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iversity in STE A M www.diversityinsteam.com
WHAT'S TRENDING
sound waves affect our inner ears and how different chemical compounds interact with re- ceptors in our nose and mouth generating smell and taste. We also have other ways to perceive the world around us. Imagine walking barefoot across a lawn on a hot summer's day. You can feel the heat of the sun, the caress of the wind and the individual blades of grass underneath your feet. These im- pressions of temperature, touch and movement are essential for our adaptation to the constantly changing surrounding. In the latter part of the 1990s, David Julius saw the possibility for major advances by analyzing how the chemical compound capsaicin causes the burning sensation we feel when we come into contact with chili 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 hypothesized 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 identi- ied that was able to make cells capsaicin sensitive. 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 realized that he had discovered a heat-sensing receptor that is activated at temperatures perceived as painful. The discovery of TRPV1 was a major breakthrough leading the way to the unravelling of additional temperature-sensing receptors. Independently of one another, both David Julius and 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 laborato- ries pursued research programs to investigate the roles of these channels in thermal sensation by using genetically manipu- lated mice that lacked these newly discovered genes. David Julius' discovery of TRPV1 was the breakthrough that allowed us to understand how differenc- es in temperature can induce electrical signals in the nervous system.
Answering Lingering Questions
While the mechanisms for temperature sensation were unfolding, it remained unclear how mechanical stimuli could be converted into our senses of touch and pressure. Re- searchers had previously found mechanical sensors in bacteria, but the mechanisms underlying touch in vertebrates remained unknown. Ardem Patapoutian, working at Scripps Research in La Jolla, Calif., wished to identify the elusive receptors that are activated by mechanical stimuli. Patapoutian and his collab- orators first identified a cell line that gave offa measurable electric signal when individual cells were poked with a micro- pipette. It was assumed that the receptor activated by mechani- cal 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-work- ers 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 chan- nels that are directly activated by the exertion of pressure on cell membranes The breakthrough by Pata- poutian 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 propriocep- ion. In further work, Piezo1 and Piezo2 channels have been shown to regulate additional important physiological pro- cesses including blood pressure, respiration and urinary bladder control.
Award-Winning Work
The groundbreaking discov- eries of the TRPV1, TRPM8 and Piezo channels by this year's Nobel Prize laureates 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. This knowledge is being used to develop treatments for a wide range of disease conditions, including chronic pain. The two men will be honored for their work in Oslo, Norway in September 2022. Of the work they have been doing, Patapou- ian stated, I came here with very little money and hardly spoke the language, I worked in a lab and just fell in love with doing research. Ever since then, this has been my life and joy.
Source: The Nobel Prize, La Jolla Light
NOAH BERGER/UCSF VIA GETTY IMAGES
Dr. David Julius PhD poses for a photo at UCSF Mission Bay in San Francisco.
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