Nerve fibres transmit signals by a complex set of interacting biochemical and electrical processes. A nerve impulse (action potential) is generated by the rapid movement of ions across the cell membrane of the nerve. Initially sodium ions enter the nerve to generate the beginning of the electrical impulse, and then potassium ions leave the cell to effectively terminate the electrical pulse. These electrochemical pulses travel along the nerve fibres at speeds of 0.1m/sec to nearly 100m/sec depending on the type of nerve.
Electrochemical impulses (action potentials, pale green lighting bolts) reach the expanded nerve terminal at a synapse with a muscle cell. Packets of chemical messenger (neurotransmitter, bright green) are released into the space between the nerve ending and the muscle cell. There they bind to receptor molecules (green USB symbols) leading to an electrochemical impulse in the muscle (dark green lighting bolts) which in turn stimulates it to contract. Nerve fibres like these are typically 1-10µm in diameter where 1µm (micrometre) = 1/1000th of a millimetre. Each packet of transmitter contains about 1000 messenger molecules.
Nerve cells communicate with each other or with muscle cells via specialised contact zones called synapses. One nerve cell communicates with another nerve cell or a muscle cell by releasing a chemical messenger (a neurotransmitter) at the synapse. When the electrochemical impulse reaches the synaptic area, the chemical messengers which have been stored in little intracellular packets (synaptic vesicles) are released into the gap between the nerve cell and its target cell. Within the synaptic area of the target cell, the membrane contains an array of specialised receptor molecules that respond selectively to these chemical messengers. Depending on the type of cell, the type of messenger, and the type of receptor, the target cell may become more or less active.
The primary neurotoxin confirmed to be in the current bloom is brevetoxin. Brevetoxin was originally isolated from the dinoflagellate Karenia brevis1, which has never been detected in Australian waters. Brevetoxin also can be made by Karenia cristata2 and Karenia papilionacea3, both of which have been detected in the current bloom, with Karenia cristata dominating, but it is not made by Karenia mikimotoi. Consequently, regular testing of water at South Australian shellfish farms has detected brevetoxin during this bloom, leading to the closure of some facilities. Biochemically similar neurotoxins, brevisulcatic acids, are made by Karenia brevisuclata4 which also has been detected in the South Australian bloom.
Brevetoxin is released from the dinoflagellates when they break up in turbulent conditions. Once out of the cells, it can linger in the water from where it can be aerosoled by wave and wind action. Surprisingly, the biological functions of brevetoxin in the lives of Karenia species are not well understood.
Like most other neurotoxins, brevetoxin has a complicated synthesis pathway and is resistant to breakdown. It exists in two main forms with many variants of them5. Structurally, it is a polyether that is lipid soluble: this means it can easily enter cells and tissues it contacts.
The interactions of brevetoxin and fish are complex6. At least some species of fish can feed on or ingest Karenia brevis, a potent source of brevetoxins, with little obvious effect, even though the toxin accumulates in their tissues. However, others can be paralysed and killed, especially if exposed to brevetoxin released from damaged Karenia cells7. Fish that have had their gills damaged by cytotoxins may be more susceptible to poisoning by brevetoxin.
Brevetoxin accumulates at sub-lethal levels by filter-feeding shellfish such as oysters and mussels. Eating shellfish with high levels of brevetoxin leads to neurotoxin shellfish poisoning (NSP) in humans, marine mammals and birds, which can include symptoms of nausea, numbness, loss of coordination and other neural dysfunctions (see references in footnote 1 below).
Surprisingly, Karenia brevis also produces a natural antagonist to the actions of brevetoxin: brevenal8. It is not known if other dinoflagellates produce brevenal.
