How Your Body Senses Temperature and Spice Through Ion Channels: Exploring the Science Behind Sensory Perception

Written by Shasha Feng, Department of Biological Sciences, Lehigh University

Photo by Hari Krishnan on Unsplash

Anna, a big fan of spicy food, ordered a bowl of spicy salsa with extra Valentina hot sauce while dining at a Mexican restaurant. It was really spicy, and she felt hot and a bit of pain. Anna paused to let the spiciness cool down while also taking sips of yogurt drink, which helped a lot.

Have you ever wondered why dairy products are effective in soothing the burn from spices? The major compound in chili peppers is capsaicin, which is an oily chemical that sticks to the tongue. To dissolve capsaicin, fats are required, which were present in the yogurt drink that Anna was consuming, helping to soothe her taste buds. The reason that spiciness and hot pain lead to similar sensations is that capsaicin, the active compound from chili peppers, and exposure to high temperatures both activate the same kind of protein called ion channels.

The sensory information that we receive from the surrounding environment is transmitted to our body through ion channels on the surface of our cell membranes. Small drugs can modulate their functions (opening/closing), making it critical to understand the mechanisms involved in affecting them for drug discovery.

Photo by JOSHUA COLEMAN on Unsplash

The human body is composed of tissues, which in turn are made of cells. Cells have a protective barrier known as the cell membrane that regulates what enters and exits the cell. Ion channels are like detectives that are embedded in the membrane and respond to sensory cues in the environment, allowing cells to communicate and interact with their surroundings. When an ion channel is activated, it opens and allows the ions to follow inside, which further activates other proteins and signaling pathways. Through this, our neurons perceive the environment and take actions.

When you take your hand back after touching a hot kettle or enjoy the great coolness while drinking ice water in the summer, or like Anna, indulge in super spiciness, without your realization, the ion channels in your body are hard at work to keep you aware of the sensory cues in your environment. Sensing environmental cues has been crucial since ancient times when people did not have modern homes to protect them from the elements.

The Nobel Prize for Physiology 2021 was awarded to David Julius and Ardem Patapoutian for their breakthrough discovery of the thermosensory transient receptor potential (TRP), and mechanosensory Piezo ion channels. The TRP channels are proteins that, upon activation by stimuli, open the channel and let ions flow inside. The ions, especially calcium, are important signals. Once the ions enter the cell, the cell membrane’s electric voltage also changes, and the electric signals can be transmitted to other neurons. The influx of calcium also sends further signals instructing cells to synthesize new proteins or recruit more ion channels to the membrane surface.

My thesis research focuses on proteins from this TRP channel family, including TRPV2, TRPM8, TRPC5. Each has its characteristics. TRPV2 senses the harmful temperature range (> 52 C°), TRPM8 senses cold temperature and is the major channel responsible for cold sensing and a target for cooling agents such as menthol, and TRPC5 senses a temperature range of 25-30 C° (Figure 1). In the paper published in Protein Science this year, we investigated how TRPV2 is regulated by small molecules, including lipids (main component of the cell membrane) and drugs.7

TRPV2 is an ion channel that plays a role in cardiac rhythms, cancer cell migration, immune systems, and pancreatic tissues. An increasing number of studies have found TRPV2 as an important biomarker for multiple types of cancers, including prostate cancer, triple-positive breast cancer, and blastoma.

The main technique we used in our study is molecular dynamics (MD) simulations. Similar to the objects in the physical world, protein molecules also undergo movement and vibrations. In our computational model, we can mimic the various factors that cause the proteins to move and shake. Then, we used a high-performance computing (HPC) cluster to simulate how protein motions unfold and use data science to extract key information about protein conformation and dynamics from it.

