Affinage

TRPM8

Transient receptor potential cation channel subfamily M member 8 · UniProt Q7Z2W7

Length
1104 aa
Mass
127.7 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRPM8 is a cold- and menthol-activated, Ca²⁺-permeable non-selective cation channel that serves as the principal molecular transducer of innocuous cold sensation in somatosensory neurons. The channel assembles as a homotetramer requiring PI(4,5)P₂ as an obligatory co-activator; menthol increases PI(4,5)P₂ binding potency, while Gαq reduces its apparent affinity, sensitizing the channel to inhibition upon GPCR activation (PMID:20844147, PMID:31127000). Cryo-EM structures reveal a malleable ligand-binding pocket with two discrete agonist sites, Ca²⁺-dependent desensitization involving large S4–S5 linker rearrangements, and a disordered-to-ordered transition of the S6 gate helix during activation, while temperature sensitivity is conferred by a folding–unfolding equilibrium of the C-terminal coiled-coil domain (PMID:31488702, PMID:36227998, PMID:32747539). Beyond its channel function, TRPM8 acts as a Rap1 GTPase inhibitor through direct protein–protein interaction to suppress endothelial cell migration independently of ion conduction, and a gain-of-function p.Arg30Gln mutation causes familial trigeminal neuralgia (PMID:28550110, PMID:33977138).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2006 High

    Establishing that TRPM8 assembles as a tetramer with essential pore-region cysteines flanking the N-glycosylation site at Asn-934 resolved the basic quaternary architecture of the functional channel.

    Evidence Site-directed mutagenesis with SDS-PAGE, PFO-PAGE, and calcium imaging in heterologous cells

    PMID:17015441

    Open questions at the time
    • No high-resolution structure yet available
    • Stoichiometry of heteromeric assemblies unexplored
  2. 2007 High

    Demonstrating that lysophospholipids raise the TRPM8 temperature activation threshold toward body temperature while PUFAs inhibit channel activity established a lipid-metabolite regulatory axis for tuning cold sensitivity.

    Evidence Patch-clamp and calcium imaging in CHO cells and DRG neurons expressing TRPM8

    PMID:17376995

    Open questions at the time
    • Binding sites for lysophospholipids and PUFAs on TRPM8 not mapped
    • In vivo physiological relevance of iPLA2-dependent regulation not tested genetically
  3. 2008 High

    Genetic reporter tracing revealed that TRPM8-expressing DRG neurons constitute a dedicated cold-sensing population with unique peripheral bush/cluster endings and superficial dorsal horn projections, defining the anatomical substrate of TRPM8-mediated thermosensation.

    Evidence TRPM8-EGFPf knock-in mouse with calcium imaging, anatomical tracing, and immunohistochemistry

    PMID:18199758

    Open questions at the time
    • Whether all cold sensation requires TRPM8 or parallel pathways exist not resolved by this study
    • Central circuit integration of TRPM8 input not addressed
  4. 2009 High

    The discovery that TRPM8 forms a stable complex with inorganic polyphosphate and that polyphosphate degradation inhibits channel activity identified an unexpected inorganic co-factor requirement.

    Evidence Planar lipid bilayer reconstitution, biochemical co-purification, whole-cell patch-clamp

    PMID:19404398

    Open questions at the time
    • Polyphosphate binding site on TRPM8 not identified
    • Physiological polyphosphate levels in sensory neurons not established
  5. 2010 High

    Reconstitution in planar lipid bilayers definitively established that cold, menthol, and icilin gate TRPM8 directly without requiring cellular signaling intermediates, and that PI(4,5)P₂ is an obligatory co-activator binding the channel protein with agonist-enhanced potency.

    Evidence Purified TRPM8 in planar lipid bilayers, patch-clamp, phosphoinositide binding assays, mutagenesis

    PMID:20844147

    Open questions at the time
    • PI(4,5)P₂ binding site on TRPM8 not structurally resolved
    • Mechanism coupling cold temperature to channel opening still unknown
  6. 2017 High

    Multiple studies revealed that TRPM8 functions beyond ion conduction: it acts as a Rap1 GTPase inhibitor through direct pore-independent protein–protein interaction, suppressing endothelial migration, and interacts with NF-κB to suppress its nuclear translocation under cold stress.

    Evidence Co-immunoprecipitation, dominant-negative/overexpression, migration/tube formation assays (Rap1); nuclear fractionation, qRT-PCR (NF-κB)

    PMID:28332601 PMID:28550110

    Open questions at the time
    • Structural basis of TRPM8–Rap1 interaction unknown
    • Relevance of NF-κB interaction beyond hypothalamic cold stress not tested
    • Whether Rap1 inhibition and NF-κB interaction are coordinated is unexplored
  7. 2018 High

    Tacrolimus was shown to directly gate TRPM8 independently of calcineurin/PLC at a binding site distinct from menthol and icilin, explaining clinical cold hypersensitivity in transplant patients.