Brevetoxin disrupts activity of the nerves in a characteristic way. It binds to the molecules in the nerve cell membrane that let sodium in (voltage-gated sodium channels), opens these channels, and effectively jams them open. Initially, this makes the nerve fibres fire much more quickly than usual, which in turn releases much more neurotransmitter than usual. The excess neurotransmitter overloads the receptor molecules on the muscle causing it to maximally contract with spasms or cramps. Eventually, this toxin-induced hyperactivity of the nerve causes the electrochemical system to fail and no more nerve pulses can be generated. The nerves, the muscles and the poisoned animal become paralysed. If sensory nerves are exposed to brevetoxin, they also will fire in rapid and uncoordinated ways, leading to sensations of tingling and numbness. The nerves of nearly all types of animals have these molecules9 and so all could be affected by brevetoxin. However, the sensory nerves responsible for sensations of pain associated with burning and inflammation, for example, are largely unaffected by brevetoxin, since they mostly lack the molecules targeted by the toxin. Thus, exposure to brevetoxin is unlikely to directly cause stinging or burning sensations in the absence of any other symptoms. A mode of action similar to that of brevetoxin is found in several other types of toxins from a wide range of organisms including poison dart frogs (batrachotoxin), funnel-web spiders, scorpions, cone snails, snakes, and plants, such as some rhododendrons (grayanotoxin), lilies (veratridine) and daisies (pyrethrins)10.
Sharks and rays have a unique system of electrosensors in the skin around their head11. They respond to electric fields generated by electrical activity underlying muscle contraction in prey animals. If brevetoxin causes excessive firing of impulses in these nerves, it could lead to the abnormal disoriented behaviour observed in some sharks and rays exposed to the bloom.
Some brevetoxin variants have non-neurotoxic actions on the airways, leading to respiratory symptoms. Click here to read more about these actions.
The toxin greatly increases the rate of nerve impulse generation, leading to enhanced neurotransmitter release and over-loading of the receptor molecules on the muscle. The muscle contracts more and more, and does not get a chance to relax, ending up in spasms and cramps. Eventually the nerve impulse generation fails leading to paralysis. Colours and symbols the same as in the previous diagram.
The electrical impulse of a nerve (action potential) is generated by the movement of sodium (Na+) and potassium (K+) ions across the cell membrane. The ions cross the cell membrane via specific protein channels that can be open or closed depending on the voltage across the cell membrane (voltage-gate sodium or potassium channels. At rest, sodium ion concentrations are high outside the nerve cell and low inside it. Potassium ion concentrations are the opposite way around. This difference means that thecell membrane acts like a battery with a charge of about 70mV, negative, compared with the outside of the cell. When the sodium channels open, sodium ions rush in and the battery effectively not only discharges but reverses its charge for a short time (a few milliseconds). This change in voltage triggers the sodium channels to close and the potassium channels to open. Potassium ions enter the nerve cell and restore the negative charge inside the cell. Over time other processes ensure that the overall concentration of sodium and potassium in the cell are maintained.
Brevetoxin binds to the sodium channels and locks them in an open position12. This makes the action potentials longer and more frequent producing more nerve impulses. Eventually the increased sodium entry overloads the system and the nerve cell will stop operating. It may undergo cytolytic breakdown due to the persistent ionic imbalance. There are several molecular types of sodium channels, only some of which are activated by brevetoxin: nerves that mostly lack those types of channels, such as those mediated burning or inflammatory pain, are not directly affected by brevetoxin at concentrations that affect other types of nerves13.
The green line in the diagrams below shows how the voltage across the nerve cell membrane changes with time, from -70mV at rest, to strongly positive as sodium enters the cell during the action potential and then returning to -70mV as potassium leaves the cell.
The mechanism of action of ciguatoxin, a potent dinoflagellate neurotoxin from Gambierdiscus toxicus, is very similar to that of brevetoxin, which has a closely related chemical structure and binds to the same site on the sodium channels14. As mentioned above, a similar mode of action is also found in several other types of toxins including those from poison dart frogs (batrachotoxin), funnel-web spiders, scorpions, cone snails, snakes, and plants, such as some rhododendrons (grayanotoxin), lilies (veratridine) and daisies (pyrethrins).
