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Relationship: 1857


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

ACh Synaptic Accumulation leads to Activation, Muscarinic Acetylcholine Receptors

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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
Acetylcholinesterase Inhibition Leading to Neurodegeneration adjacent Moderate High Karen Watanabe (send email) Under development: Not open for comment. Do not cite

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 High NCBI
zebrafish Danio rerio High NCBI
rat Rattus norvegicus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

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

Acetylcholine (ACh) is a neurotransmitter within the central nervous system and peripheral nervous system that activates both muscarinic and nicotinic receptors (Haga, 2013). Muscarinic receptors are metabotropic and act using slower transmission signaling compared to the more direct ionotropic receptors (Miller and Yeh, 2016).

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 was collected in multiple ways: literature searches of external databases, review of related KEs and KERS in the AOPWiki, and consultation with experts.   Extensive literature searches were conducted in Scopus, Pubmed, and Google Scholar using keywords applicable to each KE, with an initial focus on zebrafish data to then focusing on rat data. Related KEs and KERs in the AOPWiki were also reviewed for relevant evidence and their sources.  The “snowball method” was used to find additional articles, i.e., relevant citations within an article were obtained if they provided additional evidence. EndNote reference managing software was used to store results from the literature searches and when possible, a pdf of the manuscript was attached to each record. Papers were reviewed and categorized by whether they contained data to support one or more parts of the AOP. An Excel spreadsheet was used to record reviewed papers and any information worth noting.

Evidence Supporting this KER

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

Binding of Ach to muscarinic receptors has been well documented to activate the receptor (Miller and Yeh, 2016). Using radiolabeled ACh ([3H]-ACh), experimenters have determined the binding kinetics between ACh and muscarinic receptors (Kellar et al., 1985, Uchida et al., 1978). Additionally, a computational model was recently developed modeling a CA1 pyramidal neuron’s response to activation of M1 receptors in the presence of ACh (Mergenthal et al., 2020)

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

It is well known that muscarinic receptors bind ACh. Muscarinic receptors are found in the target organs of parasympathetic neurons and in various parts of the central nervous system (Haga, 2013). Muscarinic receptors expressed in the brain are the M1, M2, and M4 subtypes more than the M3 or M5 subtypes (Lebois et al., 2018).

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

There are no known uncertainties or inconsistencies with this relationship.

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

Muscarinic receptors are found in a wide variety of species, both vertebrates and invertebrates, and cholinergic transmissions occur at all stages in (Burke et al., 2017, Garcia et al., 2016, Miller and Yeh, 2016).


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

Burke, R. D., Todd, S. W., Lumsden, E., Mullins, R. J., Mamczarz, J., Fawcett, W. P., Gullapalli, R. P., Randall, W. R., Pereira, E. F. R. & Albuquerque, E. X. 2017. Developmental neurotoxicity of the organophosphorus insecticide chlorpyrifos: from clinical findings to preclinical models and potential mechanisms. Journal of Neurochemistry, 142, 162-177. DOI: 10.1111/jnc.14077.

Falkenburger, B. H., Jensen, J. B. & Hille, B. 2010. Kinetics of M1 muscarinic receptor and G protein signaling to phospholipase C in living cells. The Journal of general physiology, 135, 81-97. DOI: 10.1085/jgp.200910344.

Faria, M., Garcia-Reyero, N., Padrós, F., Babin, P. J., Sebastián, D., Cachot, J., Prats, E., Arick Ii, M., Rial, E., Knoll-Gellida, A., Mathieu, G., Le Bihanic, F., Escalon, B. L., Zorzano, A., Soares, A. M. & Raldúa, D. 2015. Zebrafish Models for Human Acute Organophosphorus Poisoning. Sci Rep, 5, 15591. DOI: 10.1038/srep15591.

Garcia, G. R., Noyes, P. D. & Tanguay, R. L. 2016. Advancements in zebrafish applications for 21st century toxicology. Pharmacology and Therapeutics, 161, 11-21. DOI: 10.1016/j.pharmthera.2016.03.009.

Haga, T. 2013. Molecular properties of muscarinic acetylcholine receptors. Proceedings of the Japan Academy Series B: Physical and Biological Sciences, 89, 226-256. DOI: 10.2183/pjab.89.226.

Harris, L. W., Stitcher, D. L. & Heyl, W. C. 1980. The effects of pretreatments with carbamates, atropine and mecamylamine on survival and on soman-induced alterations in rat and rabbit brain acetylcholine. Life Sci, 26, 1885-91. DOI: 10.1016/0024-3205(80)90617-7.

Kellar, K. J., Martino, A. M., Hall, D. P., Jr., Schwartz, R. D. & Taylor, R. L. 1985. High-affinity binding of [3H]acetylcholine to muscarinic cholinergic receptors. J Neurosci, 5, 1577-82. DOI: 10.1523/jneurosci.05-06-01577.1985.

King, A. M. & Aaron, C. K. 2015. Organophosphate and Carbamate Poisoning. Emergency Medicine Clinics of North America, 33, 133-151. DOI: 10.1016/j.emc.2014.09.010.

Lebois, E. P., Thorn, C., Edgerton, J. R., Popiolek, M. & Xi, S. 2018. Muscarinic receptor subtype distribution in the central nervous system and relevance to aging and Alzheimer's disease. Neuropharmacology, 136, 362-373. DOI: 10.1016/j.neuropharm.2017.11.018.

Mergenthal, A., Bouteiller, J.-M. C., Yu, G. J. & Berger, T. W. 2020. A Computational Model of the Cholinergic Modulation of CA1 Pyramidal Cell Activity. Frontiers in Computational Neuroscience, 14. DOI: 10.3389/fncom.2020.00075.

Miller, S. L. & Yeh, H. H. 2016. Neurotransmitters and Neurotransmission in the Developing and Adult Nervous System. Conn's Translational Neuroscience.

Uchida, S., Takeyasu, K., Ichida, S. & Yoshida, H. 1978. Muscarinic cholinergic receptors in mammalian brain: differences between bindings of acetylcholine and atropine. Jpn J Pharmacol, 28, 853-62. DOI: 10.1254/jjp.28.853.