The Nobel Assembly at the Karolinska Institutet decided on 04/10/2021 to award the 2021 Nobel Prize in Physiology or Medicine jointly to David Julius and Ardem Patapoutian “for their discoveries of receptors for temperature and touch.”
Our ability to sense heat, cold and touch is essential for survival and underpins our interaction with the world around us. In our daily lives we take these sensations for granted, but how are nerve impulses initiated so that temperature and pressure can be perceived? This question has been solved by this year’s Nobel Prize laureates.
David Julius utilised capsaicin, a pungent compound from chilli peppers that induces a burning sensation, to identify a sensor in the nerve endings of the skin that responds to heat. Ardem Patapoutian used pressure-sensitive cells to discover a novel class of sensors that respond to mechanical stimuli in the skin and internal organs.
The groundbreaking discoveries of the TRPV1, TRPM8 and Piezo channels by this year’s Nobel Prize laureates David Julius and Ardem Patapoutian have allowed us to understand how heat, cold and mechanical force can initiate the nerve impulses that allow us to perceive and adapt to the world around us.
The TRP channels are central for our ability to perceive temperature. The Piezo2 channel endows us with the sense of touch and the ability to feel the position and movement of our body parts. TRP and Piezo channels also contribute to numerous additional physiological functions that depend on sensing temperature or mechanical stimuli. Intensive ongoing research originating from this year’s Nobel Prize awarded discoveries focuses on elucidating their functions in a variety of physiological processes. This knowledge is being used to develop treatments for a wide range of disease conditions, including chronic pain.
David Julius – awarded the 2021 Nobel Prize in Physiology or Medicine – used capsaicin from chilli peppers to identify TRPV1, an ion channel activated by painful heat.
In the latter part of the 1990’s, Julius at the University of California, San Francisco, USA, saw the possibility for major advances by analysing how the chemical compound capsaicin causes the burning sensation we feel when we come into contact with chilli peppers.
Capsaicin was already known to activate nerve cells causing pain sensations, but how this chemical actually exerted this function was an unsolved riddle. Julius and his co-workers created a library of millions of DNA fragments corresponding to genes that are expressed in the sensory neurons which can react to pain, heat, and touch. Julius and colleagues hypothesised that the library would include a DNA fragment encoding the protein capable of reacting to capsaicin. They expressed individual genes from this collection in cultured cells that normally do not react to capsaicin. After a laborious search, a single gene was identified that was able to make cells capsaicin sensitive (see figure). The gene for capsaicin sensing had been found!
Further experiments revealed that the identified gene encoded a novel ion channel protein and this newly discovered capsaicin receptor was later named TRPV1. When Julius investigated the protein’s ability to respond to heat, he realised that he had discovered a heat-sensing receptor that is activated at temperatures perceived as painful (see figure).
The discovery of TRPV1 was a major breakthrough leading the way to the unravelling of additional temperature-sensing receptors. Independently of one another, both Julius and his co-laureate Ardem Patapoutian used the chemical substance menthol to identify TRPM8, a receptor that was shown to be activated by cold. Additional ion channels related to TRPV1 and TRPM8 were identified and found to be activated by a range of different temperatures. Many laboratories pursued research programs to investigate the roles of these channels in thermal sensation by using genetically manipulated mice that lacked these newly discovered genes. Julius’ discovery of TRPV1 was the breakthrough that allowed us to understand how differences in temperature can induce electrical signals in the nervous system.
Ardem Patapoutian, awarded the 2021 Nobel Prize in Physiology or Medicine, used pressure-sensitive cells to discover a novel class of sensors that respond to mechanical stimuli in the skin and internal organs. Patapoutian and his collaborators first identified a cell line that gave off a measurable electric signal when individual cells were poked with a micropipette. It was assumed that the receptor activated by mechanical force is an ion channel and in a next step 72 candidate genes encoding possible receptors were identified. These genes were inactivated one by one to discover the gene responsible for mechanosensitivity in the studied cells. After an arduous search, Patapoutian and his co-workers succeeded in identifying a single gene whose silencing rendered the cells insensitive to poking with the micropipette.
A new and entirely unknown mechanosensitive ion channel had been discovered and was given the name Piezo1, after the Greek word for pressure. Through its similarity to Piezo1, a second gene was discovered and named Piezo2. Sensory neurons were found to express high levels of Piezo2 and further studies firmly established that Piezo1 and Piezo2 are ion channels that are directly activated by the exertion of pressure on cell membranes (see figure below).
The breakthrough by Patapoutian led to a series of papers from his and other groups, demonstrating that the Piezo2 ion channel is essential for the sense of touch. Moreover, Piezo2 was shown to play a key role in the critically important sensing of body position and motion, known as proprioception. In further work, Piezo1 and Piezo2 channels have been shown to regulate additional important physiological processes including blood pressure, respiration and urinary bladder control.
Source: The Nobel Committee for Physiology or Medicine
