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The 2021 Nobel Prize in Medicine was recently awarded to two scientists who advanced our understanding of how the nervous system senses and interprets our environment 1. In particular, they contributed to the dissection of the mechanisms underlying how temperature and mechanical stimuli are converted into electrical signals in the mammalian nervous system.
First, David Julius at the University of California, San Francisco, analyzed how the chemical compound capsaicin induces a burning sensation, such as when coming into contact with chili peppers. While capsaicin had previously been known to activate nerve cells and cause pain sensations, the mechanistic underpinnings had remained unknown to date. To this end, Julius and his team created a repository of millions of DNA fragments corresponding to different sensory neuron-expressed genes which react to heat, pain, and touch, hypothesizing that this repository was likely to include a DNA fragment encoding the capsaicin-responsive protein. Individual genes from this collection were expressed in cultured cells that are not normally capsaicin-responsive, leading the team to identify a gene uniquely able to render cells capsaicin-sensitive 2. This novel ion channel, responsible for sensing capsaicin-triggered temperature changes and heat-associated pain, was identified as TRPV1. In the same line of work, the team also subsequently identified a uniquely cold-activated receptor, TRPM8. Consistently, the TRP channel family, in general, was found to detect temperatures over a broad range, encoding the primary thermal stimuli sensors of the peripheral nervous system 3.
In parallel, Ardem Patapoutian of the Scripps Research Institute in La Jolla, California, sought to identify the skin’s receptors that are activated by mechanical stimuli. While researchers had previously identified mechanical sensors in prokaryotes, the mechanisms underlying touch perception in complex vertebrates had remained unknown. Patapoutian and his team first selected a cell line that emitted a small electrical signal when an individual cell was poked with a micropipette. Assuming that the mechanically activated receptor was an ion channel, 72 possible candidate genes encoding the receptor were shortlisted. In a strategy similar to that of Julius’ team, these genes were individually inactivated, which led to the identification of the piezo-electric PIEZO1 and PIEZO2 channels. Research subsequently demonstrated that these channels played key roles not only in proprioception, but also in the regulation of breathing, blood pressure, and urinary bladder control.
These newly identified ion channels represent a heretofore missing link in our modeling of the complex interplay between our environment and senses, including how our senses adapt to a rapidly changing environment. In addition, these mechanisms and underlying ion channels are critical to many physiological processes and diseases. Our ability to sense temperature and touch is essential to survival and many facets of our interactions with our surrounding environments, such as avoiding harmful temperatures, nonverbal communication in social settings, and more. Deficits in these processes are related to a number of now increasingly treatable diseases, including chronic pain 4–6. Future research will continue to build upon these breakthrough discoveries, such as through advanced drug discovery efforts, in order to best understand, prevent, and treat such diseases 7.
References
1. Press release: The Nobel Prize in Physiology or Medicine 2021 – NobelPrize.org. Available at: https://www.nobelprize.org/prizes/medicine/2021/press-release/.
2. Caterina, M. J. et al. The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature (1997). doi:10.1038/39807
3. McKemy, D. D., Neuhausser, W. M. & Julius, D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature (2002). doi:10.1038/nature719
4. Yue, L. & Xu, H. TRP channels in health and disease at a glance. J. Cell Sci. (2021). doi:10.1242/jcs.258372
5. Wang, R., Tu, S., Zhang, J., Shao, A. & Ostrowski, R. Roles of TRP Channels in Neurological Diseases. Oxidative Medicine and Cellular Longevity (2020). doi:10.1155/2020/7289194
6. González-Ramírez, R., Chen, Y., Liedtke, W. B. & Morales-Lázaro, S. L. TRP Channels and Pain. Neurobiol. TRP Channels 125–148 (2017). doi:10.4324/9781315152837-8
7. Koivisto, A. P., Belvisi, M. G., Gaudet, R. & Szallasi, A. Advances in TRP channel drug discovery: from target validation to clinical studies. Nature Reviews Drug Discovery (2021). doi:10.1038/s41573-021-00268-4
