Affinage

TRPM3

Transient receptor potential cation channel subfamily M member 3 · UniProt Q9HCF6

Length
1732 aa
Mass
197.6 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRPM3 is a polymodal, Ca2+/Zn2+-permeable nonselective cation channel that functions as a thermosensitive nociceptor in sensory neurons and as a metabolic and vascular signaling channel in non-neuronal tissues (PMID:12672799, PMID:21555074, PMID:20401728). It is directly gated by multiple stimuli — the neurosteroid pregnenolone sulfate acting at a chiral, proteinaceous binding site distinct from the nifedipine site (PMID:24251620), sphingosine (PMID:15550678), noxious heat (PMID:21555074), and membrane phosphoinositides, with PIP2 being obligatory for activity (PMID:26123194, PMID:26655382). Alternative splicing of the pore-forming region tunes the channel's biophysical and pharmacological identity: pore-loop length controls divalent cation selectivity and ligand sensitivity, distinguishing PS/nifedipine-sensitive short-pore variants from the clotrimazole-selective long-pore variant (PMID:15824111, PMID:32780479), and a splice-derived ICF region is indispensable for functional channel assembly and surface trafficking (PMID:22961981). Beyond its canonical central pore, TRPM3 conducts cations through a non-canonical voltage-sensor-domain pathway whose permeation depends on specific S4 gating-charge residues (PMID:29604058). Channel activity is gated by an intracellular regulatory network: Ca2+/calmodulin and S100A1 bind competing N-terminal sites to set Ca2+-dependent activity (PMID:22451665, PMID:22989896, PMID:29880196), CK2 phosphorylation at S1172 suppresses the channel (PMID:34884938), and Gi/o-coupled GPCRs — including µ-opioid, GABA-B and NPY receptors — inhibit TRPM3 through direct membrane-delimited binding of released Gβγ subunits, a mechanism resolved structurally by cryo-EM showing PIP2-dependent Gβγ engagement (PMID:28826482, PMID:28826490, PMID:36283409). Downstream of Ca2+ influx, TRPM3 drives an ERK→Elk-1→Egr-1 transcriptional cascade that promotes insulin gene expression and is required for glucose-induced insulin secretion (PMID:21257751, PMID:33166100), supports CGRP release from perivascular nociceptors to mediate vasodilation (PMID:30853321), and fuels oncogenic autophagy via CAMKK2/AMPK/ULK1 in clear cell renal carcinoma (PMID:25517751). Gain-of-function missense mutations in TRPM3 cause autosomal dominant neurodevelopmental and epileptic encephalopathy, with overactive channels inhibited by the antagonist primidone (PMID:32343227, PMID:32427099, PMID:36648066).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    Established TRPM3 as a bona fide ion channel by showing it forms a constitutively active, Ca2+/Mn2+-permeable nonselective cation channel, defining its core biophysical identity.

    Evidence Whole-cell and single-channel patch-clamp with Ca2+/Mn2+ entry assays in transfected HEK293 cells

    PMID:12672799

    Open questions at the time
    • Physiological activating stimuli not yet identified
    • Native cellular context and expression undefined
  2. 2005 High

    Showed that alternative splicing of the pore-forming region is a switch for divalent cation selectivity, revealing that a single gene generates channels with distinct permeation properties.

    Evidence Whole-cell patch-clamp and ion substitution across individual splice variants in HEK293 cells

    PMID:15824111

    Open questions at the time
    • Tissue distribution of isoforms not mapped
    • Functional consequences in native cells unknown
  3. 2004 High

    Identified sphingosine as a direct lipid agonist of TRPM3, the first endogenous activator and an early sign of polymodal lipid gating.

    Evidence Fura-2 Ca2+ imaging and patch-clamp with pharmacological dissection in transfected HEK293 cells

    PMID:15550678

    Open questions at the time
    • Binding site not localized
    • Physiological relevance of sphingosine activation in vivo unestablished
  4. 2010 High

    Extended TRPM3 function beyond neurons by defining its roles in β-cell zinc handling and vascular smooth muscle contraction, including cholesterol suppression and PS/sphingosine activation.

    Evidence FluoZin3/Ca2+ imaging, patch-clamp, siRNA and aortic contraction assays in β-cells and vascular smooth muscle

    PMID:20360246 PMID:20401728

    Open questions at the time
    • Downstream secretory and contractile coupling not yet mechanistically resolved
    • Cholesterol binding site not defined
  5. 2011 High

    Defined TRPM3 as a noxious-heat sensor in DRG/TG nociceptors required for heat avoidance and inflammatory hyperalgesia, and linked PS-driven Ca2+ influx to an ERK→Egr-1 transcriptional program controlling insulin gene expression.

    Evidence Patch-clamp and behavioral assays in Trpm3−/− mice; dominant-negative/pharmacological dissection and ChIP in INS-1 insulinoma cells

    PMID:21257751 PMID:21555074

    Open questions at the time
    • Molecular basis of intrinsic thermosensitivity unresolved
    • Direct heat-sensing domain not identified
  6. 2012 Medium

    Resolved intracellular regulatory architecture by identifying the indispensable ICF region for functional assembly/trafficking and Ca2+-dependent CaM/S100A1 binding sites on the N-terminus that overlap with PIP2 interaction regions.

    Evidence Mutagenesis, co-IP, surface expression analysis, pulldown and competition binding assays in transfected cells

    PMID:22451665 PMID:22961981 PMID:22989896

    Open questions at the time
    • Functional impact of CaM/S100A1 binding on gating not yet established here
    • ΔICF dominant-negative stoichiometry undefined
  7. 2014 High

    Established the chirality and biochemical requirements of the steroid binding site (negative C3 charge, distinct from nifedipine site) and uncovered an oncogenic role driving CAMKK2/AMPK/ULK1 autophagy in ccRCC under VHL/miRNA control.

    Evidence Steroid analog/enantiomer SAR with patch-clamp; shRNA, dominant-negative and pharmacological pathway analysis in ccRCC cells

    PMID:24251620 PMID:25517751

    Open questions at the time
    • Atomic structure of the steroid site not yet defined
    • Generality of oncogenic autophagy role across tumor types unknown
  8. 2015 High

    Demonstrated that PIP2 is an obligatory cofactor for TRPM3 gating and that ATP sustains activity via PIP resynthesis, and identified a synthetic agonist (CIM0216) opening both the central and non-canonical permeation pathways while driving CGRP and insulin release.

    Evidence Inside-out and planar bilayer reconstitution with direct lipid application; patch-clamp and CGRP/insulin release with Trpm3−/− controls

    PMID:25733887 PMID:26123194 PMID:26655382

    Open questions at the time
    • PIP2 binding site not structurally localized
    • Cellular factors enabling robust heat gating not identified
  9. 2017 High

    Revealed a major inhibitory input: Gi/o-coupled GPCRs (µOR, GABA-B, NPY) suppress TRPM3 via direct membrane-delimited Gβγ binding independent of cAMP, providing a molecular basis for peripheral opioid analgesia.

    Evidence Patch-clamp in DRG neurons, Gβγ application to excised patches, co-IP, and in vivo pain behavioral assays (two concurrent eLife studies)

    PMID:28826482 PMID:28826490

    Open questions at the time
    • Gβγ binding interface not yet structurally defined
    • Relationship between Gβγ and PIP2 regulation unresolved
  10. 2018 High

    Mapped functional Ca2+/CaM regulation and the structural determinants of the non-canonical (omega-like) permeation pathway, linking specific N-terminal CaM sites and S4 gating-charge residues to channel function.

    Evidence Mutagenesis with CaM binding assays and patch-clamp; Shaker-homology-guided mutagenesis of voltage-sensor residues

    PMID:29604058 PMID:29880196

    Open questions at the time
    • How CaM binding mechanistically modulates the pore is not resolved
    • Physiological role of the non-canonical pathway in native cells unclear
  11. 2020 High

    Connected TRPM3 to human disease and metabolic physiology by showing that recurrent mutations are gain-of-function with distinct biophysical mechanisms, all primidone-sensitive, and that TRPM3 is required for glucose-induced insulin secretion in vivo.

    Evidence Patch-clamp/Ca2+ imaging of disease mutants (two concurrent studies); CRISPR knockout in INS-1 cells and β-cell-specific KO mice with glucose tolerance tests; pore-loop pharmacology mutagenesis

    PMID:32343227 PMID:32427099 PMID:32780479 PMID:33166100

    Open questions at the time
    • How distinct mutations produce different gating defects structurally unresolved at this stage
    • In vivo neuronal consequences of gain-of-function not fully dissected
  12. 2021 High

    Defined trafficking and tissue-specific signaling roles: ATF4/KIF17-dependent surface delivery in DRG neurons controls heat nociception, while TRPM3 controls thermosensitive spontaneous glutamate release at vagal-NTS synapses and CK2 phosphorylation at S1172 negatively regulates the channel.

    Evidence Co-IP and trafficking assays with patch-clamp in ATF4 cKO neurons; synaptic patch-clamp in brainstem slice; in vitro kinase assay, S1172A mutagenesis and Ca2+ imaging

    PMID:33296617 PMID:33658516 PMID:34884938

    Open questions at the time
    • Integration of phosphorylation and trafficking regulation not unified
    • Generality of the NTS thermosensing role to other synapses unknown
  13. 2022 High

    Provided the structural basis for Gβγ inhibition and PIP2 dependence, showing Gβγ binds TRPM3 in a PIP2-dependent manner across variable interfaces.

    Evidence Single-particle cryo-EM of mouse TRPM3 ± Gβγ ± PIP2 combined with electrophysiology

    PMID:36283409

    Open questions at the time
    • Conformational transitions during gating not fully captured
    • Steroid agonist site not resolved in this study
  14. 2023 High

    Consolidated the disease mechanism by showing multiple additional neurodevelopmental disorder variants are uniformly gain-of-function with Ca2+ overload and primidone-reversible basal activity.

    Evidence Ca2+ imaging and patch-clamp of disease mutants with primidone in mammalian cells

    PMID:36648066

    Open questions at the time
    • Long-term therapeutic efficacy of primidone in patients not addressed by these in vitro data
    • How gain-of-function translates to network-level epileptogenesis unknown
  15. 2025 High

    Resolved distinct binding sites for neurosteroid agonist, synthetic agonist, and the inhibitor primidone, providing a structural framework for agonist gating and inhibitor design.

    Evidence Cryo-EM structures of mouse TRPM3 bound to cholesteryl hemisuccinate, primidone, and PregS+CIM0216

    PMID:39809942

    Open questions at the time
    • Full open-state gating trajectory not defined
    • Structural basis of heat sensing still unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular basis of intrinsic thermosensitivity and the identity of the cellular cofactors required for robust heat gating remain unresolved.
  • No defined heat-sensing domain or thermosensor residues
  • Bilayer reconstitution shows weak intrinsic heat response, implying unidentified cellular factors
  • Structural correlate of thermal gating not captured by current cryo-EM states

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0008289 lipid binding 3 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005929 cilium 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-1643685 Disease 2 R-HSA-9612973 Autophagy 1
Partners
ATF4CALM1/CALMODULINCSNK2/CK2GNB1/GΒΓKIF17OPRM1PKD2/TRPP2S100A1
Complex memberships
TRPM3 channel tetramerciliary TRPP2 (PKD2) large-conductance channel

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 TRPM3 forms a constitutively active, Ca2+- and Mn2+-permeable nonselective cation channel when expressed in HEK293 cells, with single-channel conductances of 133 pS (Cs+), 83 pS (Na+), and 65 pS (Ca2+); its activity is enhanced by hypotonic (cell-swelling) conditions, indicating volume-regulated gating. Whole-cell and cell-attached patch-clamp, Ca2+/Mn2+ entry assays in transfected HEK293 cells The Journal of biological chemistry High 12672799
2005 Alternative splicing in the pore-forming region of TRPM3 switches divalent cation selectivity: TRPM3α2 (short pore loop) is well permeated by Ca2+ and Mg2+ and blocked by extracellular monovalent cations, whereas TRPM3α1 (long pore loop) is poorly permeable to divalent cations and unaffected by monovalent block; both isoforms show outwardly rectifying currents regulated by intracellular Mg2+. Whole-cell patch-clamp and ion substitution experiments in HEK293 cells expressing individual splice variants The Journal of biological chemistry High 15824111
2004 D-erythro-sphingosine activates TRPM3 Ca2+ entry and cation currents in transfected HEK293 cells; this activation is not mediated by PKC inhibition, store depletion, or conversion to sphingosine-1-phosphate. Sphingosine-1-phosphate and ceramide had no effect; structural analogs dihydro-D-erythro-sphingosine and N,N-dimethyl-D-erythro-sphingosine were also activating, identifying sphingosine as a direct TRPM3 agonist. Fura-2 Ca2+ imaging and whole-cell patch-clamp in transfected HEK293 cells with pharmacological dissection Molecular pharmacology High 15550678
2011 TRPM3 functions as a thermosensitive nociceptor channel in dorsal root and trigeminal ganglion neurons: it is steeply activated by noxious heat, mediates nocifensive responses to pregnenolone sulfate (PS) in vivo, and is required for normal avoidance of noxious heat and for development of inflammatory heat hyperalgesia in mice. Whole-cell patch-clamp in DRG neurons, Ca2+ imaging, behavioral assays in Trpm3−/− mice Neuron High 21555074
2010 TRPM3 channels in pancreatic β-cells are highly permeable to zinc ions; pregnenolone sulfate-activated TRPM3 mediates zinc influx even at low extracellular zinc concentrations, and subsequent membrane depolarization drives additional zinc entry through voltage-gated Ca2+ channels. FluoZin3 zinc imaging and patch-clamp in pancreatic β-cells and recombinant TRPM3-expressing cells Pflugers Archiv : European journal of physiology High 20401728
2010 TRPM3 in vascular smooth muscle cells is activated by PS and sphingosine, is tonically suppressed by endogenous cholesterol, and positively modulates contractile responses of aorta independently of L-type Ca2+ channels; in proliferating cells it negatively couples to IL-6 secretion. Ca2+ imaging, patch-clamp, RNA interference knockdown, cholesterol loading/depletion, aortic contraction assays Circulation research High 20360246
2015 The synthetic TRPM3 agonist CIM0216 opens both the central Ca2+-conducting pore and a non-canonical (voltage-sensor domain) cation permeation pathway in a membrane-delimited manner; CIM0216 is more potent than PS and elicits CGRP release from sensory nerve terminals and insulin release from pancreatic islets in a TRPM3-dependent manner. Whole-cell patch-clamp, Ca2+ imaging, CGRP/insulin release assays, Trpm3−/− genetic controls Proceedings of the National Academy of Sciences of the United States of America High 25733887
2017 µ-opioid receptor (µOR) activation strongly inhibits TRPM3 channels in DRG nociceptors via Gβγ proteins, which form a direct complex with TRPM3; this inhibition is more pronounced than for TRPV1 or TRPA1 in the same cells and is responsible for a component of peripheral µOR-mediated analgesia in vivo. Patch-clamp in mouse DRG neurons, Co-IP/complex formation assays, in vivo pain behavioral assays with Gβγ pathway pharmacology eLife High 28826482
2017 TRPM3 activity in DRG neurons is inhibited by agonists of Gi-coupled µ-opioid, GABA-B, and NPY receptors via direct inhibition by Gβγ subunits, independent of the canonical cAMP pathway; constitutive GPCR activity tonically suppresses TRPM3 and inverse agonists potentiate it both in vitro and in vivo. Patch-clamp in mouse DRG neurons, Gβγ direct application to excised patches, in vivo nociceptive behavioral assays eLife High 28826490
