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The rare coral snake Micrurus mipartitus (type locality, Caracas,
Venezuela). Credit: Alejandro Solórzano
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For more than a decade, a vial of rare snake venom refused
to give up its secret formula for lethality; its toxins had no effect on the
proteins that most venoms target. Finally, an international team of researchers
figured out its recipe: a toxin that permanently activates a crucial type of
nerve cell protein, preventing the cells from resetting and causing deadly
seizures in prey. The details will be published online in the Proceedings of
the National Academy of Sciences the week of Feb. 9.
"What we found are the first known animal toxins, and
by far the most potent compounds, to target GABA(A) receptors," says Frank
Bosmans, Ph.D., 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."
Biochemical studies revealed the identity of the 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.
Further testing showed that MmTX binds to GABA(A) receptors
more tightly than any other compound known -- 100 times tighter than the
plant-derived compound PTX, for example. 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," says Bosmans. His team plans to use
MmTX as a tool for learning more about how GABA(A) receptors work. Since errors
in the receptors can cause epilepsy, schizophrenia and chronic pain, the team
hopes that their future work will be able to shed light on these and other
disorders.
Other authors of the report include Jean-Pierre Rosso,
Brigitte Ceard and Pierre Bougis of Aix Marseille University in France; Jurgen
Schwarz and Matthias Kneussel of the University Medical Center
Hamburg-Eppendorf in Germany; Marcelo Diaz-Bustamante of The Johns Hopkins
University; Maria Gutierrex of the Universidad de Costa Rica; and Olaf Pongs of
the Universitat des Saarlandes in Germany.
This work was supported by the Centre National de la
Recherche Scientifique.
Citation
Rosso J-P, Schwarz JR, Diaz-Bustamante M, Céard B, Gutiérrez JM, Kneussel M, Pongs O, Bosmans F, and Bougis PE. MmTX1 and MmTX2 from coral snake
venom potently modulate GABAA receptor activity. PNAS February 9, 2015 DOI:
10.1073/pnas.1415488112.