In contrast, this mechanism is the functional opposite of that of another neurotoxin, saxitoxin, found in a range of dinoflagellates, including Alexandrium spp, Gymnodinium spp and Pyrodinium spp. Saxitoxin targets the same sodium channels as brevetoxin, but, in this case, blocks them, rendering them inoperable15. Thus the nerve fibres can no loner generate action potentials or transmit nerve impulses, leading to numbness and paralysis. This mode of action is the same as that of tetrodotoxin16 (made by cyanobacteria and found in blue-ringed octopus and toadfish, amongst others) and local anaesthetics, such as lidocaine (also known as lignocaine or Xylocaine). Saxitoxin affects a wide ranges of species and has a long life in the environment. In humans, it can produce paralytic shellfish poisoning if shellfish containing the toxin are eaten17.
Another Karenia species, Karenia selliformis, produces yet a different family of neurotoxins: gymnodimines. Trace levels of these toxins have been found in other Karenia species including K. mikimotoi18. These toxins block the receptors on the muscles that respond to neurotransmitter released from nerve endings (nicotinic acetylcholine receptors), leading to paralysis. The nerves are still working properly but the muscles can no longer respond to their signals. This action is very like that of curare. However, its potency seems to be low in the natural environment and it is probably not a major contributor to toxic effects of the bloom. A Chilean strain of K. selliformis recently has been shown to produce a neurotoxin with similar actions to brevetoxin, but which is not brevetoxin. This strain probably also produces a cytotoxin. 19
Brevetoxin binds to sodium channels on nerves with high affinity. This means that you don’t need much for it to have an effect. On average, the concentration of brevetoxin required to activate neural sodium channels is in the range 1-3nM (1nM = 10-9 mol/l).20 Concentrations of brevetoxin in seawater with blooms of Karenia brevis have been measured in the range from 1nM to nearly 200nM, with each Karenia cell containing about 10-50pg of toxin.21
Another way of looking at these numbers is to consider that:
• if each Karenia cell contains about 50pg of brevetoxin;
• and there is a typical bloom density of 10,000 cells per litre;
• and if all these cells were to lyse and release their brevetoxin;
• then the resulting concentration of brevetoxin would be about 5nM.
This is at the low end of the observed range, but still theoretically capable of having effects on marine creatures which are in constant contact with the seawater containing this level of brevetoxin.
If the brevetoxin in the water has access to nerve endings in living animals, this concentration would be enough to affect neural function, leading to abnormal behaviour, paralysis and ultimately, death. Indeed, the lethal range of brevetoxin has been observed to lie in the range of 5-20nM (see Baden et al, 2005, below).
The critical thing here is how much of the brevetoxin can enter the body in order to reach the nerves. Brevetoxin is lipophilic, which means that it can cross the lipid-rich membranes of cells reasonably easily. Thus, it probably enters the blood of fish via their gills. Such access would be enhanced if the gills are damaged by cytotoxin actions. Brevetoxin does accumulate in the tissues of fish, so clearly it is taken up via the gills into the circulation. Blood concentrations of brevetoxin can reach or exceed the threshold for neural effects, and they can stay elevated long after the exposure. But it is still is unclear how these levels related to neural dysfunction and mortality in fish.22
Nerves near the surface of the body, such as those supplying the lateral line organ of fish, might be more susceptible to the actions of water-borne toxins. The lateral line detects vibrations in the water (it is closely related to the sensors of the inner ear) and it is used by fish for orientation, especially in relation to other fish in their school. Other algal toxins have been shown to affect lateral line function, leading to abnormal orientation and swimming behaviour in affected fish23. So, in principle, brevetoxin could access these nerves in a similar manner leading to abnormal orientation and swimming behaviour.
Brevetoxin is mostly released from Karenia cells when they break down. Consequently, the highest concentrations of brevetoxin would be expected in are areas where the concentrations of Karenia cells are highest. Although brevetoxin is relatively stable in seawater, once it has been released into the water that no longer contains intact Karenia, it would be rapidly diluted to levels that are well below threshold for any effects on neural activity. Nevertheless, brevetoxin can accumulate and persist in marine sediments and seagrass beds, where it could continue to have effects on organisms living in those environments.24
To get an idea of what these levels mean, the total amount of brevetoxin a person would need to ingest to get minimal symptoms of neurotoxic shellfish poisoning (NSP) is at least about 100µg.25 So…
• if each Karenia cell has a maximum of 50pg of brevetoxin,
• and there is a high bloom density of 100,000 cells per litre,
• and if every Karenia was broken to release its full content of brevetoxin,
• and all that brevetoxin remained in that volume of seawater,
• then there would be about 5µg of brevetoxin per litre.
