Scientists have discovered a "suicide" mechanism in ion channel receptors that sense heat and pain. The ability to accurately detect heat and pain is critical to human survival. However, the molecular mechanisms behind how our bodies recognize these dangers have long been a mystery to scientists.

Now, University at Buffalo researchers have uncovered the complex biological phenomena that drive these critical functions. Their research, recently published in the Proceedings of the National Academy of Sciences, reveals a previously unknown and completely unexpected "suicide" response in ion channel receptors, explaining the complex mechanism of sensitivity to temperature and pain. This research could be used to develop more effective painkillers.

"The reason why we are sensitive to high temperatures is obvious. We need to distinguish what is cold and what is hot so that we can be warned when our bodies are about to be in danger," said Dr. Qin Feng, corresponding author of the study and professor of physiology and biophysics at Columbia University's Jacobs School of Medicine and Biomedical Sciences.

Therefore, it is not possible to separate sensitivity to temperature and pain.

Qin said: "Receptors that sense temperature also mediate the conduction of pain signals, such as harmful heat. Therefore, these temperature-sensing receptors are also one of the most critical targets for pain treatment. Understanding how they work is the first step in designing a new generation of new analgesics with fewer side effects."

The Columbia University researchers focused on a family of ion channels called TRP (transient receptor potential) channels, specifically TRPV1, which is a receptor activated by capsaicin, the spicy ingredient in chili peppers. These are cutaneous receptors located on the endings of peripheral nerves in the skin.

However, proving the thermosensitivity of these receptors has been a challenge. Qin explained that proteins absorb heat and convert it into a form of energy called an enthalpy change, which is related to changes in protein conformation. The greater the temperature sensitivity of the receptor, the larger the enthalpy change needs to be.

He and his colleagues previously developed an ultrafast temperature clamp for detecting the activation of temperature sensors in real time. The researchers estimate that its activation energy is large, nearly an order of magnitude greater than that of other receptor proteins. They then decided to try to directly measure the heat absorption of the thermoreceptor, which was a "difficult" task because it required the development of new methods and the acquisition of expensive and sophisticated instruments.

Like detonating an atomic bomb

Using the TRPV1 receptor as a prototype, they found that heat can induce strong and complex heat transitions in this receptor on an extraordinary scale. It's like detonating an atomic bomb inside the protein.

The researchers also found that these dramatic thermal transitions of the receptor occurred only once. "We found that in order to achieve its high-temperature sensitivity, the ion channel needs to undergo extreme structural changes in its functional state, and these extreme changes compromise the stability of the protein," Qin explains. "These surprising and unconventional findings mean that the channel folds irreversibly after opening - it commits suicide."

What makes this finding even more remarkable, he continued, is that it defies conventional expectations that a temperature receptor should be more thermally stable, especially when activated within the temperature range it can detect. The new findings defy this expectation and the concept of reversibility, which occurs in almost all other types of receptors.

One possible explanation is a dilemma between physical principles and biological needs. He said: "Biological demands - the strong sensitivity of receptors to temperature - clearly require greater energy than reversible structural changes in the protein can provide. Therefore, receptors must resort to unconventional means of self-destruction to meet their energy needs. It is remarkable how temperature receptors can use a process usually considered destructive to physiological function to turn protein unfolding to their advantage."

Whether new ion channels will be formed to replace the old ones is one of the questions Qin and his colleagues plan to study next. It's even possible, he says, that neurons detect and "rescue" damaged ion channels in some unexpected way, or replenish them with newly synthesized ion channels.

"It is worth noting that since the high temperature sensed by the receptors may cause tissue damage, the body may not care about the fate of the destroyed ion channels because the tissue needs to be regenerated anyway," Qin speculates. "This may be a 'clever' strategy devised by nature to best meet the channel's need for high temperature sensitivity."

Reference: Andrew Mugo, Ryan Chou, Felix Chin, Beiying Liu, Qiu-XingJiang, and Feng Qin published in Proceedings of the National Academy of Sciences on August 28, 2023: "Suicide Mechanism of TRPV1 Temperature Sensitivity."

DOI:10.1073/pnas.2300305120

Compiled source: ScitechDaily