Acetylcholine fasciculins

Onchidal and fasciculins are natural toxins, which produce their toxicity in mammalian systems by virtue of primarily acetylcholinesterase (AChE) inhibition. AChE hydrolyzes and inactivates acetylcholine, thereby regidating the concentration of the transmitter at the synapse. Termination of activation is normally dependent on dissociation of acetylcholine from the receptor and its subsequent diffusion and hydrolysis, except in diseases where acetylcholine levels are limiting or under AChE inhibition, conditions that increase the duration of receptor activation (Silver, 1963). 

Fasciculin inhibition of AChE is prevented by chemical modification of the enzyme at a peripheral site (Duran et al, 1994). The specific interaction of fasciculin 2 with peripheral sites present in Electrophorus electricus AChE Ki, 0.04 nM fasciculin) was investigated by chemical modification with A,A-dimethyl-2-phenylaziridium (DPA) in the presence of active or peripheral anionic site protective agents. An enzyme was obtained that compared to the native AChE and was 10 times less sensitive to fasciculin 2. This enzyme was fully inhibited by edrophonium and tacrine, and was 25-170 times less sensitive to several peripheral site ligands. It seems fasciculin 2 binding to an AChE peripheral site partially overlaps the site of other peripheral site ligands including acetylcholine. 

The toxin binds to acetylcholinesterase and renders acetylcholine unhydrolyzed. This causes continuous excitement of the muscle. The inhibition of acetylcholinesterase is seen not only in vitro, but also in vivo. For instance, 80% of the acetylcholinesterase activity in the locus coeruleus was inhibited by the injection of fasciculin 2 in rats (Abo et al., 1989). The inhibition of the enzyme by fasciculin is longlasting, and a 74% inhibition five days after injection was observed (Quillfeldt et al., 1990). 

Because of the inhibition of acetylcholinesterase, dendrotoxins or other facilitatory toxins enhance the release of acetylcholine. Thus, dendrotoxins and fasciculins have synergistic action that enhances the lethality. 

Puu, G., and Koch, M. (1990). Comparison of kinetic parameters for acetylcholine, soman, ketamine and fasciculin towards acetyl-cholinesterase in liposomes and in solution. Biochem. Pharmacol. 40 2209-2214. 

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