between an endosomal compartment and the cell membrane through a Rho-dependent endocytic pathway. A significant percentage of total Orai1 is intracellular at steady state. Store depletion completely shifts endosomal Orai1 to the cell membrane. These results define vesicular trafficking mechanisms in the oocyte that control Orai1 subcellular localization at steady state, during meiosis, and after store depletion.
    The Journal of Cell Biology 11/2010; 191(3):523-35. DOI:10.1083/jcb.201006022 · 9.69 Impact Factor
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