    Evidence Purified TRPM8 in lipid bilayers, patch-clamp, mutagenesis distinguishing Y745H (menthol) and N799A (icilin) sites

    PMID:30545944

    Open questions at the time
    • Structural identity of the tacrolimus binding pocket not resolved
    • Whether tacrolimus gating shares the PIP₂-dependent pathway is unclear
  8. 2019 High

    Cryo-EM structures of TRPM8 in ligand-free, antagonist-bound, and Ca²⁺-bound states resolved the architecture of the malleable ligand-binding pocket, revealed two non-conducting states (closed and desensitized), and showed that Ca²⁺ binding drives desensitization through large S4–S5 linker rearrangements.

    Evidence Cryo-electron microscopy at multiple functional states

    PMID:31488702

    Open questions at the time
    • Open-state structure not captured
    • PI(4,5)P₂ binding mode not resolved in these structures
  9. 2019 High

    The mechanism of Gαq-mediated TRPM8 inhibition was established: Gαq binding reduces the apparent affinity of TRPM8 for PI(4,5)P₂ independently of PLC activity, sensitizing the channel to inhibition upon receptor-mediated PI(4,5)P₂ depletion.

    Evidence Whole-cell patch-clamp with voltage-sensitive phosphatase, PI(4,5)P₂ supplementation, calcium imaging in DRG neurons

    PMID:23508958 PMID:31127000

    Open questions at the time
    • Gαq binding site on TRPM8 not mapped
    • Whether other Gα subunits modulate PI(4,5)P₂ affinity is untested
  10. 2019 Medium

    Src-family kinase-mediated constitutive tyrosine phosphorylation was shown to positively regulate TRPM8, as Src inhibition reduced both phosphorylation and cold-induced channel activation.

    Evidence Co-immunoprecipitation, western blot, calcium imaging, patch-clamp, RNAi in HEK293T cells and DRG neurons

    PMID:31729029

    Open questions at the time
    • Specific tyrosine residue(s) phosphorylated by Src not identified in this study
    • Relationship to LCK-mediated Y1022 phosphorylation not clarified
  11. 2020 High

    The molecular basis of TRPM8 temperature sensitivity was resolved: a folding–unfolding equilibrium of the C-terminal coiled-coil domain generates the large enthalpy change underlying steep temperature dependence (Q10 ~40), with progressive CTD deletion proportionally reducing enthalpy and the last 36 residues being essential.

    Evidence Patch-clamp with progressive CTD deletions, denaturing agents, osmoticant assays, structural analysis

    PMID:32747539

    Open questions at the time
    • Atomic-level description of the folding transition at different temperatures not available
    • How CTD folding couples to pore opening is structurally unresolved
  12. 2020 High

    Chronic morphine was found to sensitize TRPM8 by PKCβ-mediated phosphorylation at S1040 and S1041, reducing activation-evoked desensitization; this mechanism links opioid receptor signaling to cold hypersensitivity.

    Evidence Site-directed mutagenesis (S1040A/S1041A), patch-clamp, pharmacological inhibition in DRG neurons and HEK cells, in vivo morphine treatment

    PMID:32290846

    Open questions at the time
    • Whether S1040/S1041 phosphorylation alters TRPM8 structure is unknown
    • Clinical relevance in opioid-induced cold allodynia not validated in patients
  13. 2021 High

    Mass spectrometry-guided mutagenesis identified constitutive N-terminal serine phosphorylation (especially S29) as a tonic brake on TRPM8 activity: S29A shifts voltage-dependent activation to more negative potentials and increases active channel density at the plasma membrane.

    Evidence Mass spectrometry, site-directed mutagenesis, calcium imaging, patch-clamp, TIRF microscopy

    PMID:34446569

    Open questions at the time
    • Kinase(s) responsible for constitutive S29 phosphorylation not identified
    • Whether S29 phosphorylation is dynamically regulated in vivo is unknown
  14. 2021 Medium

    A gain-of-function TRPM8 variant p.Arg30Gln was identified in a family with trigeminal neuralgia; the mutation enhances basal current, intracellular Ca²⁺, and menthol responsiveness, establishing TRPM8 as a disease gene for inherited facial pain.

    Evidence Calcium imaging and whole-cell patch-clamp of mutant vs. wild-type TRPM8

    PMID:33977138

    Open questions at the time
    • Single family studied; prevalence among trigeminal neuralgia patients unknown
    • Structural consequence of R30Q substitution not modeled
  15. 2022 High

    Multiple cryo-EM studies captured closed, intermediate, and open states of TRPM8, revealing two discrete agonist binding sites, a disordered-to-ordered S6 gate transition along the PIP₂/agonist gating pathway, and showing that Ca²⁺/icilin occupy the cytosol-facing VSLD cavity with minimal conformational change.

