The ‘Nobel’ Feeling - Understanding how we ‘feel’ the world around us

Saptarshi Maji

  We all react to touch and heat, but how do we perceive that sensation? This article talks about the mechanism of touch and temperature receptors that won the Nobel prize in Physiology and Medicine in 2021.



  Vision, smell, taste, hearing, and touch; are the five senses that help us understand the environment surrounding us. These are not only the most fundamental inputs from the environment but also the most important for surviving in one. The basic understanding of how we perceive these senses has always been thought-provoking to scientists.

  An in-depth understanding of senses like vision, smell, taste, or hearing was described by scientists much earlier. Hungarian biophysicist Georg von Békésy was awarded the Nobel in 1961 for his discoveries of the physical mechanism of stimulation within the cochlea (a part of the inner ear which enables hearing), which converts the sound wave into electrical stimuli. Six years later, Ragnar Arthur Granit, along with Haldan Keffer Hartline and George Wald, received the Nobel prize in physiology or medicine for their discoveries in understanding the primary physiological and chemical processes in the eye, that are important for our vision. In 2004, American molecular biologists Richard Axel and Linda B. Buck were awarded the Nobel in the same category for their work on the smell-identifying odorant receptor and organization of the olfactory system.

  Senses like the feeling of touch have always been neglected. Skin, the largest organ of our body, has the highest amount of interaction with the environment and provides us with necessary information about our surroundings like temperature, wind, touch, etc. Back in the 17th century, French philosopher René Descartes proposed the presence of ‘threads’ spread all over our body which are connected to the brain and are responsible for relaying these messages. Later it was found that these threads are sensory neurons that keep track of changes in the environment. Not only that, but these neurons are also highly specialized in registering different types of stimuli.

  To feel any sensation, a physical stimulus is converted into an electrical signal. Only then, our body perceives the sensation. In 1944, American physiologists Joseph Erlanger and Herbert Gasser won the Nobel prize for their work on the specialization of neurons or nerve cells. They confirmed that to feel any sensation, a physical stimulus activates a neuron, results in a voltage difference and secretion of messenger chemical substances which propagates to the next neuron and thus reaches our brain in a relay process. But how heat or a physical force is transformed into an electrical signal in our nervous system remained unanswered for a long time. This year, the Nobel prize in physiology or medicine was awarded to Ardem Patapoutian and David Julius for their work on understanding this question.

  In the early ’90s, David Julius started his career as faculty at the University of California, San Francisco. His work was mainly on different receptors, necessary for different types of moods that we feel. One of them was to find the receptor for capsaicin, a chemical substance in chili pepper causing burning sensation when touched. From previous knowledge, it was already known that capsaicin causes pain sensation by activating nerve cells. In their quest for the capsaicin receptor, they first made a library of genes in the nerve cells. Since nerve cells are activated in the presence of capsaicin, one of the genes should be responsible for this activity. Next, they started expressing the genes in non-neuronal cells one by one and began monitoring their activity in response to capsaicin. In 1997, the quest, which was similar to searching for a needle in a haystack, ended with finding the receptor for capsaicin. The newly found protein was named TRPV1, which was found to be a channel protein.

  As the name suggests, channel proteins are a group of membrane-embedded proteins that connect two sides of the membrane. Channel proteins are highly specialized in transporting specific or a group of specific small molecules (mostly ions and water molecules). In this case, TRPV1 was found to be a nonspecific cation channel that, when activated, imports cations (positively charged ions) into the cell. In this particular case, mostly sodium (Na+) and calcium (Ca2+) ions are imported into the cell, as their concentration is several fold higher outside of the cell than inside). This results in a change in the ionic balance inside the cell that stimulates the nerve cell. Surprisingly, they found, this channel is also active in response to heat. And that is how they discovered the first-ever heat-sensitive receptor that causes a similar painful experience as chili pepper does.

  The scientists overcame the main problem in working with heat receptors, that is, stimulating heat sensor-protein using high temperature can kill the cells in a laboratory culture petri dish. Although, the exact mechanism of how heat activates TRPV1 is still not known.

  Later, they discovered numerous other heat-sensing receptors in different animals with various temperature ranges for activation. For example, TRPV4, another heat-responsive protein, has an activity range of 27º-34ºC and is vital for the hibernation of reptiles. In cold temperatures, the expression of this receptor is reduced in most of the tissues except the skin, which helps in sensing the environmental conditions during the hibernation period.

  TRPV8, another cold receptor, was discovered independently by Ardem Patapoutian, the other Nobel awardee of this year. Interestingly, instead of capsaicin, menthol, a cooling substance, was found to activate this specific receptor.

  Ardem Patapoutian, assistant professor at Scripps Research in La Jolla, California, was also working on how physical pressure is converted into a nerve signal. Numerous mechano-sensors were already discovered in bacteria but none in higher animals. Patapoutian and his collaborators first identified a specific cell line that produces some electric signal when poked. Similar to the method opted by Julius, Patapoutian also made a library of genes. But unlike Julius, who expressed the genes in a non-native cell line, Patapoutian started deactivating the genes one by one. Through the laborious process, they identified the 72nd gene that, when deactivated, produced no electric signal. This was the first-ever mechano-sensor or mechanical force sensor that was discovered in the higher animals. They named it Piezo1, after the Greek word for pressure (píesi). Later, they found another sensor very similar to Piezo1 which they named Piezo2.

  Structural analysis shows that Piezo1 is a gigantic membrane protein that passes the membrane 37 times, which is known as the ‘Transmembrane domain.’ Three monomers of Piezo1 come together and aggregate to form the giant membrane protein. While one end of the protein forms a channel pore (hole like pathway), the remaining part of the protein is spread far away from the pore center, replicating a three-blade propeller-like structure. The large propeller part is responsible for mechano-sensing. Due to the large spread area of this protein, it can sense membrane undulations very rapidly, which in turn acts as a lever that opens the ion channel.

  Piezo1 not only senses external pressure like touch, wind etc, but internal pressure as well, including blood pressure, urinary bladder control, etc. Our daily movement is highly dependent on responses from Piezo2 as it helps us in feeling the presence of ground under our feet and positioning our body accordingly. This process is also known as ‘Proprioception.’

  Intense research has continued in this field since the discovery of these receptors. Since both are somehow related to pain sensation, scientists are trying to use them for treatments of several diseases, e.g., chronic pain and many more.

  Research on pressure and temperature receptors were an excellent addition to understanding the basic fundamentals of our senses and our perception of the world around us. The recognition of the discoveries by the highest scientific accolade was just a matter of time.

Bibliography

  1. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997:389:816-824.
  2. Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A. A TRP channel that senses cold stimuli and menthol. Cell 2002:108:705-715
  3. Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, Dubin AE, Patapoutian A. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 2010:330: 55-60
  4. Nagai K, Saitoh Y, Saito S, Tsutsumi K. Structure and hibernation-associated expression of the transient receptor potential vanilloid 4 channel (TRPV4) mRNA in the Japanese grass lizard (Takydromus tachydromoides) Zoological science. 2012;29:185–190.
  5. Q. Zhao, H. Zhou, X. Li, and B. Xiao, “The mechanosensitive Piezo1 channel: a three-bladed propeller-like structure and a lever-like mechanogating mechanism,” The FEBS Journal, vol. 286, no. 13, pp. 2461–2470, 2019.

Saptarshi Maji completed his Masters in Life Sciences in 2018 from IISER Kolkata and joined as Ph.D. student. Currently he is working on maintenance of copper homeostasis inside the cell under supervision of Dr. Arnab Gupta.

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