The Costa Rican coral snake has finally given up some the secrets behind the lethality of its venom, — after more than a decade of research — thanks to new work from an international group of scientists.
Until this work, the mechanisms behind the lethality of the venom of reclusive coral snake species Micrurus mipartitus was a complete mystery — it appeared that it must be operating via a very different set of biological pathways than other snake venoms. And there’s a good reason for that, it does operate by a very different pathway and mechanism — the primary toxin simply permanently activates a crucial type of nerve cell protein, stops the cells from resetting, and thereby triggers deadly seizures.
“What we found are the first known animal toxins, and by far the most potent compounds, to target GABA(A) receptors,” stated Frank Bosmans, PhD, assistant professor of physiology and neuroscience at the Johns Hopkins University School of Medicine. “Once they bind to the receptors, they don’t let go.”
A recent press release detailing the findings provides more:
Biochemical studies revealed the identity of the snake venom’s active ingredient: it’s actually twin proteins, dubbed micrurotoxins (MmTX) after their serpentine source, the reclusive coral snake Micrurus mipartitus. Most toxins in snake venoms target specialized nicotinic acetylcholine receptors on the surface of nerve cells that make muscles contract, paralyzing the snakes’ victims. But when the researchers tested MmTX on lab-grown cells saturated with nicotinic acetylcholine receptors, nothing happened. This was puzzling because, in mice, MmTX was known to cause a repeating pattern of relaxation and seizures, similar to what’s seen in epilepsy.
By tagging the protein with a radioactive label, the team at Aix Marseille University was able to find out what protein it acted on. To the team’s surprise, MmTX binds to GABA(A) receptors — pores on nerve cells in the brain and spinal cord. GABA(A) receptors’ job is to respond to the molecule GABA by opening to let negatively charged chloride ions flow into a nerve cell that has just fired. Doing so resets the cell’s equilibrium so that it can fire another signal when needed.
Repeated testing then demonstrated that MmTX binds to GABA(A) receptors considerably more “tightly” than any other known compound — roughly 100 times more tightly than the plant-derived compound PTX, for instance. In addition, MmTX also binds to a unique site on the GABA(A) receptor protein.
“Binding at that site changes the receptor’s shape, making it far too sensitive to GABA molecules. When GABA binds, the receptor’s pore opens permanently and the nerve cell is never able to reset, causing it to misfire, convulsing the animal and potentially causing death.”
“Anti-anxiety medications like diazepam and alprazolam bind to GABA(A) receptors too, but they cause relaxation instead of seizures because they bind much more loosely,” stated Bosmans.
The researchers behind these findings are now planning to utilize MmTX to explore how GABA(A) receptors work in greater detail — thereby possibly shedding light common “disorders” that involve them.
The new research was published online in the journal the Proceedings of the National Academy of Sciences.