When it comes to survival, the nervous system doesn’t take any risks. To detect and avoid extreme temperatures, animals rely not on one or two but three different members of a family of proteins called TRP channels. This is according to a new study led by Joris Vriens and Thomas Voets at the University of Leuven in Belgium.
The team made this discovery by using mice that were genetically modified to lack two of these proteins, known as TRPV1 and TRPM3. While neurons (nerve cells) from these animals could still detect painful heat, this sensitivity disappeared when animals were also without a third TRP family member, called TRPA1. Consistently, mice without all three TRP proteins seemed unfazed by high temperatures.
Together, the results support the long-held idea that animals have evolved a “fault-tolerant” mechanism, at the molecular level, that can compensate for a failing heat sensor. This would ensure that animals can protect themselves from harm even when another part of the system goes awry.
“The data are very strong,” says Michael Caterina, from Johns Hopkins University in Baltimore. “The new information here is not the concept of a fault-tolerant mechanism but the precise identification of what will probably be the three most important [molecules] involved in painful heat detection,” says Caterina, who did not take part in the research.
The findings were published March 14 in the journal Nature.
Still feeling the heat
TRP proteins in neurons form pores, or channels, which open to allow electrically charged molecules to flow into the cell. This raises the electrical activity of peripheral neurons (that is, neurons outside of the brain and spinal cord) that are part of the pain system.
In 2000, Caterina and his colleagues confirmed that one such channel, TRPV1, opens not only in response to capsaicin (the component of chili peppers that makes them “hot”), but also in response to intense heat. Building upon earlier work, the group found that genetically engineered mice missing TRPV1 responded less strongly to both capsaicin and intense heat, compared to normal animals.
Still, they responded. As for how, the researchers posited the existence of additional heat sensors, such as other members of the TRP family of proteins.
In the following years, many of the prime candidates were ruled out. But in 2011, Vriens and Voets made two key observations. First, a large fraction of pain-sensing neurons containing TRPV1 also contained TRPM3. And, like Caterina’s genetically modified mice missing TRPV1, animals without TRPM3 had blunted responses to high temperatures.
“It turned out TRMP3 was another heat sensor,” says Vriens.
When three is not a crowd
To test if there was yet a third player, the researchers created a new group of so-called “knockout mice.” These genetically engineered animals lacked both TRPV1 and TRPM3.
The researchers recorded the activity of peripheral neurons taken from these animals after exposing the cells to a surrounding temperature of 113 degrees Fahrenheit. It turned out that about 40 percent of the cells responded. And, in a follow-up experiment, the mice continued to avoid water or surfaces heated to the point of causing burns. Because the animals could still detect painful heat, TRPV1 and TRMP3 seemed part of a larger ensemble of heat sensors.
That ensemble, it turned out, also included TRPA1, as mice without all three TRP proteins showed little changes in behavior in response to high heat.
“If you knock out two of the channels, as long as you have one left over, you’ll still have acute heat sensing,” says Vriens. In other words, no single TRP channel is absolutely essential to detect painful heat.
Still, it’s unknown whether this redundancy drives pain when it turns chronic.
“It seems that all three of the channels play a role in pathological [disease] conditions, but their roles are a little bit different,” says Vriens, referring to previous work from other groups.
He and Voets are now trying to study the role of the TRP channels in animal models of chronic pain. In addition, “we are developing [drugs] against one of the three TRP channels as a novel class of analgesics [pain relievers], which we hope to be able to test in humans in the coming years.”
To read about the research in more detail, see the related IASP Pain Research Forum news story here.
Matthew Soleiman is a science writer residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman.