Affinage

TRPM8

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

Length
1104 aa
Mass
127.7 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRPM8 is a Ca2+-permeable, tetrameric non-selective cation channel that serves as the principal molecular sensor for cold and chemical cooling agents such as menthol and icilin (PMID:36227998, PMID:17015441). Cryo-EM structures resolved across closed, open, and desensitized states show that cooling compounds and PIP2 occupy two discrete agonist sites within a malleable cytosolic-facing cavity of the voltage-sensing-like domain, with PIP2 acting as an obligate allosteric co-activator and a disordered-to-ordered transition of the gate-forming S6 helix underlying channel opening (PMID:36227998, PMID:35662242). A short, wide selectivity filter accounts for Ca2+ permeability, and direct Ca2+ binding drives stimulus-evoked desensitization—a conformational pathway shared by cold, cooling agonists, and inhibitors, which bind selectively to the desensitized state (PMID:31488702, PMID:35662242, PMID:39093967). An evolutionarily acquired MHR1-3 region within the N-terminus is required to confer cold sensitivity to the pore domain (PMID:35594403). Channel activity is tuned by a dense regulatory network: constitutive N-terminal phosphorylation at S29 negatively regulates gating (PMID:34446569), Src- and LCK-mediated tyrosine phosphorylation (the latter at Y1022, promoting 14-3-3ζ–dependent multimerization) potentiate activity (PMID:31729029, PMID:35665750), MOR-PKCβ phosphorylation at S1040/S1041 reduces desensitization to drive opioid-induced cold hypersensitivity (PMID:32290846), and PLC-mediated PIP2 depletion and direct Gαq binding inhibit the channel (PMID:23508958, PMID:34066977). Plasma-membrane channel density is dynamically set by agonist-evoked vesicular recruitment and by PSA/bradykinin-2-receptor signaling (PMID:20531306, PMID:25589752), while testosterone both directly gates purified TRPM8 and, via non-genomic engagement of the androgen receptor in lipid rafts, inhibits it to modulate cold perception and tumor cell migration (PMID:25480785, PMID:31501416, PMID:32277850). Beyond sensory neurons, TRPM8 functions in Merkel cells, mast cells, prostate epithelium, mitochondria-associated ER membranes (as a 4TM ER Ca2+-release isoform), and the circadian system, and contributes to itch suppression, anti-tumor signaling through Cdc42/Rac1/ERK/FAK inhibition, and inflammatory modulation (PMID:32277850, PMID:29288650, PMID:29678654, PMID:35743115, PMID:29138055, PMID:36251565). A gain-of-function variant p.Arg30Gln links TRPM8 to trigeminal neuralgia (PMID:33977138).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2006 High

    Established the oligomeric architecture and post-translational requirements of the channel by showing that TRPM8 assembles as a tetramer and depends on a pore-region glycosylation and a double-cysteine motif for function.

    Evidence Site-directed mutagenesis of glycosylation and cysteine residues with PFO-PAGE oligomer analysis and calcium imaging in heterologous cells

    PMID:17015441

    Open questions at the time
    • Did not resolve the gating mechanism or ligand-binding sites
    • Functional role of glycosylation in trafficking versus gating unclear
  2. 2009 High

    Identified an endogenous cofactor requirement beyond protein structure by showing inorganic polyphosphate forms a stable complex with TRPM8 and is needed alongside PIP2 for activity.

    Evidence Planar lipid bilayer reconstitution of purified channel, patch-clamp, calcium imaging, and biochemical co-purification with polyP degradation by scPPX1

    PMID:19404398

    Open questions at the time
    • polyP binding site on TRPM8 not mapped
    • Physiological regulation of polyP levels in sensory neurons unknown
  3. 2010 Medium

    Connected TRPM8 surface density to extracellular protease signaling, showing PSA increases functional plasma-membrane channels via the bradykinin 2 receptor and reduces prostate cancer cell motility.

    Evidence Electrophysiology, calcium imaging, cell-surface biotinylation, and migration assays in PC3 cells

    PMID:20531306

    Open questions at the time
    • Trafficking machinery linking BK2R signaling to TRPM8 insertion not defined
    • Single cell-line context
  4. 2014 High

    Revealed a steroid-gating mechanism by demonstrating testosterone directly and physically binds purified TRPM8 to activate it at picomolar concentrations, independent of transcription.

    Evidence Planar lipid bilayer electrophysiology with purified protein, co-immunoprecipitation, immunohistochemistry, and patch-clamp across prostate, DRG, and HEK cells

    PMID:25480783 PMID:25480785

    Open questions at the time
    • Testosterone binding site on the channel not structurally resolved
    • Reconciliation with later AR-dependent inhibition unaddressed at this stage
  5. 2017 Medium

    Distinguished a PLC-independent inhibitory input by showing activated Gαq directly inhibits TRPM8, separating it from the canonical PLC-PKC sensitization of TRPV1.

    Evidence Calcium imaging of DRG neurons with pharmacological pathway dissection of chloroquine/MrgprA3 signaling

    PMID:23508958

    Open questions at the time
    • Gαq interaction interface on TRPM8 not mapped
    • No direct biochemical demonstration of Gαq–TRPM8 binding
  6. 2018 Medium

    Expanded TRPM8 function to intracellular Ca2+ handling by identifying a 4TM isoform that acts as an ER Ca2+-release channel at mitochondria-associated membranes.

    Evidence Subcellular fractionation, ER membrane electrophysiology, Ca2+ imaging, and co-localization

    PMID:29678654

    Open questions at the time
    • Regulation and gating of the 4TM isoform distinct from full-length channel unresolved
    • Single-lab finding
  7. 2019 High

    Defined the structural basis of gating states and Ca2+-driven desensitization through cryo-EM of ligand-free, antagonist-bound, and Ca2+-bound TRPM8.

    Evidence Cryo-EM in multiple conformational states identifying a malleable ligand pocket, pore lipid contributions, and the Ca2+-binding desensitization site

    PMID:31488702

    Open questions at the time
    • Open-state conformation not captured in this study
    • PIP2 co-activation mechanism not yet resolved structurally
  8. 2019 Medium

    Identified tyrosine-phosphorylation as a positive regulatory input by showing Src constitutively phosphorylates TRPM8 to potentiate cold-evoked activity.

    Evidence Patch-clamp, calcium imaging, immunoprecipitation, RNAi, and PP2 inhibition in HEK293T and rat DRG neurons

    PMID:31729029

    Open questions at the time
    • Specific Src target tyrosine not identified
    • Reciprocal effect on desensitization untested
  9. 2020 High

    Resolved the testosterone-androgen receptor paradox by showing nanomolar testosterone inhibits TRPM8 through non-canonical surface AR binding, modulating cold perception in vivo.

    Evidence Whole-cell and single-channel patch-clamp, behavioral cold assays after castration, and biochemical/imaging analysis in DRG neurons and HEK cells

    PMID:32277850

    Open questions at the time
    • Mechanistic relationship between direct testosterone gating and AR-mediated inhibition not unified
    • AR-TRPM8 interaction interface unmapped
  10. 2020 High

    Pinpointed phosphorylation sites controlling desensitization, showing MOR-PKCβ phosphorylation at S1040/S1041 reduces desensitization to produce opioid-induced cold hypersensitivity.

    Evidence Site-directed mutagenesis, patch-clamp, calcium imaging, PLC/PKCβ/PKA pharmacology, and behavioral assays

    PMID:32290846

    Open questions at the time
    • Structural effect of S1040/S1041 phosphorylation on the desensitization conformation unknown
    • Whether PKCβ phosphorylates the channel directly versus via intermediates not fully resolved
  11. 2021 High

    Established constitutive negative regulation by mapping basal serine phosphorylation, with S29 dephosphorylation shifting voltage activation and increasing surface channel number.

    Evidence Mass spectrometry, S29A mutagenesis, patch-clamp, calcium imaging, TIRF microscopy, and mathematical modeling

    PMID:34446569

    Open questions at the time
    • Kinase responsible for constitutive S29 phosphorylation not identified
    • Roles of S26/S541/S542 phosphosites undefined
  12. 2021 Medium

    Linked TRPM8 to human disease by demonstrating the trigeminal-neuralgia variant p.Arg30Gln is gain-of-function, enhancing activation and basal Ca2+.

    Evidence Whole-cell patch-clamp and calcium imaging of the mutant channel

    PMID:33977138

    Open questions at the time
    • In vivo pathogenic mechanism in neurons not established
    • Single variant in a single study
  13. 2022 High

    Captured the activation transition structurally, revealing dual cooling-agonist and PIP2 sites and an S6 disordered-to-ordered transition as the gating mechanism.

    Evidence Cryo-EM of mouse TRPM8 in closed, intermediate, and open states with electrophysiology and MD simulations

    PMID:35662242 PMID:36227998

    Open questions at the time
    • How cold (versus chemical agonists) couples to the same gate not resolved structurally
    • Lipid identity at pore not fully assigned
  14. 2022 Medium

    Identified LCK as a tyrosine kinase that drives multimerization, phosphorylating Y1022 to promote 14-3-3ζ binding and increase current density, with feedback inhibition of LCK.

    Evidence Co-immunoprecipitation, Y1022F mutagenesis, patch-clamp, calcium imaging, and knockdown

    PMID:35665750

    Open questions at the time
    • Physiological context where LCK regulates TRPM8 in sensory tissue unclear
    • Structural basis of multimerization enhancement not resolved
  15. 2022 Medium

    Defined the evolutionary determinant of cold sensing, showing the MHR1-3 domain is necessary to confer pore-domain cold activation across tetrapod orthologs.

    Evidence Domain-swapping electrophysiology across vertebrate TRPM8 orthologs

    PMID:35594403

    Open questions at the time
    • Molecular contacts coupling MHR1-3 to the pore not defined
    • Mechanism by which positive selection altered pore efficacy unresolved
  16. 2024 High

    Unified desensitization and pharmacology by showing inhibitors bind selectively to the desensitized state and that cold and cooling agonists share a common desensitization pathway.

