hERG Potassium Channels in Drug Discovery and Development - Ion Channels and Their Inhibitors - page 150

potassium channels due to their involvement in life-threatening cardiac arrhythmia.
hERG is a gene that encodes the pore-forming -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.

a

Keywords K v 11.1 • Long QT syndrome • Electrocardiogram • ICH • Tdp • Protein
Trafficking • hERG assays

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

IK i Inward rectifier potassium current