ArticleThe Journal of biological chemistry2018
Critical role of the pore domain in the cold response of TRPM8 channels identified by ortholog functional comparison.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 1 of them a synthesis that pooled it.
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Who cites it
27 citing papers in PubMed, 1 synthesis or guideline pooled it, 37 citations in OpenAlex.
- Modulation of transient receptor potential (TRP) channels by plant derived substances used in over-the-counter cough and cold remedies.Respiratory research · 2023Pooled it
- Molecular basis for cold and menthol sensing by mammalian TRPM8.Nature communications · 2026Article
- Decreased cold-sensing function of the transient receptor potential channel TRPM8 from tailed amphibians.FEBS open bio · 2026Article
- Temperature-Dependent Menthol Binding across TRPM8 Conformational States.Journal of the American Chemical Society · 2026Article
- Deep mutational scan of the pore of the cold-sensing TRPM8 channel.bioRxiv : the preprint server for biology · 2026Article
- Cold- and TRPM8-dependent shaking in mammals and birds.Communications biology · 2025Article
- Rational tuning of temperature sensitivity of the TRPM8 channel.EMBO reports · 2025Article
- Residues of TRPM8 at the Lipid-Water-Interface have Coevolved with Cholesterol Interaction and are Relevant for Diverse Health Disorders.The Journal of membrane biology · 2024Article
- TRPM8 Mutations Associated With Persistent Pain After Surgical Injury of Corneal Trigeminal Axons.Neurology. Genetics · 2024Article
- Evidence that the cold- and menthol-sensing functions of the human TRPM8 channel evolved separately.Science advances · 2024Article
- Temperature-Dependent Activation of Thermosensitive Transient Receptor Potential Channels.Advances in experimental medicine and biology · 2024Review
- Molecular determinants of TRPM8 function: key clues for a cool modulation.Frontiers in pharmacology · 2023Review
- Mutations of TRPM8 channels: Unraveling the molecular basis of activation by cold and ligands.Medicinal research reviews · 2022Review
- Activation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIPScience (New York, N.Y.) · 2022Article
- The acquisition of cold sensitivity during TRPM8 ion channel evolution.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- In Vitro and In Vivo Pharmacological Characterization of a Novel TRPM8 Inhibitor Chemotype Identified by Small-Scale Preclinical Screening.International journal of molecular sciences · 2022Article
- Constitutive Phosphorylation as a Key Regulator of TRPM8 Channel Function.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Structural and in Vitro Functional Characterization of a Menthyl TRPM8 Antagonist Indicates Species-Dependent Regulation.ACS medicinal chemistry letters · 2021Article
- Temperature Sensation: From Molecular Thermosensors to Neural Circuits and Coding Principles.Annual review of physiology · 2021Review
- Negative Modulation of TRPM8 Channel Function by Protein Kinase C in Trigeminal Cold Thermoreceptor Neurons.International journal of molecular sciences · 2020Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In mammals, the main molecular entity involved in innocuous cold transduction is TRPM8. This polymodal ion channel is activated by cold, cooling compounds such as menthol and voltage. Despite its relevance, the molecular determinants involved in its activation by cold remain elusive. In this study we explored the use of TRPM8 orthologs with different cold responses as a strategy to identify new molecular determinants related with their thermosensitivity. We focused on mouse TRPM8 (mTRPM8) and chicken TRPM8 (cTRPM8), which present complementary thermosensitive and chemosensitive phenotypes. Although mTRPM8 displays larger responses to cold than cTRPM8 does, the avian ortholog shows a higher sensitivity to menthol compared with the mouse channel, in both HEK293 cells and primary somatosensory neurons. We took advantage of these differences to build multiple functional chimeras between these orthologs, to identify the regions that account for these discrepancies. Using a combination of calcium imaging and patch clamping, we identified a region encompassing positions 526-556 in the N terminus, whose replacement by the cTRPM8 homolog sequence potentiated its response to agonists. More importantly, we found that the characteristic cold response of these orthologs is due to nonconserved residues located within the pore loop, suggesting that TRPM8 has evolved by increasing the magnitude of its cold response through changes in this region. Our results reveal that these structural domains are critically involved in cold sensitivity and functional modulation of TRPM8, and support the idea that the pore domain is a key molecular determinant in temperature responses of this thermo-transient receptor potential (TRP) channel.
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