    Evidence Cryo-EM at 2.5–3.2 Å resolution with electrophysiological validation

    PMID:35662242 PMID:36227998

    Open questions at the time
    • Full open-state structure with PIP₂ simultaneously bound not obtained
    • Structural basis for temperature-induced gating transition not captured
  16. 2022 Medium

    LCK was identified as a direct TRPM8 kinase phosphorylating Y1022, which enhances channel multimerization and recruits 14-3-3ζ; phospho-Y1022 feeds back to inhibit LCK Tyr505 phosphorylation, establishing a reciprocal regulatory loop.

    Evidence Co-immunoprecipitation, patch-clamp, site-directed mutagenesis (Y1022F), western blot

    PMID:35665750

    Open questions at the time
    • In vivo significance of LCK–TRPM8 loop not demonstrated
    • Whether 14-3-3ζ binding alters TRPM8 trafficking or gating kinetics is unclear
  17. 2024 High

    Cryo-EM and functional studies demonstrated that TRPM8 inhibitors bind selectively to the desensitized state and that cold- and agonist-induced desensitization share overlapping structural mechanisms, unifying inhibition and desensitization pathways.

    Evidence Cryo-EM, electrophysiology, molecular dynamics simulations

    PMID:39093967

    Open questions at the time
    • Whether state-selective inhibitor design can achieve therapeutic selectivity in vivo is untested
    • Kinetics of closed-to-desensitized transitions under physiological conditions not measured
  18. 2024 Medium

    TRPM8 RNA packaged in extracellular vesicles was found to activate TLR3/NF-κB sterile inflammatory signaling in recipient epithelial cancer cells, revealing a non-channel, RNA-level function of the TRPM8 gene product.

    Evidence Extracellular vesicle isolation, TLR3/NF-κB reporter assays, xenograft models with translation-defective TRPM8 RNA

    PMID:38316991

    Open questions at the time
    • Whether TRPM8 RNA is selectively sorted into EVs is not established
    • Physiological relevance outside tumor xenograft context unknown
    • Whether other TRP channel mRNAs share this TLR3-activating property is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of temperature-induced conformational change at atomic resolution, the identity of kinases maintaining constitutive S29 phosphorylation, the structural determinants of the Rap1-binding interface, and whether the non-channel functions (Rap1 inhibition, NF-κB interaction, EV-RNA signaling) operate in physiological cold sensing or are context-restricted.
  • No cryo-EM structure capturing the temperature-induced gating transition
  • Kinase responsible for constitutive S29 phosphorylation unidentified
  • TRPM8–Rap1 binding interface not structurally mapped
  • Physiological integration of channel and non-channel functions not addressed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-9709957 Sensory Perception 3 R-HSA-112316 Neuronal System 1
Partners
ARGNAQLCKRAP1ASRCTCAF2YWHAZ

