page_title: Anatoxin-a
section_title: Mechanism of toxicity
hierarchical_section_title: Anatoxin-a / Mechanism of toxicity
caption_attribution_description: English: The effects of anatoxin-a on nicotinic acetycholine receptors at the neuromuscular junction
context_page_description: Anatoxin-a, also known as Very Fast Death Factor, is a secondary, bicyclic amine alkaloid and cyanotoxin with acute neurotoxicity. It was first discovered in the early 1960s in Canada, and was isolated in 1972. The toxin is produced by seven different genera of cyanobacteria and has been reported in North America, South America, Central America, Europe, Africa, Asia, and Oceania. Symptoms of anatoxin exposure include loss of coordination, muscular fasciculations, convulsions and death by respiratory paralysis. Its mode of action is through the nicotinic acetylcholine receptor where it mimics the binding of the receptor's natural ligand, acetylcholine. As such, anatoxin-a has been used for medicinal purposes to investigate diseases characterized by low acetylcholine levels. Due to its high toxicity and potential presence in drinking water, anatoxin-a poses a threat to animals, including humans. While methods for detection and water treatment exist, scientists have called for more research to improve reliability and efficacy.
context_section_description: Anatoxin-a is an agonist of both neuronal α4β2 and α4 nicotinic acetylcholine receptors present in the CNS as well as the α12βγδ muscle-type nAchRs that are present at the neuromuscular junction. Anatoxin-a has an affinity for these receptors that is about 20 times greater than that of acetylcholine. However, the cyanotoxin has little effect on muscarinic acetylcholine receptors; it has a 100 fold lesser selectivity for these types of receptors than it has for nAchRs. Anatoxin-a also shows much less potency in the CNS than in neuromuscular junctions. In hippocampal and brain stem neurons, a 5 to 10 times greater concentration of anatoxin-a was necessary to activate nAchRs than what was required in the PNS.
  In normal circumstances, acetylcholine binds to nAchRs in the post-synaptic neuronal membrane, causing a conformational change in the extracellular domain of the receptor which in turn opens the channel pore. This allows Na⁺ and Ca²⁺ ions to move into the neuron, causing cell depolarization and inducing the generation of action potentials, which allows for muscle contraction. The acetylcholine neurotransmitter then dissociates from the nAchR, where it is rapidly cleaved into acetate and choline by acetylcholinesterase.  
  Anatoxin-a binding to these nAchRs cause the same effects in neurons. However, anatoxin-a binding is irreversible,  and the anatoxin-a nAchR complex cannot be broken down by acetylcholinesterase. Thus, the nAchR is temporarily locked open and after a period of time becomes desensitized. In this desensitized state the nAchRs no longer let cations pass through, which ultimately leads to a blockage of neuromuscular transmission.
  Two enantiomers of anatoxin-a, the positive enantiomer, (+)anatoxin-a, is 150 fold more potent than the synthetic negative enantiomer, (−)anatoxin-a. This is because (+)anatoxin-a, the s-cis enone conformation, has a distance a 6.0 Å between its nitrogen and carbonyl group, which corresponds well to the 5.9 Å distance that separate the nitrogen and oxygen in acetylcholine.
  Respiratory arrest, which results in a lack of an oxygen supply to the brain, is the most evident and lethal effect of anatoxin-a. Injections of mice, rats, birds, dogs, and calves with lethal doses of anatoxin-a have demonstrated that death is preceded by a sequence of muscle fasciculations, decreased movement, collapse, exaggerated abdominal breathing, cyanosis and convulsions. In mice, anatoxin-a also seriously impacted blood pressure and heart rate, and caused severe acidosis.
caption: The effects of anatoxin-a on nicotinic acetylcholine receptors at the neuromuscular junction
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