Scorpion toxin targeting ‘wasabi receptor’ could help solve mystery of chronic pain

Scorpion toxin targeting 'wasabi receptor' could help solve mystery of chronic pain
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Researchers found a scorpion toxin targeting the ‘wasabi receptor’, a chemical-sensing protein located in nerve cells responsible for the sinus-jolting sting of wasabi.

At UC San Francisco, USA, and the University of Queensland, Australia, researchers have discovered as the scorpion toxin triggers a pain response, it could possibly be used as a tool for studying chronic pain, inflammation and may eventually lead to the development of new kinds of non-opioid pain relievers.

The scorpion toxin

Researchers have discovered a scorpion toxin that targets the ‘wasabi receptor’, a chemical-sensing protein found in nerve cells that’s responsible for the sinus-jolting sting of wasabi and the flood of tears associated with chopping onions.

The scientists isolated the toxin, a short protein (or peptide) that they named the ‘wasabi receptor toxin’ (WaTx), from the venom of the Australian Black Rock scorpion.

The discovery came as the researchers were conducting a systematic search for compounds in animal venom that could activate, and therefore be used to probe and study, the wasabi receptor – a sensory protein officially named TRPA1 that’s embedded in sensory nerve endings throughout the body. When activated, TRPA1 opens to reveal a channel that allows sodium and calcium ions to flow into the cell, which can induce pain and inflammation.

“Think of TRPA1 as the body’s ‘fire alarm’ for chemical irritants in the environment,” said John Lin King, a doctoral student in UCSF’s Neuroscience Graduate Programme.

“When this receptor encounters a potentially harmful compound – specifically, a class of chemicals known as ‘reactive electrophiles,’ which can cause significant damage to cells – it is activated to let you know you’re being exposed to something dangerous that you need to remove yourself from.”

Reactive electrophiles

For example, environmental pollutants and cigarette smoking are rich in reactive electrophiles which can trigger TRPA1 in the cells that line the surface of the body’s airway, which can cause reactions such as coughing fits and sustained airway inflammation.

The receptor can also be activated by chemicals in pungent foods like wasabi, onions, mustard, ginger and garlic – compounds that, according to Lin King, may have evolved to discourage animals from eating these plants. WaTx appears to have evolved for the same reason.

Many animals use venom to paralyze or kill their prey, WaTx seems to serve a purely defensive purpose. Almost all animals, from worms to humans, have some form of TRPA1.

But the researchers found that WaTx can only activate the version found in mammals, which is not something Black Rock scorpions consume, suggesting that the toxin is mainly used to ward off mammalian predators.

“Our results provide a beautiful and striking example of convergent evolution, whereby distantly related life forms – plants and animals – have developed defensive strategies that target the same mammalian receptor through completely distinct strategies,” said David Julius, PhD, professor and chair of UCSF’s Department of Physiology, and senior author of the new study.

However, what the researchers found most interesting about WaTx was its mode of action. Though it triggers TRPA1, just as the compounds found in pungent plants do – and even targets the very same site on that receptor – the way it activates the receptor was novel and unexpected.

The dynamics of the scorpion toxin

“It was surprising to find a toxin that can pass directly through membranes. This is unusual for peptide toxins,” Lin King said. “But it’s also exciting because if you understand how these peptides get across the membrane, you might be able to use them to carry things – drugs, for example – into the cell that can’t normally get across membranes.”

Once inside the cell, WaTx attaches itself to a site on TRPA1 known as the ‘allosteric nexus’, the same site targeted by pungent plant compounds and environmental irritants like smoke.

Plant and environmental irritants alter the chemistry of the allosteric nexus, which causes the TRPA1 channel to rapidly flutter open and closed. This creates positively charged sodium and calcium ions to flow into the cell, triggering pain.

Could we get a better understanding of acute pain?

The researchers believe their findings will lead to a better understanding of acute pain, as well as the link between chronic pain and inflammation, which were previously thought to be experimentally indistinguishable. The findings may even lay the groundwork for the development of new pain drugs.

“The discovery of this toxin provides scientists with a new tool that can be used to probe the molecular mechanisms of pain, in particular, to selectively probe the processes that lead to pain hypersensitivity,” Lin King added.

“And for those interested in drug discovery, our findings underscore the promise of TRPA1 as a target for new classes of non-opioid analgesics to treat chronic pain.”

Additional authors include Joshua J. Emrick, Mark J.S. Kelly and Katalin F. Medzihradszky of UCSF; Volker Herzig and Glenn F. King of the Institute for Molecular Bioscience at the University of Queensland.

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