Nordic Life Science 1
S it has been demonstrated that nerve cells are h
ighly specialized for detecting and transducing differing types of stimuli, allowing a nuanced perception of our surroundings, stated the Nobel Assembly at Karolinska Institutet at the Prize announcement. However, how temperature and mechanical stimuli are converted into electrical impulses in the nervous system was until the 1990s unknown. The Nobel Laureates in Physiology or Medicine 2021 discovered that receptors (i.e., sensors) are able to detect and convert heat and touch into impulses, and identified which receptors are the main players. These findings have led to a rapid increase in our understanding of how the nervous system senses heat, cold and mechanical stimuli. “These receptors translate our surroundings into something we can perceive and adapt to. This is incredibly important, for example for everyday things like lifting a glass of water to your mouth or walking, but also when we reflexively snatch our hand away from a hot stove. You could say that this year’s Laureates unlocked one of nature’s secrets,” said Patrik Ernfors, Professor and member of the Nobel Committee at Karolinska Institutet after the Prize announcement. In the late 1990s David Julius, working at the University of California in San Francisco, became interested in the chemical compound capsaicin, an active component of chili peppers, which are plants belonging to the genus Capsicum. He wanted to understand how capsaicin causes the burning sensation we feel from chili peppers. It was already known that capsaicin activated nerve cells that caused pain sensation but exactly how this worked was not known. Together with his colleagues he created a library consisting of millions of DNA fragments that corresponded to genes that are expressed in the sensory neurons, which can react to pain, heat, and touch. By searching this library in the lab (they expressed individual genes in cultured cells that normally do not react to capsaicin), they were hoping to find a DNA fragment encoding the specific protein that was capable of reacting to capsaicin. Luckily, they were able to identify the one gene for capsaicin sensing. They also showed that this gene encoded a new ion channel protein, a capsaicin receptor, which was later named TRPV1. When they investigated TRPV1’s ability to respond to heat, Julius realized that he had discovered “a heat-sensing receptor that is activated at temperatures perceived as painful,” describes the Nobel Assembly at Karolinska Institutet. His finding of TRPV1 was published in 1997. Capsaicin had thus been the right tool for understanding painful heat. If you have ever eaten (or accidentally eaten) a hot chili pepper, perhaps you remember that what you feel afterwards is not only uncomfortable, but even painful. Many of us would also start sweating, indicating that capsaicin tricks the brain into thinking that there is a temperature change. Julius’ findings led to many more findings, and additional temperature-sensing receptors have been identified since TRPV1. For example, both Julius and his co-Laureate, Ardem Patapoutian, were able to identify a receptor that activated cold, TRPM8. Besides activation of cold, Ardem Patapoutian, working at the Scripps Research Institute in La Jolla, also set out to understand more about how mechanical stimuli could be converted into our senses of touch and pressure. Together with collaborators, he identified a cell line that gave off an electrical signal when individual cells were poked with a micropipette (i.e., pressure-sensitive cells). He assumed that the receptor activated by mechanical force was an ion channel, and 72 candidate genes encoding possible receptors were identified. These genes were inactivated one by one in order to find the gene responsible for mechanosensitivity. Patapoutian was able to identify the gene and a new mechanosensitive ion channel had been discovered. The choice of model system was crucial for his success, said Patrik Ernfors in a news release from Karolinska Institutet. “He understood that we would never find how touch translates into electrical impulses if you don’t have a simple model system. Another key was that he understood that he had to look for genes with certain properties, which made them probable as receptors, but it was still an incredibly arduous job,” said Ernfors. T he new ion channel was named Piezo1, after the Greek word for pressure and Patapoutian’s findings were published in 2010. A second gene, similar to Piezo1, was also discovered, and named Piezo2. Further studies established that these two ion channels are directly activated by the exertion of pressure on cell membranes. Subsequent studies showed that Piezo2 is essential for the sense of touch and was also shown to play an important role in proprioception i.e., the sensing of body position and motion. “This means your sense of where your limbs are compared to your body. Most people don’t even think about that being an important sense. Without it you cannot walk, you cannot stand up, and so it’s a very important part of physiology,” described Patapoutian in a Nobel Media interview just after the Prize announcement. NORDICLIFESCIENCE.ORG 63