ION CHANNELS (hERG)

Ion channels open and close to allow Na+, K+, and Ca+2 ions that are electrically charged to flow in and out of the cell.

Each of this channel has right shape and size with the corresponding ions to fit through.  For example, a K+ ion can pass perfectly through a potassium channel and Na+ ion through sodium channel.  

However, a K+ ion is incapable of passing through a sodium channel, similarly a Na+ ion is incapable of passing through a potassium channel.

Movement of these ions into and outside of the cell is what causes the electrical activity in the heart.  This then spreads across the cells in the heart from top to bottom making them to contract and pump blood.

hERG K+ channel is responsible for length of QT interval.  When the channel is hERG blocked then K+ ions are delayed in leaving the heart muscle.

What is hERG?

·         hERG (the human Ether-à-go-go-Related Gene) is a gene (KCNH2) that codes for a protein known as K_v11.1, the alpha subunit of a potassium ion channel.

·         The hERG channel is a voltage-gated potassium channel and, like other voltage-gated potassium channels, it is highly selective for potassium and is a tetramer formed of four subunits, each containing six transmembrane domains.

·         hERG is expressed in multiple tissues and cell types, including neural, smooth muscle and tumour cells.  However, hERG is most highly expressed in the heart, and this is where its function-and dysfunction-is best understood.

What is its function?

·         This potassium ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to the electrical activity of the heart that coordinates the heart's beating.

·         The human ether-a-go-go related gene (hERG) encodes the inward rectifying voltage gated potassium channel in the heart (IKr) which is involved in cardiac repolarisation.

Why should we be interested in hERG?

·         When this channel's ability to conduct electrical current across the cell membrane is inhibited or compromised, by rare mutations in some families, it can result in a potentially fatal disorder called long QT syndrome.  Inhibition of the hERG current causes QT interval prolongation resulting in potentially fatal ventricular tachyarrhythmia called Torsade de Pointes (TdP).

·         hERG K⁺ channels are also remarkably susceptible to block by a wide range of drugs, which in turn can cause drug-induced long-QT syndrome (LQTS or TdP) and an increased risk of sudden death. This has made hERG inhibition an important antitarget that must be avoided during drug development.

What can be done?

·         To reduce the risk of a drug candidate failing in preclinical safety studies because of blockade of hERG channels and associated QT prolongation, it is important to screen compounds for activity on hERG channels early in the lead optimization process

·         Although binding assays do not measure hERG function, they offer a rapid, robust and inexpensive measure of the ability of compounds to interact with the hERG channel.  Combined with electrophysiology on a few benchmark compounds to characterize the nature of the compound-channel interaction, binding assays can be used as an efficient means to develop the structure-function relationship of hERG interactions within a structural class of test compounds. This strategy should facilitate the development of new small molecule drugs with improved cardiovascular safety profiles.

·         The hERG channel inhibition assay is a highly sensitive measurement which will identify compounds exhibiting cardiotoxicity related to hERG inhibition in vivo. It is important to note, however that not all compounds which inhibit hERG activity in vitro will proceed to cause cardiotoxicity in vivo. The relevance of the in vitro data will be dependent on other factors such as the plasma concentrations reached in vivo.