Researchers from the Laboratory of Protein Structure at the International Institute of Molecular and Cell Biology in Warsaw, led by Prof. Marcin Nowotny, used the KRIOS cryoelectron microscope located at the SOLARIS National Synchrotron Radiation Centre to study the human TRPM8 protein.

The structure they obtained will enable a better understanding of the binding mechanism of small-molecule compounds affecting the activity of this ion channel. It will facilitate the design of new small-molecule compounds that can be used as therapeutics to treat numerous diseases associated with TRPM8 protein, such as neuropathic pain, irritable bowel syndrome, oropharyngeal dysphagia, chronic cough, and hypertension. As an example, in collaboration with scientists from Italy led by Dr. Carmine Talarico of Dompé Farmaceutici SpA, they have performed modeling of the binding of icilin, a small-molecule compound showing 200 times stronger TRPM8 channel activation than menthol. 

Perception of external stimuli is mediated by receptors located in nerve endings in our skin. These include the Transient Receptor Potential (TRP) family of ion channels – porous structures that allow the controlled flow of selected ions across the cell membrane. Activation (opening) of ion channels triggers depolarization of the cell membrane, which leads to the formation of a nerve impulse carrying information about the detected stimulus. TRPM8 receptors are responsible for the sensation of cold. Interestingly, they can also be activated by certain chemical compounds, such as menthol (a terpene group alcohol found in mint). Stimulation of these thermoreceptors is also linked to pain perception, and their desensitization by the continuous exposure to cold or menthol are known methods to reduce pain. A thorough understanding of the action of these receptors is therefore of great importance, and for the research on the molecular mechanisms of pain sensation, including the discovery and description of  TRPM8 channels, the 2021 Nobel Prize in Physiology or Medicine was awarded to David Julius and Ardem Patapoutian.

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Figure 1.  Structure of human cold receptor TRPM8

Author: Mariusz Czarnocki-Cieciura

Link to the publication: S. Palchevskyi, M. Czarnocki-Cieciura, G. Vistoli, S. Gervasoni, E. Nowak, A. R. Beccari, M. Nowotny, C. Talarico, Structure of human TRPM8 channel, Communications Biology, 6(1), 1065(2023) doi: 10.1038/s42003-023-05425-6