Heat, cold and mechanical impulses release nerve impulses that allow us to sense and adapt to the world around us. We owe our understanding of these processes to, among other things, the groundbreaking discoveries of David Julius and Erdem Patabutian, Nobel Prize laureates in the field of physiology or medicine.
The 2021 Nobel Prize in Physiology or Medicine was awarded jointly with David Julius and Erdem Patabutian for “the discovery of temperature and touch receptors”. And thanks to the work of this year’s Nobel Laureates, we know how heat, cold and touch can trigger signals in our neighborhood. Specific ion channels of the nervous system are important for many physiological processes and disease states. Based on the results of this year’s winners, research is focused on elucidating the function of receptors in various physiological processes, which could lead to the development of treatments for a range of disease conditions, including chronic pain.
The sensory mechanisms of sight, hearing, touch, smell and taste have long intrigued. In the 17th century, the philosopher René Descartes predicted the existence of threads connecting different parts of the skin to the brain. Subsequent discoveries revealed the existence of specialized sensory neurons that record changes in our environment. Joseph Erlanger and Herbert Gasser were awarded the Nobel Prize in Physiology or Medicine in 1944 for discovering different types of sensory nerve fibers that respond to different stimuli, for example, in response to painful and non-painful touch. Since then, neurons have been shown to be highly specialized in detecting and transmitting different types of stimuli, allowing a detailed visualization of our surroundings; For example, being able to feel differences in surface texture with your fingertips or distinguish between pleasant warmth and excruciating heat.
Prior to the discoveries of David Julius and Erdem Patbutian, it was unknown how temperature and mechanical stimuli are converted into electrical impulses in the nervous system.
In the second half of the 1990s, David Julius of the University of California, San Francisco (USA) studied how capsaicin – the chemical that gives chili peppers their pungent taste – causes a burning sensation. Capsaicin is known to activate nerve cells that cause the sensation of pain, but how it does so has been a mystery. Julius and his colleagues created a library of millions of DNA fragments that correspond to genes expressed in sensory neurons that can respond to pain, heat and touch. Julius and colleagues hypothesized that the library would contain a segment of DNA that encodes a protein capable of interacting with capsaicin. They activated individual genes from this group in cultured cells that do not normally respond to capsaicin until they found one that made them respond to capsaicin.
Further experiments revealed that the specific gene encoded a new ion channel protein, the capsaicin receptor, later named TRPV1. When Julius studied the protein’s ability to respond to heat, he realized he had discovered a heat-sensing receptor that is activated at temperatures thought to cause pain.
The discovery of TRPV1 was a mutation that led to the discovery of more temperature-sensing receptors. Independently of each other, David Julius and Ardem Patapoutian used cold-causing menthol to identify TRPM8 – a receptor activated by cold. Additional ion channels associated with TRPV1 and TRPM8 were also identified and found to be activated by a variety of temperatures. Several labs have studied the role of these channels in heat perception using the example of genetically manipulated mice that lack the newly discovered genes.
It has been a mystery how mechanical stimuli can turn into a sense of touch and pressure. Scientists have previously discovered mechanical sensors in bacteria, but the mechanisms behind vertebrate touch have remained unknown. Ardem Patapoutian, of Scripps Research in La Jolla, California, USA, wanted to identify the evasive receptors that were activated by mechanical stimuli.
Patbutian and colleagues were the first to identify a cell line that emits a measurable electrical signal when individual cells are perforated with a micropipette. The mechanistically active receptor was assumed to be an ion channel and 72 genes encoding potential receptors were identified in the next stage of the research. These genes were inactivated one by one to discover responsible for the mechanical sensitivity of the tested cells. After painstaking research, Patabotian and colleagues were able to identify a single gene whose silencing made cells insensitive to the prick of a micropipette. It turns out to be an entirely new, previously unknown, mechanically sensitive ion channel called Piezo1, from the Greek word for pressure (í; píesi). Due to its similarity to Piezo1, a second gene called Piezo2 was discovered. Sensory neurons have been found to express high levels of Piezo2, and further research has demonstrated that Piezo1 and Piezo2 are ion channels that are directly activated by stress on cell membranes.
It turns out that the Piezo2 ion channel is essential for the sense of touch. More research has shown that it plays a key role in detecting body postures and movements, known as proprioception. The Piezo1 and Piezo2 channels also regulate important physiological processes including blood pressure, breathing, and bladder control.
David Julius was born in 1955 in New York, USA. He holds a PhD in technical sciences. 1984 at the University of California at Berkeley and completed an internship at Columbia University in New York. In 1989 he worked at the University of California, San Francisco, where he is now a professor. He was selected for the Nobel Prize in 2014.
Ardem Patapoutian was born in 1967 in Beirut, Lebanon. In his youth, he moved from war-torn Beirut to Los Angeles, USA, and received his Ph.D. in 1996 (California Institute of Technology, Pasadena, USA). He completed an internship at the University of California, San Francisco. Since 2000, he has been at Scripps Research in La Jolla, California, where he is currently a professor. Since 2014, he has been a researcher at the Howard Hughes Medical Institute.
The winners will share the prize of 10 million Swedish kronor (980,000 euros). (PAP)
Author: Pawe Wernicki
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