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 TRPM8 is directly gated by cold, menthol, and icilin in planar lipid bilayers, excluding cellular signaling pathways; PI(4,5)P2 is the prime factor impacting TRPM8 gating through direct specific interactions with the channel protein; menthol increases PI(4,5)P2 binding potency and channel activity; icilin activation depends on intracellular calcium; cold-activated TRPM8 exhibits steep temperature dependence (Q10 ~40) with large entropy and enthalpy changes. Reconstitution in planar lipid bilayers, patch-clamp, phosphoinositide binding assays, in vitro mutagenesis The Journal of neuroscience High 20844147
2009 TRPM8 channel protein forms a stable complex with inorganic polyphosphate (polyP) and poly-(R)-3-hydroxybutyrate (PHB); enzymatic breakdown of polyP by exopolyphosphatase inhibits TRPM8 channel activity both in cells and in purified channel reconstituted in planar lipid bilayers. Whole-cell patch-clamp, fluorescent calcium measurements, planar lipid bilayer reconstitution, biochemical co-purification PloS one High 19404398
2019 Cryo-EM structures of TRPM8 in ligand-free, antagonist-bound, and calcium-bound forms reveal a malleable ligand-binding pocket, two nonconducting states (closed and desensitized), direct calcium binding mediating stimulus-evoked desensitization, and large S4-S5 linker rearrangements repositioning S1-S4 and pore domains relative to the TRP helix. Cryo-electron microscopy structure determination Science High 31488702
2022 Cryo-EM structures of mouse TRPM8 in closed, intermediate, and open states reveal two discrete agonist binding sites, state-dependent gate rearrangements, and a disordered-to-ordered transition of the gate-forming S6 helix along the PIP2- and cooling agonist-dependent gating pathway. Cryo-electron microscopy, electrophysiology Science High 36227998
2022 Cryo-EM structures of mouse TRPM8 in ligand-free and Ca2+/icilin-bound forms at 2.5-3.2 Å resolution reveal a short but wide selectivity filter, canonical S4-S5 linker, and show that Ca2+ and icilin bind in the cytosolic-facing cavity of the voltage-sensing-like domain but induce little conformational change; all ligand-bound structures adopt the closed conformation. Cryo-electron microscopy Nature communications High 35662242
2023 Cryo-EM structure of human TRPM8 in closed state at 2.7 Å resolution reveals the most complete N-terminal pre-melastatin homology region model, lipid binding sites, and icilin binding mode; pore helix S6 register distinguishes closed, desensitized, and open states across TRPM structures. Cryo-electron microscopy, molecular modeling Communications biology High 37857704
2024 TRPM8 inhibitors bind selectively to the desensitized state of the channel; cold and cooling agonists share a common desensitization pathway; structural determinants for conformational change in TRPM8 desensitization were identified; overlapping mechanisms underlie desensitization and inhibition. Cryo-electron microscopy, electrophysiology, molecular dynamics simulations Science advances High 39093967
2007 Lysophospholipids (LPCs, LPI, LPS) raise the temperature threshold of TRPM8 activation toward normal body temperature, while polyunsaturated fatty acids (e.g., arachidonic acid) inhibit TRPM8 activation by cold, icilin, and menthol; iPLA2 inhibition abolishes cold and icilin responses but not menthol responses of TRPM8. Patch-clamp, calcium imaging in CHO cells and DRG neurons expressing TRPM8 The Journal of neuroscience High 17376995
2006 TRPM8 contains two essential cysteine residues flanking the N-linked glycosylation site at Asn-934 in the pore region; mutation of either cysteine abolishes channel function and produces a non-functional homodimer; Asn-934 is the glycosylated residue (complex carbohydrate); TRPM8 forms tetramers consistent with functional TRP channel architecture. Site-directed mutagenesis, SDS-PAGE, PFO-PAGE, calcium imaging The Journal of biological chemistry High 17015441
2017 TRPM8 acts as a Rap1 GTPase inhibitor through a non-channel, pore-independent function; TRPM8 retains Rap1 intracellularly via direct protein-protein interaction, preventing Rap1 cytoplasm-to-plasma membrane trafficking, thereby impairing integrin conformational activation and suppressing endothelial cell migration, tube formation, and spheroid sprouting. Co-immunoprecipitation, live imaging, dominant-negative/overexpression, migration assays, tube formation assays The Journal of cell biology High 28550110
