Johns Hopkins. US: The reason for the lethality of venom from the rare, reclusive Costa Rican coral snake has been a mystery. An international 12-year project revealed that the two main toxins in
the venom target certain receptors on nerve cells in the brain and
spinal cord of mammals. The toxins may help reveal how flaws in these receptors cause epilepsy, schizophrenia and chronic pain.
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.