Белок hERG: структура, функция и роль в сердечных заболеваниях.

Mammalian protein found in humans

hERG (the human Ether à go go Related Gene) is a gene that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to the electrical activity of the heart: the hERG channel mediates the repolarizing IKr current in the cardiac action potential, which helps coordinate the heart's beating. When this channel's ability to conduct electrical current across the cell membrane is inhibited or compromised, either by application of drugs or by rare mutations in some families, it can result in a potentially fatal disorder called long QT syndrome. Conversely, genetic mutations that increase the current through these channels can lead to the related inherited heart rhythm disorder Short QT syndrome. A number of clinically successful drugs in the market have had the tendency to inhibit hERG, lengthening the QT and potentially leading to a fatal irregularity of the heartbeat (a ventricular tachyarrhythmia called torsades de pointes). This has made hERG inhibition an important antitarget that must be avoided during drug development. hERG has also been associated with modulating the functions of some cells of the nervous system and with establishing and maintaining cancer like features in leukemic cells.

hERG forms the major portion of one of the ion channel proteins (the 'rapid' delayed rectifier current (IKr)) that conducts potassium (K+) ions out of the muscle cells of the heart (cardiac myocytes), and this current is critical in correctly timing the return to the resting state (repolarization) of the cell membrane during the cardiac action potential.) or whether the channels include a mixture of different types (isoforms) of hERG, but, when the originally discovered form of hERG

A detailed atomic structure for hERG based on X ray crystallography is not yet available, but structures have recently been solved by electron microscopy. In the laboratory the heterologously expressed hERG potassium channel comprises 4 identical alpha subunits, which form the channel's pore through the plasma membrane. Each hERG subunit consists of 6 transmembrane alpha helices, numbered S1 S6, a pore helix situated between S5 and S6, and cytoplasmically located N and C termini. The S4 helix contains a positively charged arginine or lysine amino acid residue at every 3rd position and is thought to act as a voltage sensitive sensor, which allows the channel to respond to voltage changes by changing conformations between conducting and non conducting states (called 'gating'). Between the S5 and S6 helices, there is an extracellular loop (known as 'the turret') and 'the pore loop', which begins and ends extracellularly but loops into the plasma membrane; the pore loop for each of the hERG subunits in one channel faces into the ion conducting pore and is adjacent to the corresponding loops of the 3 other subunits, and together they form the selectivity filter region of the channel pore. The selectivity sequence, SVGFG, is very similar to that contained in bacterial KcsA channels.

Loss of function mutations in this channel may lead to long QT syndrome (LQT2), while gain of function mutations may lead to short QT syndrome. Both clinical disorders stem from ion channel dysfunction (so called channelopathies) that can lead to the risk of potentially fatal cardiac arrhythmias (e. g., torsades de pointes), due to repolarization disturbances of the cardiac action potential. There are far more hERG mutations described for long QT syndrome than for short QT syndrome. hERG containing channels are blocked by amiodarone, and it does prolong the QT interval, but its multiple other antiarrhythmic effects prevent this from causing torsades de pointes. Thioridazine causes peculiarly severe QTc prolongation by blocking hERG and was withdrawn by the manufacturer for this reason.

Due to the documented potential of QT interval prolonging drugs, the United States Food and Drug Administration issued recommendations for the establishment of a cardiac safety profile during pre clinical drug development: ICH S7B. The nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals, issued as CHMP/ICH/423/02, adopted by CHMP in May 2005. Preclinical hERG studies should be accomplished in GLP environment.

The hERG gene was first named and described in a paper by Jeff Warmke and Barry Ganetzky, then both at the University of Wisconsin–Madison.

HERG has been shown to interact with the 14 3 3 epsilon protein, encoded by YWHAE.