2019 Activated androgen receptor (AR) interacts with TRPM8 within lipid raft microdomains of the plasma membrane; this AR-TRPM8 interaction inhibits TRPM8 channel activity and promotes prostate cancer cell migration. Co-immunoprecipitation, lipid raft fractionation, patch-clamp, migration assays Cell death & disease Medium 31501416
2020 Testosterone (TST) inhibits TRPM8-mediated cold perception through noncanonical engagement of androgen receptor (AR); AR is present on the cell surface and interacts with TRPM8 in response to TST; TST in nanomolar concentrations suppresses TRPM8 currents and single-channel activity in DRG neurons and HEK cells co-expressing TRPM8 and AR, but not TRPM8 alone. Patch-clamp, calcium imaging, biochemical assays, confocal imaging, behavioral testing in castrated rodents FASEB journal High 32277850
2019 Gαq binding reduces the apparent affinity of TRPM8 for PI(4,5)P2, sensitizing the channel to inhibition by PI(4,5)P2 depletion upon GPCR activation; constitutively active Gαq inhibits TRPM8 activity independent of PLC; supplementing PI(4,5)P2 via patch pipette reduces Gαq-coupled receptor-mediated TRPM8 inhibition in DRG neurons. Whole-cell patch-clamp, voltage-sensitive 5'-phosphatase, PI(4,5)P2 supplementation, calcium imaging in DRG neurons The Journal of neuroscience High 31127000
2013 Chloroquine inhibits TRPM8 in 48.8% of TRPM8-positive DRG neurons through direct action of activated Gαq independent of the phospholipase C pathway. Calcium imaging, pharmacological dissection in DRG neurons The Journal of biological chemistry Medium 23508958
2020 Temperature-dependent gating of TRPM8 is driven by a folding-unfolding reaction of the distal C-terminal domain (CTD); progressive deletion of the CTD reduces enthalpy change proportionally; deletion of the last 36 amino acids transforms TRPM8 into a reduced temperature-sensitivity channel (Q10 ~4); channel gating involves ~1,900 Å3 change in solute-inaccessible volume matching the coiled-coil void space in cryo-EM structure. Patch-clamp with progressive CTD deletions, denaturing agent experiments, osmoticant assays, structural analysis Proceedings of the National Academy of Sciences High 32747539
2019 TRPM8 is constitutively tyrosine phosphorylated by Src kinase; Src potentiates TRPM8 activity; Src inhibition with PP2 reduces TRPM8 tyrosine phosphorylation and cold-induced channel activation in HEK293T cells and native DRG neurons. Co-immunoprecipitation, western blot, calcium imaging, patch-clamp, RNA interference Journal of cellular physiology Medium 31729029
2021 Constitutive phosphorylation of serine residues (S26, S29, S541, S542) in the N-terminus of mouse TRPM8 negatively regulates channel activity; S29A mutation is sufficient to increase TRPM8 cold- and menthol-evoked responses by shifting the voltage activation curve to more negative potentials and increasing the number of active channels at the plasma membrane. Mass spectrometry, site-directed mutagenesis, calcium imaging, patch-clamp, TIRF microscopy The Journal of neuroscience High 34446569
2020 Chronic morphine activates MOR-PKCβ signaling to phosphorylate TRPM8 at two consensus sites (S1040 and S1041), reducing TRPM8 desensitization and sensitizing TRPM8 responsiveness to cold and menthol; site-directed mutation of S1040/S1041 prevents MOR-induced reduction in TRPM8 desensitization. Patch-clamp, calcium imaging, site-directed mutagenesis, pharmacological inhibition in DRG neurons and HEK cells Molecular brain High 32290846
2022 LCK (lymphocyte-specific protein tyrosine kinase) directly interacts with TRPM8 and phosphorylates it at Y1022, enhancing TRPM8 multimerization and channel current density; 14-3-3ζ also interacts with TRPM8 and promotes multimerization; LCK enhances 14-3-3ζ-TRPM8 binding; Y1022F mutation impairs TRPM8 multimerization and 14-3-3ζ binding; TRPM8 phospho-Y1022 feeds back to inhibit LCK Tyr505 phosphorylation. Co-immunoprecipitation, patch-clamp, mutagenesis, western blot, functional cancer cell assays Cell death & disease Medium 35665750
2017 TRPM8 interacts with NF-κB and suppresses NF-κB nuclear localization under cold stress, thereby inhibiting TNFα gene transcription in the mouse hypothalamus. Co-immunoprecipitation, nuclear fractionation, qRT-PCR, western blot Scientific reports Medium 28332601
