The exact way in which the human body perceives the cold is still largely a mystery. Science knows that, when someone picks up a handful of snow or licks an ice cube, a protein called TRPM8 is activated in nerve cells, opening a kind of molecular gate to send the icy signal to the brain. That’s its modus operandi; that’s how it’s supposed to work. But this protein had never been observed in action, nor was its behavior fully understood. That is, until now.
A team of researchers from the University of California – including David Julies, who was a co-recipient of the 2021 Nobel Prize in Physiology or Medicine – has managed to capture the first atomic-level images of this cold-sensing protein in action. In an article published on March 25 in Nature – a journal that showcases the world’s best science – the authors demonstrate how this molecule changes when exposed to low temperatures. The discovery has opened up a new avenue of research for treating pain caused by cold.
Julius has dedicated his career to understanding some of the molecular intricacies that allow humans to perceive the world. The relevance of his research is such that he received a Nobel Prize for it. In 2021, this American scientist – along with Ardem Patapoutian, a Lebanese-born molecular biologist of Armenian descent – received the award for discovering how the nervous system senses cold, heat, as well as mechanical impulses.
In the skin and other organs, there are nerve endings – or sensory receptors – that allow us to perceive the intensity of chemical and physical stimuli, such as cold or heat. By working with capsaicin – a molecule present in chili peppers that’s responsible for the sensation of heat and burning when we taste it – Julius discovered which nerve ending in the skin responds to heat. His team subsequently identified the gene and protein responsible for translating the capsaicin signal into a nerve impulse that travels to the brain. This was the TRPV1 receptor.
Years later, Julius and Patapoutian – working on independent research – turned to menthol. This is an ingredient in candy that creates a cooling sensation in the mouth. The scientists used it to identify the receptor responsible for making us feel cold: TRPM8.
“We knew that the perception of cold involves the activation of a specific type or group of sensory nerve fibers. These fibers innervate most regions of the body, especially those which are sensitive to cold, such as the eyes and mouth. We also knew that these nerve fibers express a protein called TRPM8 on their surface, which allows them to detect cold temperatures or chemical agents (like menthol) that produce a cooling sensation,” Julius told EL PAÍS in an email response.
They knew all that, but a deeper understanding was lacking. They didn’t comprehend the exact behavior of this molecule when it was exposed to low temperatures, nor how it was converting information into an electrical signal that reaches the brain.
The newly-published research sheds light on this mystery. Julius explains that, when temperatures drop below 26ºC (79ºF), the TRPM8 protein “undergoes subtle but important changes in shape, culminating in the opening of a channel.” This pore-like structure, he notes, “allows ions – such as sodium and calcium – to pass into the sensory nerve fiber, thus initiating the electrical signal that’s transmitted to the spinal cord.”
“In this study,” he explains, “we mapped and visualized specific regions of TRPM8 that are more sensitive to temperature and/or move in response to cold, thereby initiating the shape transitions that lead to pore opening. We also clarified how certain lipid molecules in the cell membrane contribute to stabilizing these shape changes, [which are] associated with pore opening.”
In practice, these findings help us understand how the main cold sensor in human nerve fibers works, opening a door to treating cold-induced pain. “Nerve damage – such as that caused by chemotherapy – often leads to cold hypersensitivity, a significant and debilitating syndrome known as cold allodynia. Understanding the basic principles of a cold sensation and the detailed properties of TRPM8 – the main cold sensor in our body – could help guide the development of therapeutic agents to treat these conditions,” the American scientist emphasizes.
Teresa Giráldez – a professor of Physiology at the Institute of Biomedical Technologies of the University of La Laguna, on the Spanish island of Tenerife – and Luis Romero, a postdoctoral researcher at the same institute, agree that this research is “wonderful” and “the result of a great deal of work.”
“The most important aspect of this [new research] is that [the authors] propose a complete mechanism for the functioning of the molecule that senses the cold: [they describe] how the molecule undergoes mechanical changes and how the atoms rearrange themselves in response to the cold. It’s a molecular explanation of how we feel the cold,” Giráldez explains enthusiastically.
The professor of physiology – who was not involved in this particular study – highlights the complexity of the research and applauds the method used to arrive at the findings: “They compare two cold receptors: the one found in human cells and the one found in birds, who are less sensitive to the cold. And they find that the bird’s receptor has a slight difference in a specific area of the molecule; [the authors of the study then] describe how this protein can transform the physical phenomenon into a mechanical movement, which then translates into a cascade of processes that activate neurons and reach the brain.”
Giráldez also sees therapeutic potential in this finding: “If you determine the exact area of the molecule where the cold is felt, you can find a molecule or formula to regulate or modulate that response to cold,” she suggests.
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