    Evidence Cryo-EM, whole-cell electrophysiology, and MD simulations defining desensitization-state structural determinants

    PMID:39093967

    Open questions at the time
    • Whether all clinical antagonists share this binding mode untested
    • Kinetics of state transitions in native neurons not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse non-neuronal and oncologic roles of TRPM8 — its 4TM ER isoform, extracellular-vesicle RNA-dependent signaling, circadian regulation, and Cdc42/Rac1/ERK/FAK-mediated anti-migratory function — are mechanistically coupled to its canonical channel gating remains unresolved.
  • No structural or biochemical link between channel conformational states and downstream oncogenic signaling
  • Regulation of isoform choice and tissue-specific expression undefined
  • Causal mechanism of RNA-dependent extracellular function not reconciled with channel function

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0008289 lipid binding 2 GO:0140299 molecular sensor activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-9909396 Circadian clock 1
Partners
14-3-3 ZETAARGAQLCKNF-KBSRCTCAF2

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 Cryo-EM structures of TRPM8 in ligand-free, antagonist-bound, and calcium-bound forms revealed two non-conducting states (closed and desensitized), a malleable ligand-binding pocket accommodating diverse drug structures, the ion permeation pathway including lipid contributions to pore architecture, and direct calcium binding as the mechanism of stimulus-evoked desensitization. Large S4-S5 linker rearrangements reposition the S1-S4 and pore domains relative to the TRP helix. Cryo-electron microscopy with multiple conformational states Science High 31488702
2022 Cryo-EM structures of mouse TRPM8 in closed, intermediate, and open states revealed two discrete agonist-binding sites for cooling compounds and PIP2, state-dependent rearrangements in gate positions, and a disordered-to-ordered transition of the gate-forming S6 helix as the molecular basis of chemically induced cool sensation. PIP2 acts as an allosteric co-activator required together with cooling agonists for channel opening. Cryo-electron microscopy, electrophysiology, molecular dynamics simulations Science High 36227998
2022 Cryo-EM structures of mouse TRPM8 at 2.5–3.2 Å in ligand-free state and in presence of Ca2+ and icilin revealed full-length architecture with canonical S4-S5 linker, a short but wide selectivity filter accounting for Ca2+ permeability, and that Ca2+ and icilin bind in the cytosolic-facing cavity of the voltage-sensing-like domain but induce little conformational change in the closed state. Cryo-electron microscopy at 2.5–3.2 Å resolution Nature Communications High 35662242
2023 Cryo-EM structure of human TRPM8 at 2.7 Å resolution in closed state defined the most complete N-terminal pre-melastatin homology region model, visualized bound lipids, modeled icilin interaction, and revealed that S6 helix register distinguishes closed, desensitized, and open state conformations across TRPM structures. Cryo-electron microscopy at 2.7 Å resolution Communications Biology High 37857704
2024 Cryo-EM, electrophysiology, and molecular dynamics simulations showed that TRPM8 inhibitors bind selectively to the desensitized state of the channel, that cold and cooling agonists share a common desensitization pathway, and identified structural determinants crucial for the conformational change in TRPM8 desensitization, revealing overlapping mechanisms of desensitization and pharmacological inhibition. Cryo-electron microscopy, whole-cell electrophysiology, molecular dynamics simulations Science Advances High 39093967
2009 Inorganic polyphosphate (polyP) forms a stable complex with the TRPM8 protein, and enzymatic degradation of polyP by exopolyphosphatase (scPPX1) inhibits TRPM8 channel activity. This was demonstrated in whole-cell patch-clamp, fluorescent calcium measurements, and in purified TRPM8 channels reconstituted into planar lipid bilayers where cold- and menthol-activated activity required PIP2 and was blocked by scPPX1. Poly-(R)-3-hydroxybutyrate (PHB) was also found associated with TRPM8. Whole-cell patch-clamp, calcium imaging, planar lipid bilayer reconstitution, biochemical co-purification PLoS ONE High 19404398
2014 Testosterone directly activates purified TRPM8 channels at picomolar concentrations in planar lipid bilayers, demonstrating an ionotropic (non-genomic) mechanism. Testosterone-induced TRPM8 responses were confirmed in primary human prostate cells, PC3 cancer cells, DRG neurons, and hippocampal neurons, and were blocked by the TRPM8 antagonist AMTB. Planar lipid bilayer electrophysiology with purified TRPM8 protein, calcium imaging, whole-cell patch-clamp Journal of Biological Chemistry High 25480785