2018 Tacrolimus (FK506) directly gates TRPM8 channels, sensitizing their response to cold by inducing a leftward shift in the voltage-dependent activation curve; this direct gating is demonstrated in purified TRPM8 reconstituted in lipid bilayers; tacrolimus acts independently of calcineurin/PLC signaling and binds at a different site from menthol (TRPM8-Y745H) or icilin (TRPM8-N799A). Lipid bilayer reconstitution, patch-clamp, calcium imaging, mutagenesis in DRG neurons and heterologous cells The Journal of neuroscience High 30545944
2021 TRPM8 gain-of-function mutation p.Arg30Gln (c.89 G>A) enhances channel activation, increases basal current amplitude and intracellular Ca2+, and augments menthol response, contributing to familial trigeminal neuralgia pathogenesis. Calcium imaging, whole-cell patch-clamp recording of mutant vs. wild-type TRPM8 Neurology. Genetics Medium 33977138
2017 TRPM8 is required for glioblastoma cell migration, DNA repair, and radioresistance; ionizing radiation activates and upregulates TRPM8-mediated Ca2+ signaling, which interferes with cell cycle control via CaMKII, cdc25C, and cdc2. RNA interference, patch-clamp, calcium imaging, colony formation, flow cytometry, immunoblot Oncotarget Medium 29221175
2017 TRPM8 channel activation by menthol in adipocytes induces UCP1 expression and WAT browning through Ca2+ influx and PKA activation; the menthol-induced thermogenic gene expression is blocked by PKA inhibitor KT5720 or calcium chelator BAPTA-AM. Pharmacological inhibition, mRNA/protein expression analysis, mouse dietary model Oncotarget Medium 29088850
2017 GFRα3 activation sensitizes and upregulates TRPM8 expression and plasma membrane trafficking in DRG neurons; GFRα3 knockdown reduces TRPM8 membrane trafficking and attenuates cold hyperalgesia in CCI rats; TRPM8 inhibition blocks GFRα3 agonist-induced cold hyperalgesia. siRNA knockdown, western blot, immunofluorescence, behavioral testing, TRPM8 antagonist Brain research bulletin Medium 28867384
2024 TRPM8 secreted RNA in extracellular vesicles (EVs) from prostate cells activates TLR3/NF-κB-mediated sterile inflammatory signaling after EV endocytosis by epithelial cancer cells; translation-defective TRPM8 RNA in xenografts reduces collagen I, increases NK cell infiltration, and expands necrotic areas. Extracellular vesicle isolation, TLR3/NF-κB reporter assays, xenograft models, immunohistology The EMBO journal Medium 38316991
2022 MHR1-3 domain of TRPM8 confers independent cold sensitivity and is required for pore domain regulation of cold activation; the pore domain underwent positive selection in terrestrial tetrapods; the mature MHR1-3 domain is necessary for pore domain regulatory mechanism in TRPM8 cold activation. Domain deletion/chimera analysis, electrophysiology, evolutionary analysis Proceedings of the National Academy of Sciences Medium 35594403
2023 TCAF2 (TRP channel-associated factor 2) inhibits TRPM8 expression and activity in tumor pericytes, leading to Wnt5a secretion that activates STAT3 signaling in tumor cells to facilitate EMT and colorectal cancer liver metastasis; TRPM8 agonist menthol suppresses Wnt5a secretion in pericytes. Gain/loss-of-function, pericyte conditional Tcaf2-KO mice, co-culture assays, proteomic analysis, signaling pathway analysis Advanced science Medium 37635201
2021 TRPM8 channel activation by menthol/icilin in esophageal cancer cells promotes PD-L1 expression via the calcineurin-NFATc3 pathway, leading to immune evasion by reducing CD8+ T cell cytotoxicity. Overexpression/siRNA knockdown, co-incubation assay with CD8+ T cells, reporter assays, western blot Bioscience reports Medium 31519770
2008 TRPM8-expressing DRG neurons constitute a specific functional subpopulation where virtually all EGFPf-positive neurons respond to cold and menthol; these neurons project to superficial layer I of the spinal cord with distinct termination patterns compared to peptidergic fibers, and form unique bush/cluster endings in the superficial epidermis. Knock-in reporter mouse (TRPM8-EGFPf), calcium imaging, anatomical tracing, immunohistochemistry The Journal of neuroscience High 18199758
2021 Chronic morphine treatment sensitizes TRPM8 to cold and menthol and reduces activation-evoked desensitization via PKCβ phosphorylation of S1040 and S1041; blocking PLC or PKCβ (but not PKA or ROCK) restores desensitization; TRPM8-expressing DRG neurons show hyperexcitability after sustained morphine treatment. Site-directed mutagenesis (S1040A/S1041A), patch-clamp, pharmacological inhibition, in vivo morphine treatment Molecular brain High 32290846

