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Event: 39

Key Event Title

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

Increased Cholinergic Signaling

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
Increased Cholinergic Signaling
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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

Organ 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
nervous system

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; 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
Process Object Action
ataxia increased
hyperactivity increased
paralysis increased

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
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
AChE inhibition - acute mortality KeyEvent Cataia Ives (send email) Under Development: Contributions and Comments Welcome Under Development
AChE inhibition - acute mortality via predation KeyEvent Allie Always (send email) Under development: Not open for comment. Do not cite
Organo-Phosphate Chemicals leading to impaired cognitive function KeyEvent Brendan Ferreri-Hanberry (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 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

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


  • Cholinergic signalling refers to the activation of receptors bound with acetylcholine. Receptors for acetylcholine are collectively referred to as either acetylcholine or cholinergic receptors. They break down into 2 different classes, muscarinic and nicotinic. Each receptor type is associated with specific downstream effects. The lists below are manifestations of associated with each receptor class.

    • Muscarinic: increased salivation, lacrimation, perspiration, miosis, blurred vision, abdominal cramps, vomiting, diarrhea, increased bronchial secretion, bronchoconstriction, urinary frequency, bradycardia, hypotension (Costa)

    • Nicotinic: tachycardia, transient hypertension, muscle fasciculations, twitching, cramps, generalized weakness, flaccid paralysis (Costa)

Signal Transduction

  • The signal transmission mechanisms of both nicotinic and muscarinic cholinergic receptors has been intensively studied.

    • The nicotinic acetylcholine receptor (nAchR) is associated with triggering excitatory responses in motor neurons and skeletal muscle cells (Lodish, 2000). Overstimulation of the diaphragm via nicotinic receptors can lead to respiratory arrest (De Candole, 1953).

      • The nAchR has been extensively studied in neuromuscular junctions. It is a ligand-gated cation channel that allows passage of both potassium and sodium ions. Opening of nAchR ligand-gated ion channels produces a net depolarization at the muscle cell membrane, which leads to release of intracellular calcium, which triggers muscle contraction (Lodish, 2000). In this manner, acetylcholine accumulation can lead to paralysis via overstimulation of nicotinic receptors.  

    • Muscarinic receptors can transmit inhibitory signals. They are expressed on pre- and postsynaptic neurons, and on non-neuronal tissues throughout the body (Lodish, 2000).

    • Muscarinic receptors in the peripheral nervous system are activated by parasympathetic nerves present in airway smooth muscle, submucosal glands, and blood vessels where they trigger bronchoconstriction, mucus secretion, and vasodilatation, respectively (Coulson, 2003). 

      • All muscarinic receptors are G-protein coupled receptors, but the specific features depends on the subtype.

Neuromodulator Role

  • In addition to breaking down acetylcholine’s effects in terms of the receptor types, researchers have started to look at acetylcholine’s effects in terms of acting as a neurotransmitter and as a neuromodulator. Classical neurotransmitters act on a time scale of one millisecond to tens of milliseconds. Some researchers have proposed that acetylcholine also acts as a neuromodulator that influences synaptic transmission, plasticity and coordinated firing of groups of neurons over time scales that are much longer than the millisecond time frames associated with neurotransmitters (Picciotto, 2012, Luchicchi, 2014).

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
  • In humans

    • Pupils - human patients experiencing cholinergic poisoning constricted or pinpointed pupils are frequently reported in clinical cohort studies covering organophosphate exposure (Wadia, 1974, Peter, 2014). 

  • In embryonic fish and frogs

    • Spontaneous movements in developing fish and frog embryos are defined as flexing or side-to-side motion of the trunk or tail and free-swimming activity, defined as bilateral rhythmic flexing of the tail. Embryos were observed under a dissection microscope and the number of movements per minute was recorded. Spontaneous motion is measured at 1 day post fertilization (dpf) in zebrafish embryos and at 2 dpf in Xenopus (Watson, 2014).

    • Embryonic swimming activity in fish and frogs was measured at 5 dpf by placing larvae-containing dishes above an 8-wedged pie chart grid and counting the number of times a larvae crossed a grid line during a 1-min interval (Watson, 2014).

Domain of Applicability

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


List of the literature that was cited for this KE description. More help
  • Costa.  Toxic effects of pesticides.  In Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. pp 1055-1106.

  • 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.

  • Wadia RS, Sadagopan C, Amin RB, Sardesai HV. Neurological manifestations of organophosphorous insecticide poisoning. J Neurol Neurosurg Psychiatry. 1974 Jul;37(7):841-7.

  • Watson, Fiona L., Hayden Schmidt, Zackery K. Turman, Natalie Hole, Hena Garcia, Jonathan Gregg, Joseph Tilghman, and Erica A. Fradinger. 2014. “Organophosphate Pesticides Induce Morphological Abnormalities and Decrease Locomotor Activity and Heart Rate in Danio Rerio and Xenopus Laevis.” Environmental Toxicology and Chemistry 33 (6): 1337–45.

  • Peter, John Victor, Thomas Sudarsan, and John Moran. 2014. “Clinical Features of Organophosphate Poisoning: A Review of Different Classification Systems and Approaches.” Indian Journal of Critical Care Medicine 18 (11): 735–45.

  • Lodish, Harvey, Arnold Berk, S. Lawrence Zipursky, Paul Matsudaira, David Baltimore, and James Darnell. 2000. “Neurotransmitters, Synapses, and Impulse Transmission.” Molecular Cell Biology. 4th Edition.

  • Coulson FR, Fryer AD. Muscarinic acetylcholine receptors and airway diseases. Pharmacol Ther. 2003 Apr;98(1):59-69.