This means that a person would need to drink 20 litres of seawater containing this amount of brevetoxin to get minimal symptoms of NSP, such as tingling tongue, nausea and dizziness.
Brevetoxin has been reported to sensitise and activate sensory nerve fibres responsible for inflammatory pain, but these effects have only been seen at concentrations 1000 times higher than those needed to cause numbness and paralysis26. Consequently, it is most unlikely that these actions of brevetoxin could occur in the absence of paralysis and numbness.
Selected references
- Baden DG (1989) Brevetoxins: unique polyether dinoflagellate toxins. FASEB Journal 3: 1797-1898, https://doi.org/10.1096/fasebj.3.7.2565840
Brand LE et al (2012) Karenia: The biology and ecology of a toxic genus. Harmful Algae 14: 156-178, http://dx.doi.org/10.1016/j.hal.2011.10.020
Fusetani N & Kem W (2009) Marine toxins: an overview. Progress in Molecular and Subcellular Biology, Marine Molecular Biotechnology 46: 1-44.
Louzao MC et al (2022) Current trends and new challenges in marine phycotoxins. Marine Drugs 20: 198, https://doi.org/10.3390/md20030198
Wang D-Z (2008) Neurotoxins from marine dinoflagellates: a brief review. Marine Drugs 6: 349-371, https://doi.org/10.3390/md6020349
Watkins SM et al (2008) Neurotoxic shellfish poisoning. Marine Drugs 6: 431-455, https://doi.org/10.3390/md6030431
↩︎ - Murray S et al (2025) A catastrophic marine mortality event caused by a complex algal bloom including the novel brevetoxin producer, Karenia cristata (Dinophyceae). bioRχiv https://doi.org/10.1101/2025.10.31.685766 ↩︎
↩︎ - Fowler N et al (2015) Chemical analysis of Karenia papilionacea. Toxicon 101: 85-91, http://dx.doi.org/10.1016/j.toxicon.2015.05.007
↩︎ - Holland PT et al (2012) Novel toxins produced by the dinoflagellate Karenia brevisulcata. Harmful Algae 13: 47-57, https://doi.org/10.1016/j.hal.2011.10.002
↩︎ - Liu X et al (2024). The chemistry of phytoplankton. Chemical Reviews 124: 13099-13177, https://doi.org/10.1021/acs.chemrev.4c00177
Also see the references cited above.
↩︎ - Landsberg JH (2002) The effects of harmful algal blooms on aquatic organisms. Reviews in Fisheries Science 10: 113-390, https://doi.org/10.1080/20026491051695
↩︎ - Naar JP et al (2007) Brevetoxins, like ciguatoxins, are potent ichthyotoxic neurotoxins that accumulate in fish. Toxicon 50: 707-723. doi:10.1016/j.toxicon.2007.06.005
↩︎ - Baden DG et al (2005) Natural and derivative brevetoxins: historical background, multiplicity, and effects. Environmental Health Perspectives 113: 621-625 https://doi.org/10.1289/ehp.7499
Bourdelais AJ et al (2004) Brevenal Is a natural inhibitor of brevetoxin action in sodium channel receptor binding assays. Cellular and Molecular Neurobiology 24: 553-563;
Finol-Urdaneta RK et al (2013) Brevetoxin versus brevenal modulation of human Nav1 channels. Marine drugs 21: 396, https://doi.org/10.3390/md21070396
Hort V et al (2021) Chemodiversity of brevetoxins and other potentially toxic metabolites produced by Karenia spp. and their metabolic products in marine organisms. Marine Drugs 29: 656, https://doi.org/10.3390/md19120656
↩︎ - Zakon HH (2012) Adaptive evolution of voltage-gated sodium channels: The first 800 million years. Proceedings of the National Academy of Sciences, USA 109: Supplement 1, 10619-10625, https://www.ncbi.nlm.nih.gov/books/NBK207163/
↩︎ - Catterall WA (1977) Activation of the action potential Na+ ionophore by neurotoxins: an allosteric model. Journal of Biological ChemistryI 252: 8669-8676;
de la Ruiz & Kraus RL (2015) Voltage-gated sodium channels: structure, function, pharmacology, and clinical indications. Journal of Medicinal Chemistry 58: 7093-7118, http://dx.doi.org/10.1021/jm501981g ;
Deuis JR et al (2017) The pharmacology of voltage-gated sodium channel activators. Neuropharmacology 127: 87-108; https://doi.org/10.1016/j.neuropharm.2017.04.014
Narahashi T et al (2007) Differential actions of insecticides on target sites: basis for selective toxicity. Human Experimental Toxicology 26: 361-366;
Soderlund DM (2012) Molecular mechanisms of pyrethroid insecticide neurotoxicity: recent advances. Archives of Toxicology 86: 165-181.
