Abstract
The Nobel Prize in Physiology or medicine is awarded by the Nobel assembly [1] for extra-ordinary inventions in physiology and medicine. The Nobel Prize is basically awarded to “those who, during the preceding year, have conferred the greatest benefit to humankind”, according to Alfred Nobel’s will in1895. The Nobel Prize is basically awarded for a discovery that ensures the greatest benefits of mankind.[2] Per the requirements of the will, select persons are qualified to nominate entities for the award. These include members of academies, professors of medicine in Sweden, Denmark, Norway, Iceland, and Finland, as well as professors of selected universities and research institutions in other countries. Past Nobel laureates may also nominate.[3] True to its dictate, the committee has chosen researchers working in the basic sciences over those who have made applied science contributions. Through the 1930s, there were common prize laureates in classical physiology, but after that, the field began shattering into specialties. The awards provided to the winners include a medal, diplomas and monetary award. Each medal topographies an image of Alfred Nobel in left profile on the obverse of the medal. A diploma directly from the King of Sweden if offered to them. Each diploma is uniquely designed by the prize-awarding institutions for the laureate that receives it. The amount of the cash award may differ from year to year, based on the funding’s availability into the Nobel Foundation. For example, in 2009 the total cash awarded was 10 million SEK (US$1.4 million),[26] but in 2012, the amount was 8 million Swedish Krona, or US$1.1 million.[4] These awards are handed over to the winners yearly at a gala ceremony followed by a banquet.[5]
Pain and pressure were among the last frontiers of scientists’ efforts. It was to describe the molecular basis for ambiances. For working clarifying how smell worked, as far back as 1967, the prize was awarded to scientists studying vision gave the 2004 Nobel Prize in Medicine.
But unlike smell and sight, the perceptions of pain or touch are not located in an isolated part of the body. At an online briefing on Monday Dr. Julius said,
“It’s been the last main sensory system to fall to molecular analysis.”
The biggest obstacle in Dr. Julius’s work was about combing through a library of millions of DNA fragments that encodes different proteins in the sensory neurons to find the one reacting to capsaicin, the burning component in chili peppers. The solution was finding those genes into cells that do not respond to capsaicin until one was discovered.
At here, scientists in Dr. Julius’s lab knew about the receptor they identified — TRPV1, a channel on the surface of cells activated by capsaicin — had to have changed primarily for a common stimulus, beyond the rare cases when someone might happenstance hot peppers. That other stimulus turned out to be heat, said Dr. Michael Caterina, a professor of neurosurgery at the Johns Hopkins University School of Medicine
Tobias Rosen came up with the ingenious gratitude that what we had cloned was a hot and sour soup receptor,” Dr. Caterina said. “It has acid, it has hot temperature, and it’s spicy.”
Searching the molecular basis for touch, Dr. Patapoutian also had to select through a number of possible genes. One by one, he and his collaborators deactivated genes until they identified the single one that made the cells insensitive to the poke of a tiny pipette when inactivated.
The channel integral to the sense of touch became known as Piezo1e. That channel and a similar one is now known to regulate a number of bodily functions that involve stretching, said Dr. Walter Koroshetz, which provided funding to Dr. Julius’s and Dr. Patapoutian’s labs.
Those functions include the working of blood vessels, breathing and sensitivity to a full bladder.
Introduction
We can sense heat, cold and touch. It reinforces our interaction with the world. In our daily lives we take sensations. But how are nerve impulses introduced? This question and its answer have provided this year’s Nobel prize in physiology.
David Julius used capsaicin, a strong compound from chili peppers that persuades a burning sensation, to find a sensor in the nerve finales of the skin that responds to heat. Ardem Patapoutian used pressure- sensitive cells to determine a new class of sensors that retort to mechanical incentives in the skin and internal organs. These inventions originated a new class of research on the workings of our nerves sensing heat, cold and stimulations. Patapoutian is a professor at Scripps Research, La Jolla, California, having formerly done research at the University of California, San Francisco, and California Institute of Technology, Pasadena.
New York-born Julius, 65, is a Professor at University of California, San Francisco (UCFS), after earlier work at Columbia University, in New York. Patapoutian is qualified for finding the cellular mechanism and the fundamental gene that translates a mechanical force on our skin into an electric nerve signal. Julius’s findings were enthused by his captivation for how natural products can be used to probe biological function.
