hERG channel function: beyond long QT

Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center (JHICC), School of Medicine, Johns Hopkins University, 733 North Broadway, Baltimore, MD 21205, USA.
Acta Pharmacologica Sinica (Impact Factor: 2.91). 03/2013; 34(3):329-35. DOI: 10.1038/aps.2013.6
Source: PubMed


To date, research on the human ether-a-go-go related gene (hERG) has focused on this potassium channel's role in cardiac repolarization and Long QT Syndrome (LQTS). However, growing evidence implicates hERG in a diversity of physiologic and pathological processes. Here we discuss these other functions of hERG, particularly their impact on diseases beyond cardiac arrhythmia.

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    • "The human ether-à-go-go-related gene (hERG) product is a tetrameric potassium channel that plays an important role in cardiac action potential. Currently, a large number of clinical cases of drug-induced or acquired LQTs have been ascribed to the blockage of the hERG channel4,5. Therefore, it is necessary to measure the hERG inhibition activity of candidate compounds during drug discovery. "
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    ABSTRACT: Aim: A large number of drug-induced long QT syndromes are ascribed to blockage of hERG potassium channels. The aim of this study was to construct novel computational models to predict compounds blocking hERG channels. Methods: Doddareddy's hERG blockage data containing 2644 compounds were used, which divided into training (2389) and test (255) sets. Laplacian-corrected Bayesian classification models were constructed using Discovery Studio. The models were internally validated with the training set of compounds, and then applied to the test set for validation. Doddareddy's experimentally validated dataset with 60 compounds was used for external test set validation. Results: A Bayesian classification model considering the effects of four molecular properties (Mw, PPSA, ALogP and pKa_basic) as well as extended-connectivity fingerprints (ECFP_14) exhibited a global accuracy (91%), parameter sensitivity (90%) and specificity (92%) in the test set validation, and a global accuracy (58%), parameter sensitivity (61%) and specificity (57%) in the external test set validation. Conclusion: The novel model is better than those in the literatures for predicting compounds blocking hERG channels, and can be used for large-scale prediction.
    Acta Pharmacologica Sinica 06/2014; 35(8). DOI:10.1038/aps.2014.35 · 2.91 Impact Factor
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    ABSTRACT: Aim: Retigabine, an activator of KCNQ2-5 channels, is currently used to treat partial-onset seizures. The aim of this study was to explore the possibility that structure modification of retigabine could lead to novel inhibitors of KCNQ2 channels, which were valuable tools for KCNQ channel studies. Methods: A series of retigabine derivatives was designed and synthesized. KCNQ2 channels were expressed in CHO cells. KCNQ2 currents were recorded using whole-cell voltage clamp technique. Test compound in extracellular solution was delivered to the recorded cell using an ALA 8 Channel Solution Exchange System. Results: A total of 23 retigabine derivatives (HN31-HN410) were synthesized and tested electrophysiologically. Among the compounds, HN38 was the most potent inhibitor of KCNQ2 channels (its IC50 value=0.10±0.05 μmol/L), and was 7-fold more potent than the classical KCNQ inhibitor XE991. Further analysis revealed that HN38 (3 μmol/L) had no detectable effect on channel activation, but accelerated deactivation at hyperpolarizing voltages. In contrast, XE991 (3 μmol/L) did not affect the kinetics of channel activation and deactivation. Conclusion: The retigabine derivative HN38 is a potent KCNQ2 inhibitor, which differs from XE991 in its influence on the channel kinetics. Our study provides a new strategy for the design and development of potent KCNQ2 channel inhibitors.
    Acta Pharmacologica Sinica 08/2013; 34(10). DOI:10.1038/aps.2013.79 · 2.91 Impact Factor
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    ABSTRACT: Potassium channels are pore-forming transmembrane proteins that regulate a multitude of biological processes by controlling potassium flow across cell membranes. Aberrant potassium channel functions contribute to diseases such as epilepsy, cardiac arrhythmia, and neuromuscular symptoms collectively known as channelopathies. Increasing evidence suggests that cancer constitutes another category of channelopathies associated with dysregulated channel expression. Indeed, potassium channel-modulating agents have demonstrated antitumor efficacy. Potassium channels regulate cancer cell behaviors such as proliferation and migration through both canonical ion permeation-dependent and noncanonical ion permeation-independent functions. Given their cell surface localization and well-known pharmacology, pharmacological strategies to target potassium channel could prove to be promising cancer therapeutics.
    The Journal of General Physiology 07/2014; 206(2):151-162. DOI:10.1083/jcb.201404136 · 4.79 Impact Factor
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