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\u2019s its modus operandi; that\u2019s how it\u2019s supposed to work. But this protein had never been observed in action, nor was its behavior fully understood. That is, until now.<\/p>\n
A team of researchers from the University of California \u2013 including David Julies, who was a co-recipient of the 2021 Nobel Prize in Physiology or Medicine \u2013 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> \u2013 a journal that showcases the world\u2019s best science \u2013 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.<\/p>\n 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 \u2013 along with Ardem Patapoutian<\/a>, a Lebanese-born molecular biologist of Armenian descent \u2013 received the award for discovering how the nervous system senses cold, heat, as well as mechanical impulses.<\/p>\n In the skin and other organs, there are nerve endings \u2013 or sensory receptors \u2013 that allow us to perceive the intensity of chemical and physical stimuli, such as cold or heat. By working with capsaicin \u2013 a molecule present in chili peppers<\/a> that\u2019s responsible for the sensation of heat and burning when we taste it \u2013 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.<\/p>\n Years later, Julius and Patapoutian \u2013 working on independent research \u2013 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.<\/p>\n \u201cWe 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,\u201d Julius told EL PA\u00cdS in an email response. <\/p>\n They knew all that, but a deeper understanding was lacking. They didn\u2019t 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. <\/p>\n The newly-published research sheds light on this mystery. Julius explains that, when temperatures drop below 26\u00baC (79\u00baF), the TRPM8 protein \u201cundergoes subtle but important changes in shape, culminating in the opening of a channel.\u201d This pore-like structure, he notes, \u201callows ions \u2013 such as sodium and calcium \u2013 to pass into the sensory nerve fiber, thus initiating the electrical signal that\u2019s transmitted to the spinal cord.\u201d <\/p>\n \u201cIn this study,\u201d he explains, \u201cwe 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.\u201d <\/p>\n 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. \u201cNerve damage \u2013 such as that caused by chemotherapy<\/a> \u2013 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 \u2013 the main cold sensor in our body \u2013 could help guide the development of therapeutic agents to treat these conditions,\u201d the American scientist emphasizes.<\/p>\n