Structure and function of δ-atracotoxins: Lethal neurotoxins targeting the voltage-gated sodium channel

δ-Atracotoxins (δ-ACTX), isolated from the venom of Australian funnel-web spiders, are responsible for the potentially lethal envenomation syndrome seen following funnel-web spider envenomation. They are 42-residue polypeptides with four disulfides and an 'inhibitor cystine-knot' motif with structural but not sequence homology to a variety of other spider and marine snail toxins. δ-Atracotoxins induce spontaneous repetitive firing and prolongation of action potentials resulting in neurotransmitter release from somatic and autonomic nerve endings. This results from a slowing of voltage-gated sodium channel inactivation and a hyperpolarizing shift of the voltage-dependence of activation. This action is due to voltage-dependent binding to neurotoxin receptor site-3 in a similar, but not identical, fashion to scorpion α-toxins and sea anemone toxins. Unlike other site-3 neurotoxins, however, δ-ACTX bind with high affinity to both cockroach and mammalian sodium channels but low affinity to locust sodium channels. At present the pharmacophore of δ-ACTX is unknown but is believed to involve a number of basic residues distributed in a topologically similar manner to scorpion α-toxins and sea anemone toxins despite distinctly different protein scaffolds. As such, δ-ACTX provide us with specific tools with which to study sodium channel structure and function and determinants for phyla- and tissue-specific actions of neurotoxins interacting with site-3. © 2004 Elsevier Ltd. All rights reserved

Ciguatoxin and ciguatera

Ciguatera is a disease caused by the consumption of fishes from tropical and subtropical waters that have accumulated lipophilic sodium channel activator toxins known as ciguatoxins (CTXs) to levels sufficient to cause human poisoning. Consumption of these temperature-stable, orally active polycyclic ether compounds leads to the activation of neuronal sodium channels that produces a range of characteristic neurological, gastrointestinal, and cardiovascular signs and symptoms that clinically define the illness. Ciguatera is estimated to affect similar to 50,000 people annually worldwide after accounting for misdiagnosis and non-reporting. Currently there are no clinically validated treatments and no routine tests that can cost-effectively detect ciguatoxins prior to consumption, with government bans on capture or personal avoidance of risk fish species providing the only effective means to mitigate the risk currently. A recently developed rapid extraction method for ciguatoxins coupled to LC/MS/MS detection has potential for surveillance and confirmation of ciguatera outbreaks