2014 Testosterone physically binds to the TRPM8 protein, demonstrated by co-immunoprecipitation of endogenous testosterone with TRPM8 in prostate epithelial cells, prostate cancer cells, and HEK-293 cells stably expressing TRPM8. Immunohistochemistry showed intensive co-localization of TRPM8 protein with endogenous androgens in human prostate tissues. Co-immunoprecipitation, immunohistochemistry, calcium imaging, patch-clamp Journal of Biological Chemistry Medium 25480783
2006 TRPM8 is glycosylated at Asn-934 (pore region) but not Asn-821; mutation of either of two flanking cysteine residues abolishes channel function and forces formation of a non-functional homodimer; the double-cysteine motif is essential for function. TRPM8 forms tetramers (as well as dimer and trimer forms) consistent with tetrameric TRP channel structure. Site-directed mutagenesis, calcium imaging, Perfluoro-octanoic acid-PAGE, N-glycosylation site mutagenesis Journal of Biological Chemistry High 17015441
2010 PSA (prostate-specific antigen) activates TRPM8-mediated current via the bradykinin 2 receptor signaling pathway, and this activation increases the number of functional TRPM8 channels on the plasma membrane (demonstrated by cell-surface biotinylation). TRPM8 activation by PSA reduced motility of PC3 prostate cancer cells. Electrophysiology, calcium imaging, cell-surface biotinylation, wound-healing and migration assays Oncogene Medium 20531306
2019 Activated androgen receptor (AR) inhibits TRPM8 channel activity by direct interaction within lipid raft microdomains of the plasma membrane, providing a nongenomic mechanism by which androgens suppress TRPM8-mediated anti-migratory function in prostate cancer cells. Patch-clamp, confocal imaging of lipid rafts, co-immunoprecipitation, migration assays Cell Death & Disease Medium 31501416
2020 Testosterone inhibits TRPM8-mediated cold perception through non-canonical engagement of the androgen receptor (AR). Nanomolar testosterone suppresses TRPM8 currents and single-channel activity in DRG neurons and HEK293 cells co-expressing TRPM8 and AR, but not TRPM8 alone. AR is present on the cell surface and interacts with TRPM8 in response to testosterone, leading to channel inhibition. Castration increases cold sensitivity dependently on TRPM8 and AR. Whole-cell patch-clamp, single-channel recording, behavioral cold sensitivity assays, biochemical assays, confocal imaging FASEB Journal High 32277850
2020 Chronic morphine treatment sensitizes TRPM8 to cold and menthol via mu-opioid receptor (MOR)-PKCβ signaling. PKCβ-mediated phosphorylation at S1040 and S1041 on TRPM8 reduces activation-evoked desensitization. Site-directed mutation of S1040/S1041 prevented MOR-induced reduction in TRPM8 desensitization, identifying these residues as the molecular basis of opioid-induced cold hypersensitivity. Site-directed mutagenesis, whole-cell patch-clamp, calcium imaging, pharmacological inhibition of PLC/PKCβ/PKA, behavioral assays Molecular Brain High 32290846
2021 Constitutive phosphorylation of TRPM8 at serine 29 (S29) within the N-terminal domain negatively regulates channel activity. Mass spectrometry identified four constitutively phosphorylated serines (S26, S29, S541, S542). S29A mutation alone increases TRPM8 activity by shifting the voltage activation curve toward 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, mathematical modeling Journal of Neuroscience High 34446569
2019 Src kinase constitutively tyrosine-phosphorylates TRPM8 in HEK293T cells, potentiating channel activity. Selective Src inhibition with PP2 reduces TRPM8 tyrosine phosphorylation and cold-induced channel activation. RNA interference against Src diminished PP2-induced TRPM8 downregulation. This positive modulation by Src was confirmed in cultured rat DRG neurons. Whole-cell patch-clamp, calcium imaging, immunoprecipitation, RNA interference, pharmacological inhibition Journal of Cellular Physiology Medium 31729029
2022 LCK tyrosine kinase directly interacts with TRPM8 and phosphorylates it at Y1022, enhancing TRPM8 multimerization and increasing channel current densities. 14-3-3ζ also interacts with TRPM8 and promotes multimerization; LCK enhances 14-3-3ζ–TRPM8 binding in a Y1022-dependent manner. TRPM8-Y1022F mutation impairs multimerization and 14-3-3ζ binding. Phospho-Y1022 feedback inhibits LCK by affecting Tyr505 phosphorylation. Co-immunoprecipitation, site-directed mutagenesis, patch-clamp, calcium imaging, knockdown experiments Cell Death & Disease Medium 35665750
2018 Tacrolimus (FK506) directly activates TRPM8 channels in different species including humans, inducing a leftward shift in the voltage-dependent activation curve. The direct gating effect was demonstrated on purified TRPM8 in lipid bilayers. Cyclosporine (which shares calcineurin inhibition) had no effect, ruling out the calcineurin pathway. Tacrolimus activates menthol-insensitive (Y745H) and icilin-insensitive (N799A) TRPM8 mutants, suggesting a distinct binding site. Planar lipid bilayer electrophysiology with purified TRPM8, calcium imaging, patch-clamp, TRPM8 mutant channels, in vivo cold behavioral assays Journal of Neuroscience High 30545944