The discovery of thermosensitive ion channels
Capsaicin [C18H27NO3 or 8-Methyl-N-vanillyl-trans-6-nonenamide] is an active component of chili papers and it gives the burning sensation for spicy food. Studies in 1950 showed that sweating of the head persuades when anyone have hot peppers, a phenomenon names gustatory sweating. [6] Before the invention, capsaicin was found acting on sensory nerves [7] and inducing currents. [8-11] Parallelly, it was also shown noxious heat to be produced activation of ion channels in neurons. But it was not fully clear if the channel itself was the transducer on not.
Discovery of TRPV1 as a thermosensitive ion channel
In the late 1990s, D. Julius at the University of California, San Francisco, pursued a project of identifying the receptor of capsaicin. Together with Michael J. Caterina, Julius decided to conduct an unbiased functional screen on the consumption that a single gene can confer capsaicin sensitivity in cells that are insensitive to capsaicin. Capsaicin-insensitive cells were transfected with batches of cDNAs and a single cDNA clone was isolated that could confer responsiveness to capsaicin. [12] (Fig.1)
The isolated gene was predicted to encode an integral membrane protein with six transmembrane domains and a homology search revealing it to be belonged to the superfamily of transient receptor potential (TRP) cation channels [13,14]. Julius continued to functionally characterize the TRPV1 receptor (at the time called vanilloid receptor 1, VR1) by ectopic expression in cells and found that the capsaicin- evoked electrophysiological properties resembled those of channels found in native sensory neurons. He also noted that the transfected cells became sensitive to cytotoxic effects induced by capsaicin and that
the capsaicin-evoked responses could be blocked with an antagonist. Further characterization showed that TRPV1 was expressed in nociceptive dorsal root ganglion neurons, thus providing an explanation for the selective actions of capsaicin on these cells (Figure 1B). While exploring the physiology of TRPV1, Julius examined its sensitivity to elevated temperature and found a pronounced activation by heat leading to cellular Ca2+ influx. Direct measurement of currents using patch-clamp recordings revealed a specific heat-evoked membrane current with properties similar to those of sensory neurons. Furthermore, TRPV1 had an activation threshold (above 40°C) close to the psychophysical threshold for thermal pain (Figure 1C). After identifying TRPV1, Julius went on to show that heat directly activates this channel in the absence of other factors, and that it acts as a molecular integrator of painful heat stimuli and chemical stimuli [20].
The sensation of noxious heat and cold
Whereas TRPV1 was found to have a critical role for the increased sensitivity to heat during inflammation, it was evident that other heat sensitive receptors must exist because animals lacking Trpv1 showed only a minor loss of acute noxious heat sensation [21, 22, 30, 31]. In 2011, Voets’ group identified TRPM3 as a second sensor for noxious heat in Trpv1 knockout mice [32]. However, the inactivation of both Trpv1 and Trpm3 in mice blunted, but did not eliminate, reflex responses to noxious heat. Non-noxious cold sensation in humans and mice starts around 28°C and has a remarkable precision detecting changes as small as 0.5°C in skin temperature [33,34,35]. In 2002, the sensory transducer for cold was independently discovered by the Julius and Patapoutian laboratories [36,37] in functional screens based on the assumption that menthol, a natural compound that elicits the sensation of innocuous coolness in humans, binds an ion channel that is activated by low temperature. Both groups identified TRPM8, yet another member of the TRP superfamily, and found that it is activated by low temperature in a heterologous expression system at a temperature range at which humans perceive innocuous cold [47, 48]. Consistent with these findings, Julius, Patapoutian and other groups independently found that deletion of Trpm8 in
mice causes clear deficits in sensation of innocuous cold [38-40]. The discovery of TRPM8 as a cold sensor placed the TRP superfamily at the center stage of thermal somatosensation and paved the way to the identification of additional TRP channels responsible for thermal sensation.
