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hERG Potassium Channels in Drug Discovery and Development

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Ion Channels and Their Inhibitors

Abstract

Potassium (K+) channels play a central role in the electrical activity of excitable cells. Although there are variety of potassium channels, scientists have developed immense interest in human ether-a-go-go-related gene (hERG) potassium channels due to their involvement in life-threatening cardiac arrhythmia. hERG is a gene that encodes the pore-forming α-subunit of a voltage-gated potassium channel expressed in nervous and cardiac tissue including atrium, ventricles, purkinje fiber, SA node and AV node. Potassium flow through hERG channel plays an important role in action potential repolarization, particularly in ventricular muscle. Blockade of hERG potassium channel via pharmacological interventions or hereditary mutations of genes encoding the channel is associated with a prolongation of cardiac ventricular repolarization, that is long QT syndrome (LQTS), a disorder that predisposesindividuals to life-threatening arrhythmias and substantial risk of sudden death. Inherited or drug-induced mutations in hERG channel lead to disruption of delayed rectifier potassium current (IKr), increase in cardiac excitability subsequently torsades de pointes and sudden death. A large number of putative disease-causing mutations in hERG have been identified in affected families so far, yet mechanism behind these mutations is unspecified and undistinguished. Therefore, entire paradigm of drug discovery has shifted towards the safety of the new molecules to screen for potential cardiac arrhythmogenic effects. Non-clinical assays are not sensitive enough to accurately predict QT prolongation liabilities in humans. For this reason, International Conference on Harmonization (ICH) safety pharmacology S7B guidelines were proposed for new chemical entities. According to these guidelines, thorough studies (in vitro and in vivo) on QT are required for virtually all newly developed pharmaceutical agents. In this article, an overview on hERG channels, their functions and dysfunctions, therapeutic agents modulating these channels and associated QT prolongation, and assay have been discussed.

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Abbreviations

CFTR:

Cystic fibrosis transmembrane conductance regulator

cNBD:

C-terminal cyclic nucleotide binding domain

DMSO:

Dimethyl sulfoxide

EAD:

Early after depolarization

ECG:

Electrocardiogram

ER:

Endoplasmic reticulum

EU:

European Union

HEK:

Human embroyonic kidney cells

hERG:

Human ether-a-go-go-related gene

HSP:

Heat shock protein

I:

Current

ICH:

International conference on harmonization

IKi :

Inward rectifier potassium current

IKr :

Delayed rectifier potassium current

IND:

Investigational new drug approval

K+ :

Potassium

Kv :

Voltage-gated Potassium channel

Kv11.1:

hERG Potassium channels

LQTS:

Long QT syndrome

NCE:

New chemical entity

PD:

Pharmacodynamic

PK:

Pharmacokinetic

QTc:

QT interval correction

Rb+ :

Rubidium

SERCA:

Sarcoplasmic ER Ca2+-ATPase

Tdp:

Torsade de pointes

TEA+ :

Tetraethyl ammonium

TMO:

Trimethyl amineoxide

VSD:

Voltage sensing domain

WT:

Wild type

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Acknowledgements

Authors thank the Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Govt. of India, New Delhi and CSIR, New Delhi for the financial support. Moreover, authors are thankful of Mr. Shivsharan Balbhim Kharatmal for his critical help in preparation of this article.

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  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector- 67, S.A.S. Nagar, Punjab, 160062, India

    Shyam S. Sharma

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  1. Jitendra N. Singh
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Correspondence to Shyam S. Sharma .

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    Satya Prakash Gupta

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Singh, J.N., Sharma, S.S. (2011). hERG Potassium Channels in Drug Discovery and Development. In: Gupta, S. (eds) Ion Channels and Their Inhibitors. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-19922-6_6

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