2017 TRPM8 inhibition by activated Gαq is caused by a direct action independent of the phospholipase C pathway. Chloroquine (pruritogen acting via MrgprA3) inhibits TRPM8 activity in DRG neurons through activated Gαq, distinct from the PLC-PKC pathway by which it sensitizes TRPV1. Calcium imaging of DRG neurons, pharmacological pathway dissection Journal of Biological Chemistry Medium 23508958
2015 TRPM8 channel expression at the plasma membrane is dynamically modulated by agonist activation. Activation of TRPM8 induces short-lived recruitment of a TRPM8-containing vesicular pool to the cell surface, transiently increasing the number of functional channels. Intact vesicular trafficking was required to support sustained cold responses in mouse skin. Live-cell imaging, TIRF microscopy, vesicle trafficking assays, in vivo skin cold response measurements in mice Journal of Neuroscience Medium 25589752
2017 Cooling inhibits both histaminergic and non-histaminergic itch pathways, and this anti-pruritic effect requires functional TRPM8 channels or intact TRPM8-expressing afferent neurons. Menthol-induced itch relief is also TRPM8-dependent, demonstrated by pharmacologic blockade, genetic knockout, and ablation of TRPM8-expressing neurons. Behavioral assays, pharmacological TRPM8 blockade, TRPM8 knockout mice, ablation of TRPM8-expressing neurons Journal of Investigative Dermatology High 29288650
2017 TRPM8 activation by cold stress suppresses TNFα expression via NF-κB. Cold-induced TRPM8 expression promotes physical interaction between TRPM8 and NF-κB, suppressing NF-κB nuclear localization and thereby inhibiting TNFα gene transcription. Co-immunoprecipitation, immunofluorescence for NF-κB nuclear localization, qRT-PCR, mouse cold stress model Scientific Reports Medium 28332601
2018 4-transmembrane domain TRPM8 isoforms (4TM-TRPM8) localize to mitochondria-associated ER membranes (MAMs), form functional ER Ca2+ release channels, and regulate steady-state Ca2+ concentrations in mitochondria and the ER, distinct from classical IP3R and RyR Ca2+ release channels. Subcellular fractionation, electrophysiology of ER membranes, Ca2+ imaging, immunofluorescence co-localization Biochimica et Biophysica Acta - Molecular Cell Research Medium 29678654
2010 TRPM8 mediates cold- and menthol-induced histamine release from mast cells (RBL-2H3). Menthol or cold exposure induced Ca2+ influx and histamine release that were reversed by TRPM8 blocker or siRNA knockdown of TRPM8. Subcutaneous menthol injection evoked scratching behavior reversed by TRPM8 blockade. Calcium imaging, histamine release assay, siRNA knockdown, in vivo behavioral assay Cell Calcium Medium 20934218
2019 TRPM8 activation by menthol in esophageal cancer cells leads to PD-L1 upregulation via the calcineurin-NFATc3 signaling pathway, promoting immune evasion from CD8+ T cell cytotoxicity. Co-culture cytotoxicity assay, reporter assays, pathway inhibition, overexpression/agonist experiments Bioscience Reports Low 31519770
2022 TRPM8 overexpression inhibits prostate cancer tumor growth and metastasis dissemination in an orthotopic xenograft mouse model. Mechanistically, TRPM8 impairs cytoskeleton dynamics and focal adhesion formation via inhibition of Cdc42, Rac1, ERK, and FAK signaling pathways. Orthotopic xenograft mouse model, in vitro migration/invasion assays, signaling pathway analysis, lipid nanocapsule WS12 delivery International Journal of Molecular Sciences Medium 35743115
2021 Trigeminal neuralgia-associated TRPM8 variant p.Arg30Gln (c.89G>A) causes gain-of-function, enhancing channel activation, increasing basal current amplitude, elevating basal intracellular Ca2+, and enhancing menthol response, demonstrating that gain-of-function TRPM8 mutation contributes to trigeminal neuralgia pathogenesis. Calcium imaging, whole-cell patch-clamp recording of mutant channel Neurology: Genetics Medium 33977138
2022 Activation of peripheral TRPM8 by topical menthol applied to paw dermis attenuates ischemic stroke infarct volume and sensorimotor deficits in mice. TRPM8 knockout or antagonism abolished neuroprotection. Benefits required peripheral nerve conduction; oral menthol was ineffective, and TRPM8 expression was higher in paw skin than back skin. MCAO stroke model, TRPM8 knockout mice, TRPM8 antagonist, nerve block, immunohistochemistry, behavioral assessment Journal of Neuroinflammation Medium 35897101
