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Event: 387

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Binding of agonist, NMDARs

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

Explore in a Third Party Tool

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

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

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Drosophila melanogaster	Drosophila melanogaster	High	NCBI
Primates sp. BOLD:AAA0001	Primates sp. BOLD:AAA0001	High	NCBI
human	Homo sapiens	High	NCBI
Zalophus californianus	Zalophus californianus	High	NCBI
mice	Mus sp.	High	NCBI

Life Stages

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

Sex Applicability

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

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Biological state: Please see MIE NMDARs, Binding of antagonist

Biological compartments: Please see MIE NMDARs, Binding of antagonist

General role in biology: Please see MIE NMDARs, Binding of antagonist

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

1. Ex vivo: The most common assay used is the NMDA receptor (MK801 site) radioligand competition binding assays (Reynolds, 2001; Gao et al., 2013; http://pdsp.med.unc.edu/UNC-CH%20Protocol%20Book.pdf; http://www.currentprotocols.com/WileyCDA/CPUnit/refId-ph0120.html). This assay is based on the use of the most potent and specific antagonist of this receptor, MK801 that is used to detect and differentiate agonists and antagonists that bind to this specific site of the receptor.

2. In silico: The prediction of NMDA receptor targeting is achievable by combining database mining, molecular docking, structure-based pharmacophore searching, and chemical similarity searching methods together (Koutsoukos et al., 2011; Gao et al., 2013).

Domain of Applicability

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

The major determinants for ligand e.g. for both co-agonist glycine binding and L-glutamate binding are well-conserved between species from lower organism to mammals (reviewed in Xia and Chiang, 2009). PCR analysis, cloning and subsequent sequencing of the seal lion NMDA receptors showed 80% homology to those from rats, but more than 95% homology to those from dogs (Gill et al., 2010).

References

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

Pulido OM. Domoic acid toxicologic pathology: a review. Mar Drugs. 2008. 6: 180-219.

Gill S, Goldstein T, Situ D, Zabka TS, Gulland FM, Mueller RW. Cloning and characterization of glutamate receptors in Californian sea lions (Zalophus californianus). Mar Drugs. 2010. 8: 1637-1649.

Traynelis S, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. 2010. 62: 405-496.

Xia S, Chiang AS. NMDA Receptors in Drosophila. In: Van Dongen AM, editor. Biology of the NMDA Receptor. Boca Raton (FL): CRC Press; 2009. Chapter 10. Available from: http://www.ncbi.nlm.nih.gov/books/NBK5286/

F. W. Berman and T. F. Murray, “Domoic acid neurotoxicity in cultured cerebellar granule neurons is mediated predominantly by NMDA receptors that are activated as a consequence of excitatory amino acid release,” Journal of Neurochemistry, vol. 69, no. 2, pp. 693–703, 1997. View at Google Scholar · View at Scopus

F. W. Berman, K. T. LePage, and T. F. Murray, “Domoic acid neurotoxicity in cultured cerebellar granule neurons is controlled preferentially by the NMDA receptor Ca2+ influx pathway,” Brain Research, vol. 924, no. 1, pp. 20–29, 2002. View at Publisher · View at Google Scholar · View at Scopus

Watanabe KH, Andersen ME, Basu N, Carvan MJ 3rd, Crofton KM, King KA, Suñol C, Tiffany-Castiglioni E, Schultz IR. (2011). Defining and modeling known adverse outcome pathways: Domoic acid and neuronal signaling as a case study. Environ Toxicol Chem 30:9-21.