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Visualizing cold spots: TRPM8-expressing sensory neurons and their projections. The Journal of neuroscience : the official journal of the Society for Neuroscience 262 18199758
2004 Cool (TRPM8) and hot (TRPV1) receptors in the bladder and male genital tract. The Journal of urology 193 15311065
2007 Modulation of the cold-activated channel TRPM8 by lysophospholipids and polyunsaturated fatty acids. The Journal of neuroscience : the official journal of the Society for Neuroscience 147 17376995
2009 The contribution of TRPM8 and TRPA1 channels to cold allodynia and neuropathic pain. PloS one 140 19812688
2010 Gating of transient receptor potential melastatin 8 (TRPM8) channels activated by cold and chemical agonists in planar lipid bilayers. The Journal of neuroscience : the official journal of the Society for Neuroscience 134 20844147
2005 TRPM8 protein localization in trigeminal ganglion and taste papillae. Brain research. Molecular brain research 132 15893591
2019 Structural insights into TRPM8 inhibition and desensitization. Science (New York, N.Y.) 124 31488702
2007 Increased TRPA1, TRPM8, and TRPV2 expression in dorsal root ganglia by nerve injury. Biochemical and biophysical research communications 122 17517374
2009 Inorganic polyphosphate modulates TRPM8 channels. PloS one 121 19404398
2007 Characterisation of TRPM8 as a pharmacophore receptor. Cell calcium 108 17517434
2019 Recent Progress in TRPM8 Modulation: An Update. International journal of molecular sciences 93 31141957
2010 Estrogen regulation of TRPM8 expression in breast cancer cells. BMC cancer 84 20482834
2013 Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel-expressing sensory neurons by the pruritogen chloroquine. The Journal of biological chemistry 78 23508958
2020 TRPM8 channels: A review of distribution and clinical role. European journal of pharmacology 77 32610057
2017 Development of TRPM8 Antagonists to Treat Chronic Pain and Migraine. Pharmaceuticals (Basel, Switzerland) 74 28358322
2017 TRPM8 inhibits endothelial cell migration via a non-channel function by trapping the small GTPase Rap1. The Journal of cell biology 73 28550110
2016 TRPM8 and Migraine. Headache 73 27634619
2008 Increased transcription of cytokine genes in human lung epithelial cells through activation of a TRPM8 variant by cold temperatures. American journal of physiology. Lung cellular and molecular physiology 73 18441098
2015 Roles of TRPM8 Ion Channels in Cancer: Proliferation, Survival, and Invasion. Cancers 72 26512697
2009 Characterization of the decision network for wing expansion in Drosophila using targeted expression of the TRPM8 channel. The Journal of neuroscience : the official journal of the Society for Neuroscience 70 19295141
2014 TRPM8. Handbook of experimental pharmacology 69 24756721
2007 TRPM8. Handbook of experimental pharmacology 69 17217067
2022 Activation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIP2. Science (New York, N.Y.) 68 36227998
2018 TRPV1 and TRPM8 Channels and Nocifensive Behavior in a Rat Model for Dry Eye. Investigative ophthalmology & visual science 68 30046815
2012 Modulation of thermoreceptor TRPM8 by cooling compounds. ACS chemical neuroscience 67 22860192
2011 Scraping through the ice: uncovering the role of TRPM8 in cold transduction. American journal of physiology. Regulatory, integrative and comparative physiology 67 21411765
2017 Cooling Relief of Acute and Chronic Itch Requires TRPM8 Channels and Neurons. The Journal of investigative dermatology 66 29288650
2021 TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation. International journal of molecular sciences 64 34445208
2011 Regulation of TRPM8 channel activity. Molecular and cellular endocrinology 62 22061619
2015 Reciprocal effects of capsaicin and menthol on thermosensation through regulated activities of TRPV1 and TRPM8. The journal of physiological sciences : JPS 57 26645885
2017 Dietary menthol-induced TRPM8 activation enhances WAT "browning" and ameliorates diet-induced obesity. Oncotarget 54 29088850
2006 The cold and menthol receptor TRPM8 contains a functionally important double cysteine motif. The Journal of biological chemistry 53 17015441
2019 Expression of the cold thermoreceptor TRPM8 in rodent brain thermoregulatory circuits. The Journal of comparative neurology 52 30942489
2010 Design and optimization of benzimidazole-containing transient receptor potential melastatin 8 (TRPM8) antagonists. Journal of medicinal chemistry 52 21128593
2015 Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice. PloS one 50 26207981
2011 TRPM8 in health and disease: cold sensing and beyond. Advances in experimental medicine and biology 50 21290296
2013 The combination of TRPM8 and TRPA1 expression causes an invasive phenotype in lung cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 49 24037916
2013 Functional expression of TRPM8 and TRPA1 channels in rat odontoblasts. PloS one 49 24358160
2016 Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer. Journal of medicinal chemistry 48 27437828
2010 Distinct expression of cold receptors (TRPM8 and TRPA1) in the rat nodose-petrosal ganglion complex. Brain research 48 20079339
2017 A novel TRPM8 agonist relieves dry eye discomfort. BMC ophthalmology 45 28651550
2018 TRPM8 Channels and Dry Eye. Pharmaceuticals (Basel, Switzerland) 43 30445735
2008 Menthol regulates TRPM8-independent processes in PC-3 prostate cancer cells. Biochimica et biophysica acta 43 18955132
2012 TRPM7 and TRPM8 Ion Channels in Pancreatic Adenocarcinoma: Potential Roles as Cancer Biomarkers and Targets. Scientifica 42 24278689
2022 Structures of a mammalian TRPM8 in closed state. Nature communications 40 35662242
2018 The Immunosuppressant Macrolide Tacrolimus Activates Cold-Sensing TRPM8 Channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 40 30545944
2017 TRPM8 in the negative regulation of TNFα expression during cold stress. Scientific reports 40 28332601
2019 TRPM8-androgen receptor association within lipid rafts promotes prostate cancer cell migration. Cell death & disease 39 31501416
2014 Thyronamine induces TRPM8 channel activation in human conjunctival epithelial cells. Cellular signalling 38 25460045
2019 Reduced TRPM8 expression underpins reduced migraine risk and attenuated cold pain sensation in humans. Scientific reports 37 31873179
2018 Activation of TRPV1 and TRPM8 Channels in the Larynx and Associated Laryngopharyngeal Regions Facilitates the Swallowing Reflex. International journal of molecular sciences 37 30567389
