We feel cold and heat, strong pressure and a gentle touch through our skin – but how? This year’s Nobel Prize in Medicine goes to two researchers who have deciphered these fundamental aspects of our sensory perception: the feeling of heat and touch. The US researcher David Julius identified the heat and pain receptor TRPV1 with the help of the chilli ingredient capsaicin and millions of DNA snippets. The Lebanon-born scientist Ardem Patapoutian, who conducts research in the USA, discovered two mechanoreceptors that respond to pressure stimuli.
Our skin is our largest sensory organ. It is densely packed with sensors that register a wide variety of stimuli – from cold to heat, from a light breeze or caress to the painful prick of a needle. These perceptions not only help us to feel our environment, the pain triggered by the sensors also protect us from injuries and warn us of dangers. As early as the beginning of the 20th century, scientists found out that the various sensory perceptions are detected by the skin via different receptors and nerve conduits and transmitted to the brain. The last question that remained open for a long time was how our skin perceives the specific stimulus of heat and heat-related pain on the one hand and touch stimuli on the other.
David Julius: On the trail of heat pain
The first award winner, David Julius from the University of California in San Francisco, set out on the trail of heat pain perception. The starting point was the observation that the chilli ingredient capsaicin causes pain on the mucous membranes and skin that is very similar to that of heat. To find out which receptor the cells use to perceive the stimulus caused by this chemical substance, Julius and his colleagues used a genetic approach: They created a library of all genes that become active in rodents when they react to external stimuli. They inserted these genes individually into the genome of the cultured cells and then checked whether these reacted to capsaisin.
After an arduous, time-consuming search, the scientists finally found what they were looking for: They discovered a gene through which cells previously insensitive to capsaicin suddenly reacted to the stimulus. Further analysis revealed that this gene contains the building instructions for a previously undetected ion channel in the cell membrane – TRPV1. If this sensor comes into contact with capsaicin, it opens and the resulting ion imbalance triggers the electrical nerve stimulus that signals heat pain to the brain. The same effect occurs when TRPV1 is heated to more than 40 degrees. This confirmed that heat and capsaicin not only subjectively trigger a very similar sensation of pain, they are also physiologically based on the same receptor. Based on this discovery, Julius and, independently of him, the second award winner Ardem Patapoutian, identified a further ion channel, TRPM8, a short time later, which is responsible for our cold perception. In addition, it was shown that there are a few other receptors that jump on at different temperature ranges.
Ardem Patapoutian: A Unique Pressure Sensor
After the secret of our heat pain sensation had been clarified, one perception still remained open: the feeling of touch and other mechanical stimuli. Mechanosensors had already been found in bacteria, but how these stimuli are perceived in vertebrates and converted into nerve signals remained unclear. This is where the work of the second winner, Beirut-born Ardem Patapoutian from the Scripps Research Institute in La Jolla, began. To find the receptor he was looking for, he started with individual cells isolated from the skin and looked for the cell line that generated measurable electrical signals when nudged with a pipette. With this cell line, Patapoutian and his colleagues then began to switch off one of 72 candidate genes and to check whether the cell was still responding to mechanical stimuli.
Finally they found a gene. It turned out that this gene encoded a protein, Piezo1, which turned out to be more than just the mechanoreceptor we were looking for. It also formed a whole new class of ion channels. With 2500 amino acids and a unique topology, the protein did not resemble any previously known membrane protein. It consists of a central pore that is framed by three large propeller-like blades. If mechanical pressure acts on these calmly curved sensor sheets, they flatten and thereby open the core pore of the receptor. In this way, Piezo1 and the Piezo2 receptor variant, which was discovered shortly afterwards, are activated directly by pressure stimuli.
“The groundbreaking discoveries of TRPV1, TRPM8 and the piezo channels by this year’s Nobel Prize winners have made us understand how heat, cold and mechanical forces trigger the nerve signals through which we perceive the world around us,” said the laudatory speech Nobel Prize Committees.
Source: Nobelprize.org