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ACh Synaptic Accumulation leads to Increased Cholinergic Signaling
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Acetylcholinesterase inhibition leading to acute mortality||adjacent||High||Low||Dan Villeneuve (send email)||Under Development: Contributions and Comments Welcome||Under Development|
|Acetylcholinesterase Inhibition leading to Acute Mortality via Impaired Coordination & Movement||adjacent||Kristie Sullivan (send email)||Under development: Not open for comment. Do not cite|
|Organo-Phosphate Chemicals induced inhibition of AChE leading to impaired cognitive function||adjacent||High||Low||SAROJ AMAR (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
Acetylcholine is a neurotransmitter and neuromodulator that can exert either excitatory or inhibitory effects, depending on the receptor it binds to. Acetylcholine mediates central and peripheral functions, including somatic and autonomic functions. Excessive accumulation of acetylcholine at neural synapses and at neural-muscular junctions results in increased cholinergic signalling.
Acetylcholine is generated in presynaptic neurons and released into the synaptic cleft where it can bind to both pre- and postsynaptic receptors. Acetylcholine availability is downregulated by the degratory effect of acetylcholinesterase and by negative feedback loops controlled by muscarinic M2 receptors on the presynaptic neuron within the synapse (Soreq and Seidman, 2001).
Evidence Supporting this KER
- Biological plausibility for acetylcholine accumulation at the synapse leading to nervous system dysfunction is rooted in the well-established understanding of acetylcholine’s function as a neurotransmitter and neuromodulator. By acting upstream of a range of cellular and physiological functions, it is biologically plausible that accumulation of acetylcholine at neurological synapses will lead to systemic dysfunctions, which are often readily noticeable and measurable in clinical and research settings.
Uncertainties and Inconsistencies
No known qualitative inconsistencies or uncertainties associated with this relationship.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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De Candole, C.A., Douglas, W.W., Evans, C.L., Holmes, R., Spencer, K.E., Torrance, R.W., Wilson, K.M. 1953. The failure of respiration in death by anticholinesterase poisoning. Br J Pharmacol Chemother. 8(4):466-75.
Picciotto MR, Higley MJ, Mineur YS., Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012 Oct 4;76(1):116-29.
Luchicchi A, Bloem B, Viaña JN, Mansvelder HD, Role LW., Illuminating the role of cholinergic signaling in circuits of attention and emotionally salient behaviors. Front Synaptic Neurosci. 2014 Oct 27;6:24. doi: 10.3389/fnsyn.2014.00024. eCollection 2014.
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Grue CE, Shipley BK. 1984. Sensitivity of nestling and adult starling to dicrotophos, an organophosphate pesticide. Environ Res 35:454–465.
Verma, S.R., Tonk, I.P., Gupta, A.K., Dalela, R.C. 1981. In Vivo Enzymatic Alteration in Certain Tissues of Saccobranchus Fossilis Following Exposure to Four Toxic Substances. Environ. Pollut. (Series A). 26(2), 121-127.