Through MD simulations, we discovered that two types of lipids sit deep inside protein pockets. One type helps the protein reduce fluctuations and work more efficiently as a group, while the other type of lipid has more diverse binding configurations and its effects depend on the lipid binding configurations. We also investigated how cannabidiol (CBD), a compound found in Cannabis Sativa, or marijuana, influences protein conformation. CBD is a non-psychoactive compound and is a potent activator of TRPV2. Compared to no CBD, CBD binding induces a wider upper gate of the protein, paving the way for channel activation, which will lead to neuronal activation and human behavioral responses. These findings laid the ground for further understanding TRPV2 activation mechanisms and developing effective drugs.

It is quite amazing that a small drug molecule like CBD can exert an influence on the big TRPV2 protein, which has 240 times more molecular weight than that of CBD. Such effects are known as allostery. Think of it like a lock and key – when the right key (in this case, the CBD) is inserted into the lock (the specific site on TRPV2), it triggers a change in the shape of the protein, which in turn affects its activity. Allostery plays a crucial role in many biological processes, including signaling pathways, metabolism, and gene regulation. Understanding the mechanisms of allostery is therefore important for developing new drugs and therapies that target specific proteins and their functions.

So Anna’s case is a typical illustration of how natural compounds influence our body sensations. The spiciness and drugs in our body all route to various parts of the sensory system, either promoting certain experiences or acting to stop disease from further developing.

References

1. Fattori, V.; Hohmann, M. S. N.; Rossaneis, A. C.; Pinho-Ribeiro, F. A.; Verri, W. A., Capsaicin: Current Understanding of Its Mechanisms and Therapy of Pain and Other Pre-Clinical and Clinical Uses. Molecules 2016, 21 (7), 844.
2. Tomohiro Numata, S. K., Kenta Kato, Nobuaki Takahashi, and Yasuo Mori., Chapter 3 Activation of TRP Channels in Mammalian Systems. In TRP Channels, CRC Press/Taylor & Frances: Boca Raton (FL), 2011.
3. Martinac, B., 2021 Nobel Prize for mechanosensory transduction. Biophysical Reviews 2022, 14 (1), 15-20.
4. Song, K.; Wei, M.; Guo, W.; Quan, L.; Kang, Y.; Wu, J.-X.; Chen, L., Structural basis for human TRPC5 channel inhibition by two distinct inhibitors. eLife 2021, 10, e63429.
5. Tamura, S.; Morikawa, Y.; Senba, E., TRPV2, a capsaicin receptor homologue, is expressed predominantly in the neurotrophin-3-dependent subpopulation of primary sensory neurons. Neuroscience 2005, 130 (1), 223-8.
6. Yin, Y.; Zhang, F.; Feng, S.; Butay, K. J.; Borgnia, M. J.; Im, W.; Lee, S.-Y., Activation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIP₂. Science 2022, 378 (6616), eadd1268.
7. Feng, S.; Pumroy, R. A.; Protopopova, A. D.; Moiseenkova-Bell, V. Y.; Im, W., Modulation of TRPV2 by endogenous and exogenous ligands: A computational study. Protein Science 2023, 32 (1), e4490.
8. Elbaz, M.; Ahirwar, D.; Xiaoli, Z.; Zhou, X.; Lustberg, M.; Nasser, M. W.; Shilo, K.; Ganju, R. K., TRPV2 is a novel biomarker and therapeutic target in triple negative breast cancer. Oncotarget 2018, 9 (71), 33459-33470.
9. Katanosaka, Y.; Iwasaki, K.; Ujihara, Y.; Takatsu, S.; Nishitsuji, K.; Kanagawa, M.; Sudo, A.; Toda, T.; Katanosaka, K.; Mohri, S.; Naruse, K., TRPV2 is critical for the maintenance of cardiac structure and function in mice. Nat Commun 2014, 5, 3932.
10. Leveque, M.; Penna, A.; Le Trionnaire, S.; Belleguic, C.; Desrues, B.; Brinchault, G.; Jouneau, S.; Lagadic-Gossmann, D.; Martin-Chouly, C., Phagocytosis depends on TRPV2-mediated calcium influx and requires TRPV2 in lipids rafts: alteration in macrophages from patients with cystic fibrosis. Sci Rep 2018, 8 (1), 4310.