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Event: 593

Key Event Title

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Inhibition, Ether-a-go-go (ERG) voltage-gated potassium channel

Short name

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Biological Context

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Level of Biological Organization
Molecular

Cell term

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Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
potassium channel inhibitor activity	potassium voltage-gated channel subfamily H member 2 (human)	decreased

Key Event Overview

AOPs Including This Key Event

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AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
ether-a-go-go (ERG) inhibition	MolecularInitiatingEvent	Brendan Ferreri-Hanberry (send email)	Under Development: Contributions and Comments Welcome

Taxonomic Applicability

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Life Stages

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Sex Applicability

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Key Event Description

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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

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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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

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).

References

List of the literature that was cited for this KE description. More help

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.