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Researchers at UC San Francisco and the University of Queensland have discovered a scorpion toxin that targets the "wasabi receptor", a chemical sensing protein found in nerve cells and responsible for sinus sting wasabi and the flow of tears associated with cutting. onions. Because the toxin triggers a painful reaction by an unknown mechanism, scientists believe that it can be used as a tool to study chronic pain and inflammation, and can eventually lead to the development of new types of inflammation. 39; non-opioid analgesics.
Scientists have isolated the toxin, a short protein (or peptide) that they dubbed the "wasabi receptor toxin" (WaTx), from the venom of the Australian Black Rock scorpion. The discovery took place as researchers conducted a systematic search for compounds in the venom of animals that could be activated, and thus used to probe and study the wasabi receptor – a sensory protein officially named TRPA1 (pronounced "trip A1") that is integrated into sensory cells. nerve endings throughout the body. When activated, TRPA1 opens to reveal a channel that allows sodium and calcium ions to enter 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 Ph.D. student in UCSF's postgraduate program in neuroscience and senior author of the journal. a study published on August 22, 2019, in which Cell, which describes the toxin and its surprising mode of action. "When this receptor encounters a potentially harmful compound – particularly a class of chemicals called" electrophilic reagents, "which can cause significant cell damage, it is activated to let you know that you are exposed to something dangerous that is dangerous. 39, you must withdraw from. "
Cigarette smoke and environmental pollutants, for example, are rich in electrophilic reagents that can trigger TRPA1 in cells lining the surface of the body's airways, which can cause coughing and persistent inflammation of the airways. The receptor can also be activated by chemicals in pungent foods such as wasabi, onions, mustard, ginger and garlic – compounds that, according to Lin King, may have evolved to discourage animals from eat these plants. WaTx seems to have evolved for the same reason.
Although many animals use venom to paralyze or kill their prey, WaTx seems to have a purely defensive purpose. Virtually all animals, worms to humans, have a form of TRPA1. But the researchers found that WaTx can only activate the version found in mammals, which is not on the menu of Black Rock scorpions, suggesting that the toxin is mainly used to ward off mammalian predators.
"Our results provide a stunning and striking example of convergent evolution, in which distant life forms – plants and animals – have developed defense strategies that target the same mammalian receptor through completely separate strategies," said David Julius, PhD, professor and chairman of the UCSF board. Department of Physiology and lead author of the new study.
But what the researchers found most interesting about WaTx is its mode of action. Although this triggers TRPA1, just like the compounds found in prickly plants – and even the same site on this receptor – the way it activates the receptor was new and unexpected.
First, WaTx makes its way into the cell by bypassing standard routes that strictly limit authorized inputs and outputs. Most compounds, from tiny ions to large molecules, are either ingested by the cell via a complex process called "endocytosis", or they enter through one of the many protein channels that cover the surface of the cell and act as controllers.
But WaTx contains an unusual amino acid sequence that allows it to simply penetrate the membrane of the cell and penetrate to the inside of it. Few other proteins are capable of the same feat. The most famous example is an HIV protein called Tat, but surprisingly, WaTx does not contain any sequence similar to that found in Tat or any other protein that can pass through the cell membrane.
"It was surprising to find a toxin that could pass directly through the membranes. This is unusual for peptide toxins, "said Lin King. "But it's also exciting, because if you understand how these peptides cross the membrane, you may be able to use them to transport objects – drugs, for example – into a cell that can not normally pass through the membranes."
Once inside the cell, WaTx binds to a TRPA1 site called "allosteric link," the same site targeted by pungent plant compounds and environmental irritants such as smoke. But that's where the similarities end.
Irritant substances of plant and environmental origin modify the chemistry of the allosteric nexus, which causes the TRPA1 channel to open and close rapidly. This allows positively charged sodium and calcium ions to flow into the cell, triggering the pain. Although both ions can penetrate when TRPA1 is activated by these irritants, the channel has a strong preference for calcium and leaves much more in the cell, resulting in inflammation. In contrast, WaTx sneaks into the allosteric link and opens the channel. This abolishes his preference for calcium. As a result, the global ion levels are high enough to trigger a painful response, but calcium levels remain too low to initiate inflammation.
David Julius uses natural products, such as chili peppers and wasabi, to research pain and somatosensation – the process by which we experience touch and temperature. He talks about his research to identify molecules that detect harmful stimuli (pain generators).
Find out what he hopes this could mean for people with chronic pain.
To demonstrate this, the researchers injected mustard oil, a plant irritant known to activate the wasabi receptor, or WaTx in mouse paws. With mustard oil, they observed acute pain, hypersensitivity to temperature and touch – features of chronic pain – and inflammation, as evidenced by significant swelling. But with WaTx, they observed acute pain and hypersensitivity to pain, but no swelling.
"When they are triggered by calcium, nerve cells can emit pro-inflammatory signals that tell the immune system that something is wrong and that it needs to be repaired," said Lin King. "This 'neurogenic inflammation' is one of the key processes that becomes dysregulated in chronic pain. Our findings suggest that you can dissociate the protective response from the acute pain of inflammation that establishes chronic pain. Achieving this goal, if only in principle, is a long-standing goal on the ground. "
Researchers believe their findings will lead to a better understanding of acute pain, as well as the link between chronic pain and inflammation, previously thought impossible to distinguish experimentally. The results could even lay the foundation for the development of new pain medications.
"The discovery of this toxin provides scientists with a new tool that can be used to probe the molecular mechanisms of pain, particularly to selectively probe the processes leading to hypersensitivity to pain," said Lin King. "And for those who are interested in drug discovery, our findings highlight the promise of TRPA1 as a target for new classes of non-opioid analgesics for the treatment of chronic pain."
authors: Joshua J. Emrick, Mark J.S. Kelly and Katalin F. Medzihradszky of UCSF; Volker Herzig and Glenn F. King of the Institute of Molecular Bioscience at the University of Queensland.
Funding: This study was funded by a NSF University Research Grant (# 1650113), a UCSF Chuan-Lyu Discovery Grant and National Institutes of Health Grants (R37 NS065071, R35 NS105038 and T32 GM007449).
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