↩︎ - Camperi M et al (2007) From morphology to neural information: the electric sense of the skate. PLoS Computational Biology 3: e113, https://doi.org/10.1371/journal.pcbi.0030113 ;
Klimley AP (2013) The Biology of Sharks and Rays. University of Chicago Press, https://press.uchicago.edu/ucp/books/book/chicago/B/bo11018459.html
Newton KC et al (2019) Electroreception in marine fishes: chondrichthyans. Journal of Fish Biology 95: 135-154, https://doi.org/10.1111/jfb.14068
↩︎ - See Baden et al (2005) and Finol-Urdaneta et al (2013), cited above.
↩︎ - Pierre O et al (2020) Calcium increase and substance P release induced by the neurotoxin brevetoxin-1 in sensory neurons: involvement of PAR2 activation through both cathepsin S and canonical signaling. Cells 9: 2704, http://dx.doi.org/10.3390/cells9122704
Pierre O et al (2021) Pacific-ciguatoxin-2 and brevetoxin-1 induce the sensitization of sensory receptors mediating pain and pruritus in sensory neurons. Marine Drugs 19: 387, https://doi.org/10.3390/md19070387
↩︎ - Mattei C et al (2008) Brevenal Inhibits Pacific ciguatoxin-1B-induced neurosecretion from bovine chromaffin cells. PLoS One 3:e3448, https://doi.org/10.1371/journal.pone.0003448
Mudge EM et al (2023) Algal ciguatoxin identified as source of ciguatera poisoning in the Caribbean. Chemosphere 330: 138659, https://doi.org/10.1016/j.chemosphere.2023.138659
↩︎ - Wiese M et al (2010) Neurotoxic alkaloids: saxitoxin and its analogs. Marine Drugs 8: 2185-2211, https://doi.org/10.3390/md8072185
↩︎ - Katikou P et al (2022) An updated review of tetrodotoxin and its peculiarities. Marine Drugs 20: 47, https://doi.org/10.3390/md20010047
Zhang X et al (2024) Tetrodotoxin: the state-of-the-art progress in characterization, detection, biosynthesis, and transport enrichment. Marine Drugs 22: 531, https://doi.org/10.3390/md22120531
↩︎ - Cusick KD & Sayler GS (2013) An overview on the marine neurotoxin, saxitoxin: genetics, molecular targets, methods of detection
and ecological functions. Marine Drugs 11: 991-1018;
Starr M et al (2017) Multispecies mass mortality of marine fauna linked to a toxic dinoflagellate bloom. PLOS one: 0176299; https://doi.org/10.1371/journal.pone.0176299
Terrazas JO et al (2017) Prevalence, variability and bioconcentration of saxitoxin-group in different marine species present in the food chain. Toxins 9: 190, http://dx.doi.org/10.3390/toxins9060190 ;
Xu X et al (2026) Multiple toxicological effects of paralytic shell sh toxins and their producing microalgae on diverse aquatic organisms. Water Biology and Security 5: 100402; https://doi.org/10.1016/j.watbs.2025.100402
↩︎ - Cen J et al (2024) Five Karenia species along the Chinese coast: With the description of a new species, Karenia hui sp. nov. (Kareniaceae, Dinophyta). Harmful Algae 137: 102645, https://doi.org/10.1016/j.hal.2024.102645 ;
Kharrat R et al (2008) The marine phycotoxin gymnodimine targets muscular and neuronal nicotinic acetylcholine receptor subtypes with high affinity. Journal of Neurochemistry 107: 952-963, https://doi.org/10.1111/j.1471-4159.2008.05677.x ;
