Antillatoxin (ATX) is a potent lipopeptide neurotoxin produced by the marine cyanobacterium Lyngbya majuscula. ATX activates voltage-gated sodium channels, which can cause cell depolarisation, NMDA-receptor overactivity, excess calcium influx and neuronal necrosis.
Antillatoxin is a sodium channel gating modifier with special efficacy in cells expressing rNav1.2, rNav1.4 and rNav1.5 α subunits. It is suggested that ATX preferentially binds to the voltage-gated sodium channel in the inactivated state. The specific site of interaction of this neurotoxin is not yet known, however there is an allosteric interaction between ATX and brevetoxin (PbTx) at site 5 of the α subunit, which indicates that the neurotoxin site for ATX is topologically close and/or conformationally coupled to neurotoxin site 5. Additionally, sites 1, 2, 3, 5 and 7 were ruled out as possible binding sites.
Changing the tert-butyl-substituted diene groups reduced toxicity, which proves that the twisted shape of these groups plays a critical role in the degree of neurotoxicity of ATX.
Antillatoxin activates voltage-gated sodium channels, thus increasing sodium influx into the cell. It is hypothesized that ATX creates the increase in sodium influx by altering the voltage-gating properties of the channel. The toxin might change the voltage dependence of inactivation or augment the rate of recovery from inactivation. The effect is concentration dependent, with similar potency for the rNav1.2,rNav1.4 and rNav1.5 α-subunit types of sodium channels.
Antillatoxin-induced cytotoxicity is thought to occur through excessive activation of NMDA receptors by increased sodium influx, leading to excess calcium influx and necrosis. This seems plausible as cytotoxicity can be prevented by either tetrodotoxin or NMDA-receptor antagonists if administered early after exposure. Yet the exact mechanism is still unclear, as antillatoxin’s effect on the membrane potential is not sufficient to relieve the NMDA receptor block by magnesium.
Aside from toxic effects, ATX seems to enhance neurite outgrowth in developing immature neurons, depending on sodium influx, NMDA receptor activity, voltage-gated calcium channels and the calmodulin-kinase pathway.
Antillatoxin increases the binding affinity of voltage-gated sodium channels for Batrachotoxin at site 5 in an allosteric way, possibly by inducing a conformational change favourable for Batrachotoxin binding.
The toxin has been implicated in cases of respiratory irritation, inflammation of the eye and severe contact dermatitis in fishermen. Antillatoxin is a very potent neurotoxin, although exact toxicity differs between species. The lethal concentration LC50 is about 0.1 µM for goldfish, making it the most potent toxin known for goldfish after brevetoxin. It can be cytotoxic to single cerebellar granule cells at concentrations as low as 20 nM in rats but more typically at 50 nM.
Morphological features of antillatoxin-induced neuronal toxicity are swelling of neuronal somata, thinning of neurites and blebbing of neurite membranes.