Event:593
Contents
Event Title
Key Event Overview
Please follow link to widget page to edit this section. If you manually enter text in this section, it will get automatically altered or deleted in subsequent edits using the widgets.
AOPs Including This Key Event
AOP Name | Event Type | Essentiality |
---|---|---|
Ether-a-go-go (ERG) voltage-gated potassium channel inhibition leading to increased predation | MIE | Strong |
Chemical Initiators
The following are chemical initiators that operate through this AOP:
Taxonomic Applicability
Name | Scientific Name | Evidence | Links |
---|
Level of Biological Organization
Biological Organization |
---|
How this Key Event works
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.