2022 MHR1-3 domain confers cold sensitivity in TRPM8; this domain is absent in fish TRPM8 (cold-insensitive) but present in amphibian/reptile TRPM8. Positive selection in the pore domain tuned cold activation efficacy in advanced terrestrial tetrapods. The MHR1-3 domain is necessary for the regulatory mechanism of the pore domain in cold activation. Functional characterization of vertebrate TRPM8 orthologs, domain swapping, electrophysiology PNAS Medium 35594403
2017 Merkel cells express functional TRPM8 channels that respond to cold temperature and TRPM8 agonists with intracellular Ca2+ increases and inward currents. In TRPM8 knockout mice, cold-induced Ca2+ responses in Merkel cells are absent. Cooling mouse skin to 22°C reduced slow adapting type 1 (SAT1) receptor discharge frequency in wild-type but not TRPM8 KO mice, demonstrating TRPM8-dependent modulation of mechanoreceptor function. Calcium imaging, patch-clamp in isolated Merkel cells, TRPM8 KO mice, in vivo single-unit electrophysiology Journal of Investigative Dermatology Medium 29138055
2023 TRPM8 TCAF2-dependent inhibition of TRPM8 in pericytes promotes Wnt5a secretion, which activates STAT3 signaling in tumor cells to facilitate epithelial-mesenchymal transition and colorectal cancer liver metastasis. TRPM8 agonist menthol suppresses Wnt5a secretion in pericytes and CRCLM. Gain/loss-of-function experiments, pericyte-conditional Tcaf2-knockout mice, proteomic analysis, in vivo metastasis models Advanced Science Medium 37635201
2024 Prostate cells secrete TRPM8 RNA into extracellular vesicles (EVs); after EV endocytosis by epithelial cancer cells, TRPM8 RNA primes TLR3/NF-κB-mediated inflammatory signaling. A translation-defective form of TRPM8 RNA in prostate cancer xenografts reduces collagen type I, increases NK cell infiltration, and enlarges necrotic areas, demonstrating an RNA-dependent pro-inflammatory/anti-tumor role. Extracellular vesicle isolation, TLR3/NF-κB reporter assays, xenograft mouse model with translation-defective TRPM8 RNA EMBO Journal Medium 38316991
2019 TRPM8 mediates hyperosmotic stimuli-evoked Ca2+ responses in dental primary afferent (DPA) neurons. Selective TRPM8 antagonist AMTB abolished hyperosmolar sucrose-induced Ca2+ transients in trigeminal ganglion neurons and significantly reduced c-fos expression in the spinal trigeminal nucleus (Vi/Vc) after hyperosmolar stimulation of exposed dentin, identifying TRPM8 as a hyperosmosensor in dental afferents. Calcium imaging with antagonist, immunohistochemistry, c-fos mRNA/protein quantification, retrograde tracing Journal of Dental Research Medium 31718465
2021 Oxaliplatin treatment causes transient activation of TRPM8 (at 1 h) followed by desensitization (at 24 h) via activation of the phospholipase C (PLC) pathway and depletion of PIP2. PLC pathway inhibition reverses decreased TRPM8 activity and PIP2 depletion after oxaliplatin. Calcium imaging, patch-clamp, PIP2 measurement, pharmacological PLC inhibition International Journal of Molecular Sciences Medium 34066977
2022 TRPM8 is expressed in retinal cholinergic amacrine interneurons and melanopsin-positive ganglion cells that project to the suprachiasmatic nucleus (SCN). TRPM8-deficient mice show increased Per2 and vasopressin (AVP) expression in the SCN, increased amplitude of body temperature oscillations, and dysregulated peripheral clock gene (Per2) expression in liver and white adipose tissue, establishing TRPM8 as a regulator of circadian clock function. TRPM8 reporter mouse lines, TRPM8 KO mice, in situ hybridization, RT-qPCR, immunofluorescence, telemetric body temperature recording Acta Physiologica Medium 36251565
2023 TRPM8 knockdown in pancreatic cancer cells reduces proliferation and invasion, increases gemcitabine sensitivity, reduces multidrug resistance protein expression (P-gp, MRP-2, LRP), increases hENT1 levels, increases Bax/Bcl-2 ratio, and decreases RRM1. Ca2+ influx through TRPM8 was demonstrated in PC cell lines PANC-1 and BxPC-3. RNA interference, Ca2+ imaging, Western blot of drug resistance proteins, cell proliferation and invasion assays Pancreatology Low 30316690
2019 TRPM8 activation inhibits TRPV1 activity in cultured DRG neurons, especially in paclitaxel-treated cells; menthol application reduces capsaicin-evoked TRPV1 responses, suggesting a cross-inhibitory interaction. TRPM8 protein expression and activity decrease in DRG neurons from paclitaxel-treated rats, contributing to paclitaxel-induced neuropathic pain. Calcium imaging, Western blotting, immunofluorescence, behavioral assays International Journal of Molecular Sciences Low 38892000
2019 TRPM8 activation leads to AP-1 transcriptional activation via ERK1/2, dependent on Ca2+ influx. Pharmacological inhibition with PD98059 (MEK/ERK inhibitor) blocked TRPM8-induced AP-1 activation. The TRPM8-specific antagonist RQ-00203078 selectively blocked TRPM8-mediated AP-1 activation without affecting other Ca2+ channels. AP-1 reporter gene assays, pharmacological pathway inhibition, calcium channel specificity testing Biochemical Pharmacology Low 31654626

