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Key Event Title
Inhibition, Ether-a-go-go (ERG) voltage-gated potassium channel
|Level of Biological Organization|
Key Event Components
|potassium channel inhibitor activity||potassium voltage-gated channel subfamily H member 2 (human)||decreased|
Key Event Overview
AOPs Including This Key Event
Key Event Description
In cardiomyocytes, electical depolarization occurs upon the opening of voltage-gated sodium channels (Nav1.5) and the rapid influx of sodium ions. This influx causes the upstroke of the action potential (phase 0 in a human EKG). NaV channels turn off rapidly, but the depolarization causes Ca and K channels to open. Calcium channels (Cav1.2) open and allow maintenance of depolarization. Ca2+ entry also triggers contraction of the heart muscle. Repolarization begins as potassium channels open and allow K+ out of cell, balancing out the Ca2+ influx to create the plateau of the action potential (phase 2). Potassium channels terminate the action potential and return the cell to rest (phases 3 and 4). The ether a go-go gene (ERG;KCNH2) encodes for one of the ion channel proteins (the 'rapid' delayed rectifier current (IKr)) that conducts potassium (K+) ions out of the muscle cells. This current is critical in correctly timing the return to the resting state (repolarization) of the cell membrane during the cardiac action potential (Sanguinetti and Tristani-Firouzi, 2006). In other species,such as zebrafish, other ion channels may be absent (Alday et al., 2014), but the ERG channel is likely highly conserved.
In humans, the ERG potassium channel's pore is composed of 4 identical alpha subunits. Each 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. Arginine or lysine amino acids present in the S4 helix likely acts as the voltage-sensitive sensor. 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 four subunit pore loops form the selectivity filter inside the pore.
The relatively large inner vestibule of the ERG channel permits binding of many pharmaceutical agents of diverse structure and function. The more common drugs which can result in ERG block include antiarrhythmics (especially Class 1A and Class III), anti-psychotic agents, and certain antibiotics (including quinolones and macrolides). Binding of the ERG channel and subsequent inhibition of the Ikr can result in prolonged QT syndrome, Torsade de Points or bradycardia.
How It Is Measured or Detected
Generally, inhibition is mmeasured using patch clamp electrophysiology. There is also a commercially available hERG fluorescence polarization kit. ToxCast assay NVS_IC_hKhERGCh also measures human ERG (hERG) inhibition.
Domain of Applicability
ERG mRNA has been identified in the hearts of guinea pig, rabbit, human, dog, and rat species. In rat, erg transcript was also found in the brain, retina, thymus, adrenal gland, skeletal muscle, lung, and cornea. In isolated rat ventricular myocytes, an E-4031–sensitive current was observed, which is consistent with the presence of IKr (Wymore et al., 1997).
Sanguinetti, M. C. and M. Tristani-Firouzi (2006). "hERG potassium channels and cardiac arrhythmia." Nature 440(7083): 463-469.
Wymore, R. S., et al. (1997). "Tissue and Species Distribution of mRNA for the ikr-like K+ Channel, ERG." Circ Res 80(2): 261-268.