Cardiac arrhythmias are major causes of morbidity and mortality, including sudden cardiac death. European

Committee for Proprietary Medicinal Products has stated that “every new chemical entity intended for Phase I evaluation should be screened for potential effects on cardiac repolarization”. The human ether-a-go-go-related gene (hERG) channel, a member of a family of voltage-gated potassium (K+) channels, plays a critical role in the repolarization of the cardiac action potential. The reduction of hERG channel activity as a result of adverse drug effects may cause QT interval prolongation and potentially lead to acquired long QT syndrome resulting in potentially fatal ventricular tachyarrhythmia called Torsade de Pointes. A number of drugs have been withdrawn from late stage clinical trials due to these harmful effects, therefore it is important to identify inhibitors early in drug discovery. Hence it is necessary to highlight the relevance of novel and more efficient ion channel screening technologies for safer drug development. The present article gives an overview on role of hERG & methodologies employed for assessing the degree of hERG inhibition so as to provide more efficient drugs with lesser cardiotoxic potential.

Introduction

• Ion channels are important targets of therapeutic
• Potassium channels are one of the most diverse classes of cell membrane
• Third largest group of signaling molecule after protein kinase and G-protein-coupled
• Activity regulated by different voltage-gated ions (Na+ & Ca2+), neurotransmitters & K+

What Is hERG?

• N-terminal region contains a Per–Arnt–Sim (PAS) domain, important role in deactivation of the channel.
• The C-terminal tail contains (CNBD)- function not well
• Voltage-gated K+ channels 1 (commonly known as Kv7.1 or KCNQ1) and Kv11.1 (commonly known as hERG and KCNH2) play important role in cardiac repolarization.
• Mainly expressed in heart, but are also expressed in many other tissues including the brain, kidney, liver, and
• Ikr, encoded by 1 gene which is usually called hERG.

What Is Lqts?

• Can be drug- acquired or inherited alterations in IK
• Class III antiarrhythmic agents, which mainly block the IKr channel This is termed a class III antiarrhythmic effect.
• As IKr plays a key role in repolarization, inhibition of it causes prolongation of the QT interval on the
• This leads to life-threatening ventricular tachyarrhythmia, in particular Tdp (torsade de pointes).

Primary factors for successful accomplishment of heterologous expression of ion channels

• Choice of the mammalian cell host- transient or
• Choice of the expression vector- viral vectors or plasmid
• DNA delivery method- chemical or

Other Significant applications-

• In colon carcinomas, hERG mRNA was a more sensitive and more specific indicator for malignancy than mRNA of CEA, CK19 &
• Direct blockade of the hERG potassium channel, is expected to produce antiproliferative and proapoptotic effects that diminish tumor growth and eg. Cisapride.

Tags: MET Institute of Pharmacy