ArticleThe Journal of biological chemistry2009
Activity of the neuronal cold sensor TRPM8 is regulated by phospholipase C via the phospholipid phosphoinositol 4,5-bisphosphate.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
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Who cites it
93 citing papers in PubMed, 140 citations in OpenAlex.
- A dedicated skin-to-brain circuit for cool sensation in mice.Nature communications · 2025Article
- The structural basis of cold sensitivity.bioRxiv : the preprint server for biology · 2025Article
- TRPM8 Mutations Associated With Persistent Pain After Surgical Injury of Corneal Trigeminal Axons.Neurology. Genetics · 2024Article
- Ion channels of cold transduction and transmission.The Journal of general physiology · 2024Review
- Mechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8.Science advances · 2024Article
- Signal Transduction of Transient Receptor Potential TRPM8 Channels: Role of PIP5K, Gq-Proteins, and c-Jun.Molecules (Basel, Switzerland) · 2024Article
- Neural circuits of long-term thermoregulatory adaptations to cold temperatures and metabolic demands.Nature reviews. Neuroscience · 2024Review
- Negative self-regulation of transient receptor potential canonical 4 by the specific interaction with phospholipase C-δ1.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2023Article
- Molecular determinants of TRPM8 function: key clues for a cool modulation.Frontiers in pharmacology · 2023Review
- Regulation of ThermoTRP Channels by PIP2 and Cholesterol.Advances in experimental medicine and biology · 2023Article
- Expression of the C-Terminal Domain of Phospholipase Cβ3 Inhibits Signaling via Gαq-Coupled Receptors and Transient Receptor Potential Channels.International journal of molecular sciences · 2022Article
- Review
- On the modulation of TRPM channels: Current perspectives and anticancer therapeutic implications.Frontiers in oncology · 2022Review
- The distinctive role of menthol in pain and analgesia: Mechanisms, practices, and advances.Frontiers in molecular neuroscience · 2022Review
- Cold-inducible RNA-binding protein migrates from the nucleus to the cytoplasm under cold stress in normal human bronchial epithelial cells via TRPM8-mediated mechanism.Annals of translational medicine · 2021Article
- Colloidal Stability and Cytotoxicity of Polydopamine-Conjugated Gold Nanorods against Prostate Cancer Cell Lines.Molecules (Basel, Switzerland) · 2021Article
- Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity.International journal of molecular sciences · 2021Article
- Methods to study phosphoinositide regulation of ion channels.Methods in enzymology · 2021Article
- Implications of Transient Receptor Potential Cation Channels in Migraine Pathophysiology.Neuroscience bulletin · 2021Review
- The cool things to know about TRPM8!Channels (Austin, Tex.) · 2020Review
33 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Cold temperatures robustly activate a small cohort of somatosensory nerves, yet during a prolonged cold stimulus their activity will decrease, or adapt, over time. This process allows for the discrimination of subtle changes in temperature. At the molecular level, cold is detected by transient receptor potential melastatin 8 (TRPM8), a nonselective cation channel expressed on a subset of peripheral afferent fibers. We and others have reported that TRPM8 channels also adapt in a calcium-dependent manner when activated by the cooling compound menthol. Additionally, TRPM8 activity is sensitive to the phospholipid phosphoinositol 4,5-bisphosphate (PIP2), a substrate for the enzyme phospholipase C (PLC). These results suggest an adaptation model whereby TRPM8-mediated Ca2+ influx activates PLC, thereby decreasing PIP2 levels and resulting in reduced TRPM8 activity. Here we tested this model using pharmacological activation of PLC and by manipulating PIP2 levels independent of both PLC and Ca2+. PLC activation leads to adaptation-like reductions in cold- or menthol-evoked TRPM8 currents in both heterologous and native cells. Moreover, PLC-independent reductions in PIP2 had a similar effect on cold- and menthol-evoked currents. Mechanistically, either form of adaptation does not alter temperature sensitivity of TRPM8 but does lead to a change in channel gating. Our results show that adaptation is a shift in voltage dependence toward more positive potentials, reversing the trend toward negative potentials caused by agonist. These data suggest that PLC activity not only mediates adaptation to thermal stimuli, but likely underlies a more general mechanism that establishes the temperature sensitivity of somatosensory neurons.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.