SWITCH TURNS OFF SCORPION VENOM’S DEADLY PUNCH
"This is the real twist of nature," says Isaac Pessah. "The toxic peptide is not supposed to get inside cells, but it does, and then is phosphorylated, which not only neutralizes its toxicity but also reprograms its activity to be beneficial." (Credit:AFPMB, Michael Hasler/Flickr)
Because of their venomous sting, scorpions are usually avoided at all costs. But a new discovery suggests the toxins found in some venom might actually have a unique benefit.
Published in the Proceedings of the National Academy of Sciences, the findings show that when a toxin produced by Scorpio maurus—a scorpion species found in North Africa and the Middle East—permeates the cell membrane it loses its potency and may actually become healthful.
“This is the first time a toxin has been shown to chemically reprogram once inside a cell, becoming something that may be beneficial,” says Isaac Pessah, professor of molecular biosciences at the University of California, Davis, School of Veterinary Medicine.
“Being able to understand how this family of toxins lose their toxicity and become pharmacologically beneficial by changing activity towards the calcium channel target inside the cell is what’s novel and may have translational significance.”
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Controlled release of calcium is a key step in many cellular processes, researchers say.
“In any cell you can think of, calcium plays a role in shaping responses, activating or inhibiting enzymes, changing the shape of the cell, or triggering cell division,” Pessah says.
Calcium also is a key signal in both fertilization and programmed cell death. And, altered calcium regulation is a common step in many animal and human diseases. Pharmaceuticals that regulate cellular calcium homeostasis include drugs that suppress the immune system in organ transplant patients and treatments for high blood pressure and heart disease.
Several years ago, Pessah began working with researchers from the Institute for Neurosciences in Grenoble France and the Pasteur Institute in Tunisia to isolate a specific toxin peptide called maurocalcin, which targets a calcium channel called the ryanodine receptor inside the cell. Maurocalcin is quite unusual in that it readily permeates into cells, while most other peptide toxins target more accessible receptors on the cell’s surface.
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“We therefore thought maurocalcin should be very toxic, since we previously showed that very low concentrations can completely stabilize an open (toxic) state of the ryanodine receptor and thereby upset a cell’s calcium balance,” Pessah says.
Maurocalcin, however, was seemingly benign once inside cells. Intrigued, the researchers set out to find the reason. They discovered that once inside the cell, maurocalcin was modified by an enzymatic reaction called phosphorylation, a common cellular “switch” that normally turns reactions inside cells on or off by adding a phosphate group to a precise position on proteins.
This is the first example of a scorpion peptide being subjected to such modification once inside a mammalian cell. Phosphorylation of maurocalcin was found to completely reprogram its activity from that of a potential toxin to a potentially useful pharmacological tool.
“This is the real twist of nature,” Pessah says. “The toxic peptide is not supposed to get inside cells, but it does, and then is phosphorylated, which not only neutralizes its toxicity but also reprograms its activity to be beneficial.”
Researchers further tested the plausibility and molecular details responsible for pharmacological reprogramming by synthesizing artificial “phosphomimics,” and studying their three-dimensional structures and how they modified ryanodine receptor channels.
Identifying the best synthetic substitutes for maurocalcin could pave the way for a novel strategy to control ryanodine receptor channels that leak calcium. Leaky ryanodine receptor channels are known to contribute to a number of human and animal diseases of genetic and/or environmental origins.
The National Institutes of Health supported the work.
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