The discovery of PIEZO2 as a mechanosensitive ion channel for touch and proprioception
Ardem Patapoutian at Scripps Research, California developed a novel screening approach to search for the elusive receptor for mechanosensation in mammals. Together with the postdoctoral fellow Bertrand Coste, he identified an 6 intrinsically mechanosensitive cell line, called Neuro2A, by using brief and rapid indentation of the plasma membrane in combination with patchclamp recording to detect any possible current induced by the mechanical force (Figure 3A) [41]. Once the mechanosensitive Neuro2A cell line was identified, Patapoutian performed global expression analysis and identified 72 candidate genes predicted to encode proteins with at least two membrane-spanning domains, which included known ion channels and proteins of unknown function. The candidate genes were silenced oneby-one by RNA interference and the transfected cells were tested to determine whether the application of mechanical force resulted in a current that could be recorded using patch-clamp. Knockdown of the final gene on the list, previously known as FAM38A, eliminated the mechanically activated current and the corresponding protein was named PIEZO1 from the Greek word “piesi” meaning pressure (Figure 3B, red data point). Patapoutian proceeded to show that ectopic expression of PIEZO1 made human embryonic kidney cells (HEK-293) mechanosensitive, as pressure applied to the plasma membrane induced a large current in these cells. A second mechanosensitive channel, named PIEZO2, was subsequently discovered by sequence homology. The newly identified PIEZO channels belonged to a previously unknown protein family present in vertebrates and many other eukaryotes. PIEZO2, but not PIEZO1, was found to be expressed in dorsal root ganglion sensory neurons (Figure 3C) and knockdown of PIEZO2 abolished the mechanosensitivity of these sensory neurons (Figure 3D).
PIEZO proteins represent an entirely new class of vertebrate mechanosensitive channels without any resemblance to previously known ion channel families. They are the largest transmembrane ion channel subunits identified to date, composed of 2,500 amino acids and display a unique 38- transmembrane helix topology. Work from Patapoutian and other laboratories has revealed the high resolution structure of PIEZO1 and PIEZO2 and has shown that these channels form homotrimeric structures with a central ionconducting pore and three peripheral large mechanosensing propeller-shaped blades [42-47]. The
three blades curve out and up creating a nano-bowl configuration in the surface of the cell membrane [46-48]. When a mechanical force is applied to the membrane, the curved blades flatten out and lead to the opening of the central pore. The propeller-like structure with curved blades generates a large in-plane membrane area expansion, which likely explain the exquisite mechanosensitivity of PIEZO channels [80]. However, the exact mechanisms whereby mechanical force opens the central pore are still not completely understood. Through their mechanosensitivity, PIEZO channels serve as versatile mechanotransducers in many cell types and convert mechanical force into electrochemical signals (Figure 4)
Conclusion
The groundbreaking discoveries of the TRPV1, TRPM8 and PIEZO channels by this year’s Nobel Laureates have allowed us to understand how heat, cold and mechanical force are sensed and transformed into nervous impulses that enable 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 touch and proprioception. TRP and PIEZO channels also contribute to numerous additional physiological functions depending on sensing temperature or mechanical stimuli (Figure 5). Isn’t is a matter to celebrate? What do you think?
References
[1]. Definition of Nobel assembly and details information. https://en.wikipedia.org/wiki/Nobel_Assembly
[2]. Lindsten, Jan; Nils Ringertz. \”The Nobel Prize in Physiology or Medicine, 1901–2000\”. org. Retrieved 11 July 2010.
[3]. Foundation Books National Council of Science (2005). Nobel Prize Winners in Pictures. Foundation Books. p. viii. ISBN 978-81-7596-245-3.
[4]. \”Nobel prize amounts to be cut 20% in 2012\”. CNN. 11 June 2012. Archived from the original on 9 July 2012.
[5]. Pomp aplenty as winners gather for Nobel gala\”. The Local. 10 December 2009. Archived from the original on 15 December 2009. Retrieved 22 June
[6]. Lee, T.S., Physiological gustatory sweating in a warm climate. J Physiol, 1954. 124(3): p. 528-42
[7]. Jancsó, G., E. Kiraly, and A. Jancsó-Gábor, Pharmacologically induced selective degeneration of chemosensitive primary sensory neurones. Nature, 1977. 270(5639): p. 741-3.
[8]. Dray, A., J. Bettaney, and P. Forster, Actions of capsaicin on peripheral nociceptors of the neonatal rat spinal cord-tail in vitro: dependence of extracellular ions and independence of second messengers. British Journal of Pharmacology, 1990. 101(3): p. 727-733.
[9]. Marsh, S.J., C.E. Stansfeld, D.A. Brown, R. Davey, and D. McCarthy, The mechanism of action of capsaicin on sensory C-type neurons and their axons in vitro. Neuroscience, 1987. 23(1): p. 275-89.
