API

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Relationship: 919

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

Binding of agonist, Ionotropic glutamate receptors leads to Overactivation, NMDARs

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Binding of agonist, Ionotropic glutamate receptors
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Overactivation, NMDARs

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 of agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment. adjacent High Allie Always (send email) Open for citation & comment WPHA/WNT Endorsed
Binding of chemicals to ionotropic glutamate receptors leads to impairment of learning and memory via loss of drebrin from dendritic spines of neurons adjacent High Moderate Evgeniia Kazymova (send email) Under development: Not open for comment. Do not cite Under Development

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

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

NMDARs can be activated indirectly through initial activation of KA/AMPARs as it happens in the case of DomA exposure. DomA is an agonist of presynaptic and postsynaptic KARs and sustained activation of these receptors by DomA results in massive ion flux and excessive release of glutamate from excitatory terminals causing depolarization of the postsynaptic neuron (as descibed in MIE). Upon this depolarization the Mg2+ block is removed from the pore of NMDARs, resulting in their activation allowing sodium, potassium, and, importantly, calcium ions to enter into a cell. The sustained exposure to DomA causes pathological overactivation of NMDARs. In the case of exposure to glufosinate NMDARs activation is triggered by direct, sustained binding of glufosinate to the NMDARs.

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 Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
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

The increase in MFR induced by GLF in neuronal networks was significantly blocked by MK-801 but not entirely suggesting that GLF can increase activity in the MEA system through non-synaptic NMDARs, since these are not blocked by MK-801. It is not entirely clear whether GLF can work through an inhibition of the glutamate reuptake transporter, GLT-I, increasing the concentration of endogenous glutamate at the synaptic cleft and subsequently resulting in over activation of NMDARs (Lantz et al., 2014: Watanabe and Sano, 1998). Further studies are necessary to determine whether this alternative mechanism of GLF-induced NMDAR overactivation takes place. Additionally GLF also modulates glutamine synthetase (GS) activity. Since, astrocytic GS in the brain participates in the metabolic regulation of glutamate (endogenous agonist of NMDAR) it is not clear if this pathway contributes to NMDAR activation too.

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

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

Various studies suggest the existence of functional NMDA-like receptors in invertebrates (Xia et al., 2005). Fly and rodent NMDARs exhibit several important differences (Murphy and Glanzman, 1997). The expression and function of NMDA receptors in rodent and primates is well characterized in the existing literature.