2010 TRPM8 mediates cold and menthol allergies associated with mast cell activation. Cell calcium 37 20934218
2017 TRPM8 is required for survival and radioresistance of glioblastoma cells. Oncotarget 36 29221175
2017 Role of Transient Receptor Potential Channels Trpv1 and Trpm8 in Diabetic Peripheral Neuropathy. Journal of diabetes and treatment 34 30613832
2020 Current View of Ligand and Lipid Recognition by the Menthol Receptor TRPM8. Trends in biochemical sciences 32 32532587
2016 TRPM8 Ion Channels as Potential Cancer Biomarker and Target in Pancreatic Cancer. Advances in protein chemistry and structural biology 32 27038374
2021 Therapeutic potential of TRPM8 antagonists in prostate cancer. Scientific reports 31 34853378
2010 (-)-Menthylamine derivatives as potent and selective antagonists of transient receptor potential melastatin type-8 (TRPM8) channels. Bioorganic & medicinal chemistry letters 31 20378345
2009 Differentiation dependent expression of TRPA1 and TRPM8 channels in IMR-32 human neuroblastoma cells. Journal of cellular physiology 31 19507192
2018 Silencing of TRPM8 inhibits aggressive tumor phenotypes and enhances gemcitabine sensitivity in pancreatic cancer. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 29 30316690
2011 TRPM8 and dyspnea: from the frigid and fascinating past to the cool future? Current opinion in pharmacology 29 21723782
2023 Therapeutic potential of TRPM8 channels in cancer treatment. Frontiers in pharmacology 28 37033630
2017 Cold-sensing TRPM8 channel participates in circadian control of the brown adipose tissue. Biochimica et biophysica acta. Molecular cell research 28 28943398
2016 Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia. The journal of pain 28 27845197
2015 Identification of the cold receptor TRPM8 in the nasal mucosa. American journal of rhinology & allergy 28 26163239
2022 Activation of peripheral TRPM8 mitigates ischemic stroke by topically applied menthol. Journal of neuroinflammation 27 35897101
2021 Menthol to Induce Non-shivering Thermogenesis via TRPM8/PKA Signaling for Treatment of Obesity. Journal of obesity & metabolic syndrome 27 33071240
2019 TRPM8 facilitates proliferation and immune evasion of esophageal cancer cells. Bioscience reports 25 31519770
2016 TRPV1 and TRPM8 in Treatment of Chronic Cough. Pharmaceuticals (Basel, Switzerland) 25 27483288
2011 The emerging pharmacology of TRPM8 channels: hidden therapeutic potential underneath a cold surface. Current pharmaceutical biotechnology 25 20932258
2020 A folding reaction at the C-terminal domain drives temperature sensing in TRPM8 channels. Proceedings of the National Academy of Sciences of the United States of America 24 32747539
2018 TRPM8 and prostate: a cold case? Pflugers Archiv : European journal of physiology 24 29926226
2024 Mechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8. Science advances 23 39093967
2023 Structure of human TRPM8 channel. Communications biology 23 37857704
2022 The acquisition of cold sensitivity during TRPM8 ion channel evolution. Proceedings of the National Academy of Sciences of the United States of America 23 35594403
2020 Testosterone-androgen receptor: The steroid link inhibiting TRPM8-mediated cold sensitivity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 32277850
2023 Human Osteoarthritic Chondrocytes Express Nineteen Different TRP-Genes-TRPA1 and TRPM8 as Potential Drug Targets. International journal of molecular sciences 22 37373205
2023 TCAF2 in Pericytes Promotes Colorectal Cancer Liver Metastasis via Inhibiting Cold-Sensing TRPM8 Channel. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 22 37635201
2022 AMTB, a TRPM8 antagonist, suppresses growth and metastasis of osteosarcoma through repressing the TGFβ signaling pathway. Cell death & disease 22 35361751
2020 The cool things to know about TRPM8! Channels (Austin, Tex.) 22 33147416
2021 Trigeminal Neuralgia TRPM8 Mutation: Enhanced Activation, Basal [Ca2+]i and Menthol Response. Neurology. Genetics 21 33977138
2019 Gαq Sensitizes TRPM8 to Inhibition by PI(4,5)P2 Depletion upon Receptor Activation. The Journal of neuroscience : the official journal of the Society for Neuroscience 21 31127000
2016 Activation of Cold-Sensitive Channels TRPM8 and TRPA1 Inhibits the Proliferative Airway Smooth Muscle Cell Phenotype. Lung 21 27236325
2020 TRPM8 channel augments T-cell activation and proliferation. Cell biology international 20 33090595
2009 Comparative effects of heterologous TRPV1 and TRPM8 expression in rat hippocampal neurons. PloS one 20 19997638
2022 TRPM8 as an Anti-Tumoral Target in Prostate Cancer Growth and Metastasis Dissemination. International journal of molecular sciences 19 35743115
2015 Function and postnatal changes of dural afferent fibers expressing TRPM8 channels. Molecular pain 19 26111800
2014 Menthol inhibits detrusor contractility independently of TRPM8 activation. PloS one 19 25375115
2024 Sterile inflammation via TRPM8 RNA-dependent TLR3-NF-kB/IRF3 activation promotes antitumor immunity in prostate cancer. The EMBO journal 18 38316991
2019 Regulation of TRPM8 channel activity by Src-mediated tyrosine phosphorylation. Journal of cellular physiology 18 31729029
2024 Roles of Thermosensitive Transient Receptor Channels TRPV1 and TRPM8 in Paclitaxel-Induced Peripheral Neuropathic Pain. International journal of molecular sciences 17 38892000
2022 Both heat-sensitive TRPV4 and cold-sensitive TRPM8 ion channels regulate microglial activity. Biochemical and biophysical research communications 17 35489198
2021 Oxaliplatin Causes Transient Changes in TRPM8 Channel Activity. International journal of molecular sciences 17 34066977
2021 Constitutive Phosphorylation as a Key Regulator of TRPM8 Channel Function. The Journal of neuroscience : the official journal of the Society for Neuroscience 17 34446569
2020 Chronic morphine regulates TRPM8 channels via MOR-PKCβ signaling. Molecular brain 17 32290846
2020 TRPM8 Inhibition Regulates the Proliferation, Migration and ROS Metabolism of Bladder Cancer Cells. OncoTargets and therapy 17 32943886
2017 High-throughput proteome analysis reveals targeted TRPM8 degradation in prostate cancer. Oncotarget 17 28039451
2022 The LCK-14-3-3ζ-TRPM8 axis regulates TRPM8 function/assembly and promotes pancreatic cancer malignancy. Cell death & disease 16 35665750
2019 Pharmacological inhibition of TRPM8-induced gene transcription. Biochemical pharmacology 16 31654626
2017 Downregulations of TRPM8 expression and membrane trafficking in dorsal root ganglion mediate the attenuation of cold hyperalgesia in CCI rats induced by GFRα3 knockdown. Brain research bulletin 16 28867384