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 266 18199758
2005 How cold is it? TRPM8 and TRPA1 in the molecular logic of cold sensation. Molecular pain 204 15847696
2004 Cool (TRPM8) and hot (TRPV1) receptors in the bladder and male genital tract. The Journal of urology 194 15311065
2009 The contribution of TRPM8 and TRPA1 channels to cold allodynia and neuropathic pain. PloS one 142 19812688
2006 Cool and menthol receptor TRPM8 in human urinary bladder disorders and clinical correlations. BMC urology 133 16519806
2005 TRPM8 protein localization in trigeminal ganglion and taste papillae. Brain research. Molecular brain research 133 15893591
2019 Structural insights into TRPM8 inhibition and desensitization. Science (New York, N.Y.) 125 31488702
2009 Inorganic polyphosphate modulates TRPM8 channels. PloS one 121 19404398
2007 Characterisation of TRPM8 as a pharmacophore receptor. Cell calcium 109 17517434
2014 The TRPM8 protein is a testosterone receptor: II. Functional evidence for an ionotropic effect of testosterone on TRPM8. The Journal of biological chemistry 98 25480785
2019 Recent Progress in TRPM8 Modulation: An Update. International journal of molecular sciences 95 31141957
2010 Estrogen regulation of TRPM8 expression in breast cancer cells. BMC cancer 84 20482834
2010 PSA reduces prostate cancer cell motility by stimulating TRPM8 activity and plasma membrane expression. Oncogene 83 20531306
2014 The TRPM8 protein is a testosterone receptor: I. Biochemical evidence for direct TRPM8-testosterone interactions. The Journal of biological chemistry 82 25480783
2020 TRPM8 channels: A review of distribution and clinical role. European journal of pharmacology 79 32610057
2013 Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel-expressing sensory neurons by the pruritogen chloroquine. The Journal of biological chemistry 79 23508958
2017 Development of TRPM8 Antagonists to Treat Chronic Pain and Migraine. Pharmaceuticals (Basel, Switzerland) 74 28358322
2016 TRPM8 and Migraine. Headache 73 27634619
2015 Roles of TRPM8 Ion Channels in Cancer: Proliferation, Survival, and Invasion. Cancers 72 26512697
2022 Activation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIP2. Science (New York, N.Y.) 71 36227998
2007 TRPM8. Handbook of experimental pharmacology 70 17217067
2018 TRPV1 and TRPM8 Channels and Nocifensive Behavior in a Rat Model for Dry Eye. Investigative ophthalmology & visual science 69 30046815
2014 TRPM8. Handbook of experimental pharmacology 69 24756721
2017 Cooling Relief of Acute and Chronic Itch Requires TRPM8 Channels and Neurons. The Journal of investigative dermatology 68 29288650
2012 Modulation of thermoreceptor TRPM8 by cooling compounds. ACS chemical neuroscience 68 22860192
2021 TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation. International journal of molecular sciences 66 34445208
2016 TRPM8: a potential target for cancer treatment. Journal of cancer research and clinical oncology 64 26803314
2011 Regulation of TRPM8 channel activity. Molecular and cellular endocrinology 62 22061619
2011 TRPM8: from cold to cancer, peppermint to pain. Current pharmaceutical biotechnology 56 20932257
2006 The cold and menthol receptor TRPM8 contains a functionally important double cysteine motif. The Journal of biological chemistry 54 17015441
2011 TRPM8 in health and disease: cold sensing and beyond. Advances in experimental medicine and biology 51 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
2018 TRPM8 Channels and Dry Eye. Pharmaceuticals (Basel, Switzerland) 44 30445735
2022 Structures of a mammalian TRPM8 in closed state. Nature communications 43 35662242
2012 TRPM7 and TRPM8 Ion Channels in Pancreatic Adenocarcinoma: Potential Roles as Cancer Biomarkers and Targets. Scientifica 42 24278689
2011 TRPM8, a sensor for mild cooling in mammalian sensory nerve endings. Current pharmaceutical biotechnology 42 20932256
2012 TRPM8 ion channel ligands for new therapeutic applications and as probes to study menthol pharmacology. Life sciences 41 23159643
2011 The menthol and cold sensation receptor TRPM8 in normal human nasal mucosa and rhinitis. Rhinology 41 21991571
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
2019 Reduced TRPM8 expression underpins reduced migraine risk and attenuated cold pain sensation in humans. Scientific reports 39 31873179
2018 4TM-TRPM8 channels are new gatekeepers of the ER-mitochondria Ca2+ transfer. Biochimica et biophysica acta. Molecular cell research 37 29678654
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 36 30613832
2020 Current View of Ligand and Lipid Recognition by the Menthol Receptor TRPM8. Trends in biochemical sciences 34 32532587
2016 TRPM8 Puts the Chill on Prostate Cancer. Pharmaceuticals (Basel, Switzerland) 33 27409624
2016 TRPM8 Ion Channels as Potential Cancer Biomarker and Target in Pancreatic Cancer. Advances in protein chemistry and structural biology 32 27038374
2021 Menthol to Induce Non-shivering Thermogenesis via TRPM8/PKA Signaling for Treatment of Obesity. Journal of obesity & metabolic syndrome 31 33071240
2021 Therapeutic potential of TRPM8 antagonists in prostate cancer. Scientific reports 31 34853378