[10]. Szallasi, A. and P.M. Blumberg, Specific binding of resiniferatoxin, an ultrapotent capsaicin analog, by dorsal root ganglion membranes. Brain Res, 1990. 524(1): p. 106-11.
[11]. Wood, J.N., J. Winter, I.F. James, H.P. Rang, J. Yeats, and S. Bevan, Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture. J Neurosci, 1988. 8(9): p. 3208-20.
[12]. Caterina, M.J., M.A. Schumacher, M. Tominaga, T.A. Rosen, J.D. Levine, and D. Julius, The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature, 1997. 389(6653): p. 816-24.
[13]. Clapham, D.E., TRP channels as cellular sensors. Nature, 2003. 426(6966): p. 517-24
[14]. Voets, T., K. Talavera, G. Owsianik, and B. Nilius, Sensing with TRP channels. Nat Chem Biol, 2005. 1(2): p. 85-92.
[20]. Tominaga, M., M.J. Caterina, A.B. Malmberg, T.A. Rosen, H. Gilbert, K. Skinner, B.E. Raumann, A.I. Basbaum, and D. Julius, The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron, 1998. 21(3): p. 531-43.
[21]. Caterina, M.J., A. Leffler, A.B. Malmberg, W.J. Martin, J. Trafton, K.R. Petersen-Zeitz, M. Koltzenburg, A.I. Basbaum, and D. Julius, Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science, 2000. 288(5464): p. 306-13.
[22]. Davis, J.B., J. Gray, M.J. Gunthorpe, J.P. Hatcher, P.T. Davey, P. Overend, M.H. Harries, J. Latcham,
- Clapham, K. Atkinson, S.A. Hughes, K. Rance, E. Grau, A.J. Harper, P.L. Pugh, D.C. Rogers, S. Bingham,
- Randall, and S.A. Sheardown, Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature, 2000. 405(6783): p. 183-187.
[23]. Fernández-Carvajal, A., R. González-Muñiz, G. Fernández-Ballester, and A. Ferrer-Montiel, Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels. Expert Opin Investig Drugs, 2020. 29(11): p. 1209-1222.
[24]. Manitpisitkul, P., A. Mayorga, K. Shalayda, M. De Meulder, G. Romano, C. Jun, and J.A. Moyer, Safety, Tolerability and Pharmacokinetic and Pharmacodynamic Learnings from a Double-Blind, Randomized, Placebo-Controlled, Sequential Group First-in-Human Study of the TRPV1 Antagonist, JNJ- 38893777, in Healthy Men. Clinical Drug Investigation, 2015. 35(6): p. 353-363.
[25]. Catterall, W.A., G. Wisedchaisri, and N. Zheng, The chemical basis for electrical signaling. Nat Chem Biol, 2017. 13(5): p. 455-463.
[26]. Long, S.B., X. Tao, E.B. Campbell, and R. MacKinnon, Atomic structure of a voltagedependent K+ channel in a lipid membrane-like environment. Nature, 2007. 450(7168): p. 376-82.
[27]. Cao, E., M. Liao, Y. Cheng, and D. Julius, TRPV1 structures in distinct conformations reveal activation mechanisms. Nature, 2013. 504(7478): p. 113-8.
[28]. Liao, M., E. Cao, D. Julius, and Y. Cheng, Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature, 2013. 504(7478): p. 107-12.
[29]. Kwon, D.H., F. Zhang, Y. Suo, J. Bouvette, M.J. Borgnia, and S.Y. Lee, Heat-dependent opening of TRPV1 in the presence of capsaicin. Nat Struct Mol Biol, 2021. 28(7): p. 554- 563.
[30]. Hoffmann, T., K. Kistner, F. Miermeister, R. Winkelmann, J. Wittmann, M.J. Fischer, C. Weidner, and P.W. Reeh, TRPA1 and TRPV1 are differentially involved in heat nociception of mice. Eur J Pain, 2013. 17(10): p. 1472-82.
[31]. Woodbury, C.J., M. Zwick, S. Wang, J.J. Lawson, M.J. Caterina, M. Koltzenburg, K.M. Albers, H.R. Koerber, and B.M. Davis, Nociceptors lacking TRPV1 and TRPV2 have normal heat responses. J Neurosci, 2004. 24(28): p. 6410-5.
