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Wednesday, November 29, 2023
Dr. Brown: How we feel touch, warmth, cold and pain

Without our senses, our bodies and brains would be unable to make sense of what’s going on outside and within our bodies. 

Those senses depend on billions of sensors (receptors) and their related nerve cells, each tuned to specific, often narrow banded electromagnetic, chemical, mechanical and noxious (unpleasant) stimuli to provide the nervous system with the information needed for the brain and body to function. 

By the end of the 20th century much was known about the structure and physiological characteristics of the touch-pressure, temperature and pain systems. 

However, little was known about how those stimuli were translated (transduced) into electrical signals transmitted in the peripheral nervous system. 

David Julius and Ardem Patapoutian changed that and for their achievements were awarded the 2021 Nobel Prize in physiology or medicine, ”For their discoveries of receptors for temperature and touch.”

In the early 1990s, Julius discovered the gene that coded for the capsaicin-sensitive sensory receptor, which he called TRPV1. 

Not only was this receptor sensitive to capsaicin (which is found in chili peppers), but also to temperatures equal to or exceeding 45C. Thus, this receptor was sensitive to both pain and hot temperatures. 

In 2002, the gene, and thus the sensory receptor for cold sensation, was discovered by the Julius and Patapoutian, working independently, based on the assumption that menthol, a natural compound that elicits the sensation of mild coolness in humans, would bind to a receptor that was activated by cold. 

Using similar reasoning and methods, both groups identified another receptor, which they called TRPM8. It was activated by mildly cooling the skin (25C to 5C) and showed in later studies, again working independently, that deletion of the gene for TRPM8 in mice blocked the sensation of mild coldness. 

Of this discovery, the Nobel committee commented: “The discovery of TRPM8 as a cold sensor placed the TRP superfamily at the centre stage of thermal somatosensation and paved the way to identifying additional TRP channels responsible for thermal sensation.”

Patapoutian’s lab turned its attention to mechanosensitive receptors and identified a cell line that was sensitive to mechanical stimulation. From that line he identified 72 genes as possible candidates for the mechanosensitivity of the cells. 

By knocking out one after the other of the candidate genes, he found one that coded for the receptor. Moreover, he was able to show that introducing that same gene into cells without any sensitivity to mechanical stimuli conferred sensitivity to mechanical stimuli on the cells. They called the receptor PIEZO1, after the piezoelectricity observed in crystals, some ceramics and organic materials whose charge changes with physical stress.  

Later, a closely related receptor, PIEZO2, was found. It turned out to be the receptor protein for such ubiquitous mechanoreceptors as Merkel’s discs, Meissner’s corpuscles, Pacinian corpuscles and hair follicle receptors, which collectively provide precise, highly localized tactile information. 

In a related fashion, PIEZO2 receptors within muscles and tendons, provide information about changes in the length (muscle spindles) and tension in muscles (Golgi tendon organs) that are important for co-ordinated movement and balance. 

On the other hand, PIEZO1 receptors play important roles in monitoring distention of the bladder and urethra, and pressure within the inner lining of the heart and arteries where their sensitivity to stretch and pressure makes sense. 

The PIEZO protein is the largest transmembrane receptor yet discovered – over 2,500 amino acids with a central ion-conducting pore. 

Extending into the space outside the cell membrane are three large mechanosensitive blades that create a bowl-like structure on the surface of the membrane. Mechanical forces applied to the membrane flatten the blades and open the ion channel. 

This triggers an electrical signal that is transmitted to the spinal cord or brainstem and a chain of nerve cells, which pass the information along to the thalamus and primary sensory cortex, and beyond. 

It's really an extraordinary tale that begins with distorting a protein in a membrane and an after-stimulus trail of signals all the way to the brain. 

The story is incomplete but this year’s laureates in physiology-medicine, Julius and Patapoutian contributed mightily to a story that stands on the shoulders of the contributions of 22 other Nobel laureates, beginning with Camillo Golgi and Santiago Ramón y Cajal in 1906. Quite the ride.

The studies by Julius and Patapoutian are important because they provide information about how touch, temperature and pain are translated at the molecular level into electrical signals in the nervous system.

This information is essential for developing more effective, less-risky medications for treating pain and other sensory symptoms related to nervous system diseases. 

NOBEL SERIES: Remember to sign up for the Nobel series beginning Nov. 8 at 11 a.m. through Zoom links on the NOTL Public Library's website. Hope to see you there.

Dr. William Brown is a professor of neurology at McMaster University and co-founder of the InfoHealth series at the Niagara-on-the-Lake Public Library.  

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