2011 TRPM8 and dyspnea: from the frigid and fascinating past to the cool future? Current opinion in pharmacology 30 21723782
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
2015 Identification of the cold receptor TRPM8 in the nasal mucosa. American journal of rhinology & allergy 29 26163239
2023 Therapeutic potential of TRPM8 channels in cancer treatment. Frontiers in pharmacology 28 37033630
2022 Activation of peripheral TRPM8 mitigates ischemic stroke by topically applied menthol. Journal of neuroinflammation 28 35897101
2018 TRPM8 and TRPA1 do not contribute to dental pulp sensitivity to cold. Scientific reports 28 30181551
2015 TRPM8 function and expression in vagal sensory neurons and afferent nerves innervating guinea pig esophagus. American journal of physiology. Gastrointestinal and liver physiology 28 25591866
2024 Mechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8. Science advances 27 39093967
2023 Structure of human TRPM8 channel. Communications biology 26 37857704
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
2015 Agonist-dependent modulation of cell surface expression of the cold receptor TRPM8. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 25589752
2011 The emerging pharmacology of TRPM8 channels: hidden therapeutic potential underneath a cold surface. Current pharmaceutical biotechnology 25 20932258
2023 TCAF2 in Pericytes Promotes Colorectal Cancer Liver Metastasis via Inhibiting Cold-Sensing TRPM8 Channel. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 24 37635201
2022 The acquisition of cold sensitivity during TRPM8 ion channel evolution. Proceedings of the National Academy of Sciences of the United States of America 24 35594403
2018 TRPM8 and prostate: a cold case? Pflugers Archiv : European journal of physiology 24 29926226
2022 AMTB, a TRPM8 antagonist, suppresses growth and metastasis of osteosarcoma through repressing the TGFβ signaling pathway. Cell death & disease 23 35361751
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
2018 TrpM8-mediated somatosensation in mouse neocortex. The Journal of comparative neurology 23 29484652
2011 TRPM8 biology and medicinal chemistry. Current topics in medicinal chemistry 23 21671871
2023 Human Osteoarthritic Chondrocytes Express Nineteen Different TRP-Genes-TRPA1 and TRPM8 as Potential Drug Targets. International journal of molecular sciences 22 37373205
2021 Trigeminal Neuralgia TRPM8 Mutation: Enhanced Activation, Basal [Ca2+]i and Menthol Response. Neurology. Genetics 22 33977138
2020 The cool things to know about TRPM8! Channels (Austin, Tex.) 22 33147416
2018 TRPM8, ASIC1, and ASIC3 localization and expression in the human oropharynx. Neurogastroenterology and motility 22 29971861
2022 TRPM8 as an Anti-Tumoral Target in Prostate Cancer Growth and Metastasis Dissemination. International journal of molecular sciences 20 35743115
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
2024 Sterile inflammation via TRPM8 RNA-dependent TLR3-NF-kB/IRF3 activation promotes antitumor immunity in prostate cancer. The EMBO journal 18 38316991
2022 Both heat-sensitive TRPV4 and cold-sensitive TRPM8 ion channels regulate microglial activity. Biochemical and biophysical research communications 18 35489198
2022 The LCK-14-3-3ζ-TRPM8 axis regulates TRPM8 function/assembly and promotes pancreatic cancer malignancy. Cell death & disease 18 35665750
2021 TRPM8 channel inhibitor-encapsulated hydrogel as a tunable surface for bone tissue engineering. Scientific reports 18 33580126
2021 Oxaliplatin Causes Transient Changes in TRPM8 Channel Activity. International journal of molecular sciences 18 34066977
2019 TRPM8 Mediates Hyperosmotic Stimuli-Induced Nociception in Dental Afferents. Journal of dental research 18 31718465
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
2023 Endogenous Inflammatory Mediators Produced by Injury Activate TRPV1 and TRPA1 Nociceptors to Induce Sexually Dimorphic Cold Pain That Is Dependent on TRPM8 and GFRα3. The Journal of neuroscience : the official journal of the Society for Neuroscience 17 36898840
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
2018 TRPM8 and RAAS-mediated hypertension is critical for cold-induced immunosuppression in mice. Oncotarget 17 29560109
2023 TRPM8 promotes hepatocellular carcinoma progression by inducing SNORA55 mediated nuclear-mitochondrial communication. Cancer gene therapy 16 36609627
2022 Trpm8 Expression in Human and Mouse Castration Resistant Prostate Adenocarcinoma Paves the Way for the Preclinical Development of TRPM8-Based Targeted Therapies. Biomolecules 16 35204694
2020 TRPM8 Channel Activation Reduces the Spontaneous Contractions in Human Distal Colon. International journal of molecular sciences 16 32751347
2019 Pharmacological inhibition of TRPM8-induced gene transcription. Biochemical pharmacology 16 31654626
2022 The cold-sensing ion channel TRPM8 regulates central and peripheral clockwork and the circadian oscillations of body temperature. Acta physiologica (Oxford, England) 15 36251565
2017 Merkel Cells Sense Cooling with TRPM8 Channels. The Journal of investigative dermatology 15 29138055
2019 Evolution of the human cold/menthol receptor, TRPM8. Molecular phylogenetics and evolution 14 30980935

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