“Wasabi Receptor” Targeted Toxin May Help Develop New Pain Drugs

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Researchers have discovered a scorpion toxin that targets the “wasabi receptor,” triggering a pain response through a previously unknown mechanism and may further applied to develop new kinds of non-opioid pain relievers.




Wasabi receptor



“Wasabi receptor” is 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.


It is officially named TRPA1 (pronounced “trip A1”) that’s embedded in sensory nerve endings throughout the body. When activated TRPA1 open 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 doctorial student, "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



Reactive electrophiles are potentially harmful compounds which can cause significant damage to cells, for example, compounds in cigarette smoke and environmental pollutants. However, compounds in pungent food like wasabi, onions, mustard, ginger and garlic are also considered as reactive electrophiles and will trigger TRPA1.


The mechanism may have evolved to discourage animals from eating these plants, according to Lin King.




Wasabi receptor toxin



Scientists isolated the toxin which can activate TRPA1, named the “wasabi receptor toxin” (WaTx), from the venom of the Australian Black Rock scorpion. Similar to the evolvement of the mechanism of reactive electrophiles triggering TRPA1, WaTx appears to have evolved for the same reason.


According to researchers, though many animals use venom to paralyze or kill their prey, WaTx seems to serve a purely defensive purpose. The reason lies in the mammals-only effectiveness of WaTx, suggesting that the scorpions don’t use the toxin to their preys, but to their predators.




What’s special about WaTx



WaTx triggers the same receptor – TRPA1 – just as the compounds found in pungent plants do. However, the way it activates the receptor is novel and unexpected, and is what interests the researchers most.


Unlike most chemicals which enter the cell through a complex cell ingestion process or via one of the protein channels performing as the cell’s gatekeepers, WaTx forces its way into the cell, circumventing the standard routes that place strict limits on what’s allowed in and out.


WaTx contains an unusual sequence of amino acids that allows it to simply penetrate the cell’s membrane and pass right through to the cell’s interior. another famous example that’s capable of doing this is an HIV protein called Tat. Surprisingly though, researchers did not find similar sequences to those of Tat in WaTx.


"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."


After entering the cell, just like those reactive electrophiles which attach themselves to a site on TRPA1 called the “allosteric nexus,” WaTx triggers TRPA1.


Plant and environmental irritants alter the chemistry of the allosteric nexus, which causes the TRPA1 channel to rapidly flutter open and closed. Through this way, pain, possibly with inflammation (if there is enough calcium), is triggered.



However, WaTx wedges itself into the allosteric nexus and props the channel open, causing TRPA1 not able to control the amount of calcium, leading to pain only, but no inflammation.


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.

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