[32]. Vriens, J., G. Owsianik, T. Hofmann, S.E. Philipp, J. Stab, X. Chen, M. Benoit, F. Xue, A. Janssens, S. Kerselaers, J. Oberwinkler, R. Vennekens, T. Gudermann, B. Nilius, and T. Voets, TRPM3 is a nociceptor channel involved in the detection of noxious heat. Neuron, 2011. 70(3): p. 482-94.
[33]. Yarmolinsky, D.A., Y. Peng, L.A. Pogorzala, M. Rutlin, M.A. Hoon, and C.S. Zuker, Coding and Plasticity in the Mammalian Thermosensory System. Neuron, 2016. 92(5): p. 1079-
[34]. Vandewauw, I., K. De Clercq, M. Mulier, K. Held, S. Pinto, N. Van Ranst, A. Segal, T. Voet, R. Vennekens, K. Zimmermann, J. Vriens, and T. Voets, A TRP channel trio mediates acute noxious heat sensing. Nature, 2018. 555(7698): p. 662-666.
[35]. Frenzel, H., J. Bohlender, K. Pinsker, B. Wohlleben, J. Tank, S.G. Lechner, D. Schiska, T. Jaijo, F. Rüschendorf, K. Saar, J. Jordan, J.M. Millán, M. Gross, and G.R. Lewin, A genetic basis for mechanosensory traits in humans. PLoS Biol, 2012. 10(5): p.
[36]. McKemy, D.D., W.M. Neuhausser, and D. Julius, Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature, 2002. 416(6876): p. 52-8.
[37]. Peier, A.M., A. Moqrich, A.C. Hergarden, A.J. Reeve, D.A. Andersson, G.M. Story, T.J. Earley, I. Dragoni, P. McIntyre, S. Bevan, and A. Patapoutian, A TRP channel that senses cold stimuli and menthol. Cell, 2002. 108(5): p. 705-15.
[38]. Bautista, M., J. Siemens, J.M. Glazer, P.R. Tsuruda, A.I. Basbaum, C.L. Stucky, S.E. Jordt, and D. Julius, The menthol receptor TRPM8 is the principal detector of environmental cold. Nature, 2007. 448(7150): p. 204-8.
[39]. Colburn, R.W., M.L. Lubin, D.J. Stone, Y. Wang, D. Lawrence, Michael R. D\’Andrea, M.R. Brandt, Y. Liu, C.M. Flores, and N. Qin, Attenuated Cold Sensitivity in TRPM8 Null Mice. Neuron, 2007. 54(3): p. 379-386.
[40]. Dhaka, A., A.N. Murray, J. Mathur, T.J. Earley, M.J. Petrus, and A. Patapoutian, TRPM8 is required for cold sensation in mice. Neuron, 2007. 54(3): p. 371-8.
[41]. Coste, B., J. Mathur, M. Schmidt, T.J. Earley, S. Ranade, M.J. Petrus, A.E. Dubin, and A. Patapoutian, Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science, 2010. 330(6000): p. 55-60.
[42]. Ge, J., W. Li, Q. Zhao, N. Li, M. Chen, P. Zhi, R. Li, N. Gao, B. Xiao, and M. Yang, Architecture of the mammalian mechanosensitive Piezo1 channel. Nature, 2015. 527(7576): p. 64-9.
[43]. Saotome, K., S.E. Murthy, J.M. Kefauver, T. Whitwam, A. Patapoutian, and A.B. Ward, Structure of the mechanically activated ion channel Piezo1. Nature, 2018. 554(7693): p. 481-486.
[44]. Wang, L., H. Zhou, M. Zhang, W. Liu, T. Deng, Q. Zhao, Y. Li, J. Lei, X. Li, and B. Xiao, Structure and mechanogating of the mammalian tactile channel PIEZO2. Nature, 2019. 573(7773): p. 225-229.
[45]. Zhao, Q., H. Zhou, S. Chi, Y. Wang, J. Wang, J. Geng, K. Wu, W. Liu, T. Zhang, M.Q. Dong, J. Wang, X. Li, and B. Xiao, Structure and mechanogating mechanism of the Piezo1 channel. Nature, 2018. 554(7693): p. 487-492.
[46]. Guo, Y.R. and R. MacKinnon, Structure-based membrane dome mechanism for Piezo mechanosensitivity. Elife, 2017.
[47]. Jiang, Y., X. Yang, J. Jiang, and B. Xiao, Structural Designs and Mechanogating Mechanisms of the Mechanosensitive Piezo Channels. Trends Biochem Sci, 2021. 46(6): p. 472-488