Ciguatoxins: Cyclic Polyether Modulators of Voltage-gated Iion Channel Function

Abstract

Abstract:Ciguatoxins are cyclic polyether toxins, derived from marine dinoflagellates, which are responsible for the symptoms of ciguatera poisoning. Ingestion of tropical and subtropical fin fish contaminated by ciguatoxins results in an illness characterised by neurological, cardiovascular and gastrointestinal disorders. The pharmacology of ciguatoxins is characterised by their ability to cause persistent activation of voltage-gated sodium channels, to increase neuronal excitability and neurotransmitter release, to impair synaptic vesicle recycling, and to cause cell swelling. It is these effects, in combination with an action to block voltage-gated potassium channels at high doses, which are believed to underlie the complex of symptoms associated with ciguatera. This review examines the sources, structures and pharmacology of ciguatoxins. In particular, attention is placed on their cellular modes of actions to modulate voltage-gated ion channels and other Na + -dependent mechanisms in numerous cell types and to current approaches for detection and treatment of ciguatera.

Gambierol, a toxin produced by the dinoflagellate Gambierdiscus toxicus, is a potent blocker of voltage-gated potassium channels

“…Therefore, the development of a specific antidote has been severely hampered by the lack of information and it is only by supportive symptomatic treatment that ciguatera is currently treated. Today, at least 15 articles describe the effect of ciguatoxins on voltage-gated sodium and potassium channels Nicholson, 2006). For gambierol, there is some dispute about its ability to activate VGSCs.…”

A polyether biotoxin binding site on the lipid-exposed face of the pore domain of Kv channels revealed by the marine toxin gambierol

“…Consumption of contaminated fish causes ciguatera fish poisoning characterized by gastrointestinal and neurological symptoms and by hypotension, bradycardia, respiratory difficulties, and paralysis in severe cases (1).…”

“…In general, CTXs are potent toxins of voltage-gated sodium channels (VGSCs), with affinities in the nanomolar range (1,2). Their mechanism of action includes (i) a hyperpolarizing shift in the voltage dependence of channel activation causing channel opening at resting membrane potentials and (ii) disruption of the inactivation resulting in persistent activation (3).…”

Polyketide Polyethers

“…Ciguatoxin poisoning is the most frequent food-borne illness related to fin-fish consumption although it is rarely fatal. Symptoms include neurological, cardiovascular, and gastrointestinal disorders, and ciguatoxins can be detected in all body fluids (12). Most people recover slowly over time, which can take from weeks to years.…”