Lamas JP et al (2021) Gymnodimine A in mollusks from the north Atlantic Coast of Spain: Prevalence, concentration, and relationship with spirolides. Environmental Pollution 279: 116919, https://doi.org/10.1016/j.envpol.2021.116919 ;
Mardones JI et al (2020) Unraveling the Karenia selliformis complex with the description of a non-gymnodimine producing Patagonian phylotype. Harmful Algae 98: 101892, https://doi.org/10.1016/j.hal.2020.101892 ;
Munday R et al (2004) Acute toxicity of gymnodimine to mice. Toxicon 44: 173-178, https://doi.org/10.1016/j.toxicon.2004.05.017
↩︎ - Aballay-González A et al (2025) Deciphering the neurotoxic effects of Karenia selliformis. Toxins 17: 92, https://doi.org/10.3390/toxins17020092
↩︎ - Baden DG (1989) Brevetoxins: unique polyether dinoflagellate toxins. FASEB Journal 3: 1797-1898, https://doi.org/10.1096/fasebj.3.7.2565840
↩︎ - Murray S et al (2025) A catastrophic marine mortality event caused by a complex algal bloom including the novel brevetoxin producer, Karenia cristata (Dinophyceae). bioRχiv https://doi.org/10.1101/2025.10.31.685766
Naar JP et al (2007) Brevetoxins, like ciguatoxins, are potent ichthyotoxic neurotoxins that accumulate in fish. Toxicon 50: 707-723. doi:10.1016/j.toxicon.2007.06.005
Pierce RH et al (2003) Brevetoxin concentrations in marine aerosol: human exposure levels during a Karenia brevis harmful algal bloom. Bulletin for Environmental and Contamination Toxicology 70: 161-165, https://doi.org/10.1007/s00128-002-0170-y
Shi F et al (2012) The toxic effects of three dinoflagellate species from the genus Karenia on invertebrate larvae and finfish. New Zealand Journal of Marine and Freshwater Research 45: 149-165, http://dx.doi.org/10.1080/00288330.2011.616210.
↩︎ - Naar JP et al (2007) Brevetoxins, like ciguatoxins, are potent ichthyotoxic neurotoxins that accumulate in fish. Toxicon 50: 707-723. doi:10.1016/j.toxicon.2007.06.005 ;
Woofter RT et al (2005) Uptake and elimination of brevetoxin in blood of striped mullet (Mugil cephalus) after aqueous exposure to Karenia brevis. Environmental Health Perspectives 113: 11-16, https://doi.org/10.1289/ehp.7274;
↩︎ - Pepe-Vargas P et al (2024) Effects of the harmful algal bloom toxin, okadaic acid, on the mechanoreceptors of larval anchoveta (Engraulis ringens) under varying environmental conditions. Frontiers in Marine Science 11: 1446509, https://doi.org/10.3389/fmars.2024.1446509
↩︎ - Hitchcock GL et al (2012) Brevetoxin persistence in sediments and seagrass epiphytes of east Florida coastal waters. Harmful Algae 13: 89-94, https://doi.org/10.1016/j.hal.2011.10.008
↩︎ - Arnich N et al (2012) Guidance levels for brevetoxins in French shellfish. Marine Drugs 19: 520, https://doi.org/10.3390/md19090520
↩︎ - Pierre O et al (2020) Calcium increase and substance P release induced by the neurotoxin brevetoxin-1 in sensory neurons: involvement of PAR2 activation through both cathepsin S and canonical signaling. Cells 9: 2704, http://dx.doi.org/10.3390/cells9122704
Pierre O et al (2021) Pacific-ciguatoxin-2 and brevetoxin-1 induce the sensitization of sensory receptors mediating pain and pruritus in sensory neurons. Marine Drugs 19: 387, https://doi.org/10.3390/md19070387
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