API

Relationship: 456

Title

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Accumulation, Acetylcholine in synapses leads to Induction, Ataxia, paralysis, or hyperactivity

Upstream event

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Accumulation, Acetylcholine in synapses

Downstream event

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Induction, Ataxia, paralysis, or hyperactivity

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Directness Weight of Evidence Quantitative Understanding
Acetylcholinesterase inhibition leading to acute mortality directly leads to Strong Weak

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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How Does This Key Event Relationship Work

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  • Within neuromuscular junctions of skeletal muscles, acetycholine binds and activates nicotinic (N2 or Nm) receptors. Upon binding, acetylcholine elicits a conformational shift that opens an ion channel, allowing for influx of cations that depolarize the motor end plate eliciting muscle contraction. Excess acetylcholine at the neuromuscular junction can cause uncontrolled rapid twitching of muscles, convulsions, and/or paralysis depending on severity.

Weight of Evidence

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Biological Plausibility

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  • Given the well established role of acetylcholine at neuromuscular junctions in mediating changes in membrane potential leading to muscle contraction, it is highly plausible that excess acetylcholine accumulation at these neuromuscular junctions can lead to hyperexcitation of skeletal muscles.

Empirical Support for Linkage

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  • The role of acetylcholine in triggering muscle contraction at the neuromuscular junctions is physiological dogma and is well supported by a large body of experimental evidence.
  • Direct administration of nicotinic acetylcholine receptor agonists can elicit sustained muscle contraction.
  • Potent toxins like alpha-bungarotoxin, alpha-cobrotoxin, erabutoxin b and others are known to cause weakness and paralysis through their actions on nicotinic acetylcholine receptors.

Uncertainties or Inconsistencies

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Quantitative Understanding of the Linkage

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A systematic review of the quantitative understanding of this KER has not been performed (to date).

Evidence Supporting Taxonomic Applicability

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References

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  • Klassen CD (editor). Casarett and Doull's Toxicology, the Basic Science of Poisons, Fifth Edition, McGraw Hill, New York, NY, USA.