This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 3091

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

Increased, Intracellular Calcium overload leads to Loss of drebrin

Upstream event

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

Increased, Intracellular Calcium overload

Downstream event

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

Loss of drebrin

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 chemicals to ionotropic glutamate receptors leads to impairment of learning and memory via loss of drebrin from dendritic spines of neurons	adjacent	High	Moderate	Shihori Tanabe (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 Do not cite	Under Development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

Term	Scientific Term	Evidence	Link
human	Homo sapiens		NCBI
rat	Rattus norvegicus	High	NCBI
mouse	Mus musculus	High	NCBI

Sex Applicability

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

Sex	Evidence
Male	High
Female	High

Life Stage Applicability

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

Term	Evidence
Fetal	High

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

Calcium modulates drebrin protein stability in neuronal cultures in ways that depend on both concentration and stimulus. NMDA receptor overactivation elevates intracellular calcium leads to loss of drebrin from dendritic spines of cultured coltcal neurons, hippocampal neurons and in vivo animal study.

Glutamate stimulation induced disappearance of drebrin immunostaining from dendritic spines but led to appearance of drebrin immunostaining in dendritic shafts and somata. The glutamate-induced shift of drebrin immunostaining was blocked by an NMDA receptor antagonist (Sekino, et al. 2006). Loss of drebrin from dendritic spines induced by hight-potasium stimulation or glutamate aplication was inhibited by EGTA and AP5 (Mizui, et al. 2014). Long term potentiation stimulation induces Ca²⁺ entry through N-methyl-d-aspartate (NMDA) receptors, which causes drebrin exodus from dendritic spines (Koganezawa , et al 2017). Under NMDA-induced excitotoxic conditions with 1 mM CaCl₂, Chimura et al. (2015) report that drebrin A undergoes calpain-dependent degradation, with Western blotting and immunocytochemistry revealing the emergence of approximately 40 kDa fragments—a change prevented by calpain inhibitor-I.

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

PubMed

Evidence Supporting this KER

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

Biochemical analyses using purified drebrin and calpain revealed that calpain degraded drebrin directly in vitro　（Chimura, et al. 2015）

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

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

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

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

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)
calpain	high	increase	Chimura, et al. 2015

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

Protein quantification methods: Western blotting using specific antibodies (C-term and DAS2).

Under NMDA-induced excitotoxic conditions with 1 mM CaCl₂, Chimura et al. (2015) report that drebrin A undergoes calpain-dependent degradation, with Western blotting and immunocytochemistry revealing the emergence of approximately 40 kDa fragments—a change prevented by calpain inhibitor-I.

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

References

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

Appearance order

Sekino Y, Tanaka S, Hanamura K, Yamazaki H, Sasagawa Y, Xue Y, Hayashi K, Shirao T. Activation of N-methyl-D-aspartate receptor induces a shift of drebrin distribution: disappearance from dendritic spines and appearance in dendritic shafts. Mol Cell Neurosci. 2006 Mar;31(3):493-504. doi: 10.1016/j.mcn.2005.11.003. Epub 2005 Dec 20. PMID: 16368245.

Mizui T, Sekino Y, Yamazaki H, Ishizuka Y, Takahashi H, Kojima N, Kojima M, Shirao T. Myosin II ATPase activity mediates the long-term potentiation-induced exodus of stable F-actin bound by drebrin A from dendritic spines. PLoS One. 2014 Jan 22;9(1):e85367. doi: 10.1371/journal.pone.0085367. PMID: 24465547; PMCID: PMC3899004.

Koganezawa N, Hanamura K, Sekino Y, Shirao T. The role of drebrin in dendritic spines. Mol Cell Neurosci. 2017 Oct;84:85-92. doi: 10.1016/j.mcn.2017.01.004. Epub 2017 Feb 1. PMID: 28161364.

Chimura T, Launey T, Yoshida N. Calpain-Mediated Degradation of Drebrin by Excitotoxicity In vitro and In vivo. PLoS One. 2015 Apr 23;10(4):e0125119. doi: 10.1371/journal.pone.0125119. PMID: 25905636; PMCID: PMC4408054.