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Relationship: 667

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Reduction, Ionotropic GABA receptor chloride channel conductance leads to Reduction, Neuronal synaptic inhibition

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Reduction, Ionotropic GABA receptor chloride channel conductance

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Reduction, Neuronal synaptic inhibition

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures in adult brain	adjacent	High	High	Cataia Ives (send email)	Open for citation & comment	WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
rat	Rattus norvegicus	High	NCBI
guinea pig	Cavia porcellus	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

A decline in conductance through chloride channels in iGABARs causes a reduction in GABA-mediated inhibition of neuronal synaptic signaling, which is reflected as decreased frequency and amplitude of iGABAR-mediated spontaneous inhibitory postsynaptic currents or abolishment of GABA-induced firing action (Newland and Cull-Candy 1992). For instance, whole-cell in vitro recordings in the rat basolateral amygdala (BLA) showed that RDX reduces the frequency and amplitude of GABA_A receptor mediated spontaneous inhibitory postsynaptic currents (sIPSCs) and the amplitude of GABA-evoked postsynaptic currents, whereas in extracellular field recordings from the BLA, RDX induced prolonged, seizure-like neuronal discharges (Williams et al. 2011). These pieces of cellular level evidence support that binding to the GABA_A receptor convulsant site is the primary mechanism of seizure induction by RDX and that the key event of reduction of GABAergic inhibitory transmission in the amygdala is involved in the generation of RDX-induced seizures.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

Chloride channels play an important role in regulating neuronal excitability, especially in the context of fast synaptic inhibition mediated by GABA_A receptors. But in order for chloride channels to reduce excitability, chloride driving force must be maintained to keep a dynamic balancing of chloride influx and efflux, which also involves a variety of other ion species (Prescott 2014). If chloride regulation is compromised, the efficacy of fast synaptic inhibition can be compromised with adverse effects such as reduced neuronal inhibition.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The GABA_A receptor is part of a larger GABA/drug receptor-Cl⁻ ion channel macromolecular complex. An integral part of this complex is the Cl⁻ channel. The binding sites localized in or near the Cl⁻ channel for GABA, benzodiazepines, barbiturates, picrotoxin and anesthetic steroids modulate receptor response to GABA stimulation. The GABA-binding site is directly responsible for opening the Cl⁻ channel. Electrophysiological studies of the GABA_A-receptor complex indicate that it mediates an increase in membrane conductance with an equilibrium potential near the resting level of −70 mV. This conductance increase is often accompanied by a membrane hyperpolarization, resulting in an increase in the firing threshold and, consequently, a reduction in the probability of action potential initiation, causing neuronal inhibition (Olsen and DeLorey 1999). This reduction in membrane resistance is accomplished by the GABA-dependent facilitation of Cl⁻ ion influx through a receptor-associated channel.

Channel blockers, such as the convulsant compound picrotoxin, cause a decrease in mean channel open time. Picrotoxin acts on the gating process of the GABA_A receptor channel and works by preferentially shifting opening channels to the briefest open state (1 msec). Experimental convulsants like pentylenetetrazol and the cage convulsant t-butyl bicyclophosphorothionate (TBPS) act in a manner similar to picrotoxin, preventing Cl⁻ channel permeability (Macdonald and Olsen 1994).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

As a heteropentameric receptor, the iGABAR consists of five protein subunits arranged around a central pore to form an ion channel through the membrane. The subunits are drawn from a pool of 19 distinct gene products, including six alpha, three beta, and three gamma subunits. The high diversity of subunit genes, in combination with alternative splicing and editing, leads to an enormous variety and, consequently, variability in function and sensitivity. This constitutes the main source of uncertainties.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Is it known how much change in the first event is needed to impact the second? Yes, but very few studies reported changes in both events. One examples is Williams et al. (2011), where whole-cell in vitro recordings in the rat basolateral amygdala (BLA) showed that RDX reduced the frequency and amplitude of spontaneous GABA_A receptor–mediated inhibitory postsynaptic currents and the amplitude of GABA-evoked postsynaptic currents, whereas in extracellular field recordings from the BLA, RDX induced prolonged, seizure-like neuronal discharge.

Are there known modulators of the response-response relationships? There is no known modulator that acts in between chloride channel conductance decrease and neuronal inhibition reduction, even though there are many other players such as potassium-chloride cotransporters and sodium-potassium-chloride cotransporters that may affect chloride flux/homeostasis and electrochemical gradient (Prescott 2014), leading to changes in postsynpatic neuronal inhibition.

Are there models or extrapolation approaches that help describe those relationships? No.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

iGABARs and synaptic neurons are present in animals throughout the animal kingdom, therefore this event is applicable to a wide range of species from earthworm to humans. This relationship has been shown directly in rats (Williams et al. 2011) and guinea pig (Juarez et al. 2013).

References

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

Juarez E H, Ochoa-Cortes F, Miranda-Morales M, Espinosa-Luna R, Montano L M, Barajas-Lopez C. Selectivity of antagonists for the Cys-loop native receptors for ACh, 5-HT and GABA in guinea-pig myenteric neurons. Auton Autacoid Pharmacol 2013; 34(1-2):1-8.

Macdonald R L, Olsen R W. GABAA receptor channels. Annu. Rev. Neurosci. 1994;17:569–602.

Newland C F, Cull-Candy S G. On the mechanism of action of picrotoxin on GABA receptor channels in dissociated sympathetic neurones of the rat. J Physiol 1992; 447: 191–213.

Olsen R W, DeLorey T M. Chapter 16. GABA and Glycine: GABA Receptor Physiology and Pharmacology. In: Siegel GJ, Agranoff BW, Albers RW, et al. (Eds), Basic Neurochemistry: Molecular, Cellular and Medical Aspects (6th edition), Philadelphia: Lippincott-Raven; 1999.

Prescott S A. Chloride channels. In: Jaeger D and Jung R (Eds.), Encyclopedia of Computational Neuroscience, Springer, New York, 2014. pp.1-4.

Williams L R, Aroniadou-Anderjaska V, Qashu F, Finne H, Pidoplichko V, Bannon D I et al. RDX binds to the GABA(A) receptor-convulsant site and blocks GABA(A) receptor-mediated currents in the amygdala: a mechanism for RDX-induced seizures. Environ Health Perspect 2011; 119(3):357-363.