2022 Cryo-EM structures of mouse TRPM3 (2.7–4.7 Å) with and without Gβγ and with and without PIP2 show that Gβγ binds TRPM3 in a PIP2-dependent manner at varying interfaces; PIP2 is required for TRPM3 activity; Gβγ inhibits TRPM3 with an IC50 of ~240 nM. Single-particle cryo-EM, whole-cell electrophysiology Neuron High 36283409
2025 Cryo-EM structures of mouse TRPM3 bound to cholesteryl hemisuccinate, primidone, and PregS+CIM0216 identify distinct binding sites for the neurosteroid agonist, the synthetic agonist, and the anticonvulsant inhibitor primidone, providing a structural basis for agonist-induced gating and inhibitor mechanism. Cryogenic electron microscopy (cryo-EM) structural determination Nature structural & molecular biology High 39809942
2015 TRPM3 activity is dynamically regulated by membrane phosphoinositides: PI(4,5)P2, PI(3,4,5)P3, PI(3,5)P2 and PI(3,4)P2 directly enhance TRPM3 in cell-free inside-out patches (potency order PI(3,4,5)P3 > PI(3,5)P2 > PI(4,5)P2 ≈ PI(3,4)P2); cytosolic ATP sustains TRPM3 activity by driving PIP resynthesis via PI kinases; activation of PLC-coupled muscarinic receptors rapidly inhibits both recombinant and endogenous TRPM3. Inside-out patch-clamp with direct lipid application, pharmacological inhibitors of PI kinases, muscarinic receptor activation The Journal of general physiology High 26123194
2015 In planar lipid bilayer reconstitution, TRPM3 channel opening by PS requires the presence of PIP2 or clotrimazole; nifedipine alone suffices to open TRPM3 with distinct gating behavior; in the absence of other agonists, heat alone does not robustly open TRPM3 in the bilayer (only low open probability with PIP2), indicating that strong intrinsic thermosensitivity requires additional cellular factors. Planar lipid bilayer reconstitution with purified TRPM3 protein FASEB journal High 26655382
2012 A splice-generated 18-residue 'ICF' region is indispensable for TRPM3 channel function: TRPM3ΔICF variants lacking this region produce neither Ca2+ entry nor ionic currents alone; ΔICF proteins show reduced interaction with functional TRPM3 subunits and reduced plasma membrane localization; co-expression of ΔICF variants with functional TRPM3 reduces channel number and impairs Ca2+ entry, identifying them as dominant-negative regulatory subunits. Ca2+ imaging, patch-clamp, co-immunoprecipitation, surface expression analysis in transfected cells The Journal of biological chemistry High 22961981
2012 Calmodulin (CaM) and S100A1 bind to two independent domains on the TRPM3 N-terminus (Ala35–Lys124 and His291–Gly382) in a Ca2+-dependent manner; positively charged residues within these domains are critical for binding; CaM and S100A1 compete for the same sites; PtdIns(4,5)P2 also interacts with these CaM/S100A1 binding regions on the N-terminus. Pulldown assays, competition assays, site-directed mutagenesis of N-terminal domains, PIP2 binding assays The Journal of biological chemistry / Channels Medium 22451665 22989896
2018 TRPM3 channel activity is strongly regulated by intracellular Ca2+ via calmodulin: five CaM binding sites on the TRPM3 N-terminus display Ca2+-dependent binding affinities; mutations of lysine residues in CaM binding site 2 reduced both CaM binding and TRPM3 activity, establishing a mechanistic link between CaM binding and channel function. Ca2+ imaging, patch-clamp, CaM binding assays, site-directed mutagenesis in transfected cells Cell calcium High 29880196
2018 Mutations in S4 (W982, R985, D988, G991), S1, and S3 of the voltage-sensor domain are critical for the non-canonical (omega-like) inward cation permeation pathway in TRPM3; the R2 gating-charge arginine in S4 is uniquely conserved, and mutagenesis of these residues abolishes or alters non-canonical pore currents. Site-directed mutagenesis and patch-clamp electrophysiology guided by Shaker K+ channel homology The Journal of physiology High 29604058
2011 PS stimulation of TRPM3 in insulinoma cells triggers a signaling cascade: Ca2+ influx via TRPM3 and voltage-gated Ca2+ channels activates ERK, leading to Elk-1/TCF-dependent transcription of Egr-1; newly synthesized Egr-1 binds regulatory regions of Pdx-1, Synapsin I, and Chromogranin B genes, elevating insulin promoter activity and insulin mRNA. Pharmacological and dominant-negative genetic dissection of signaling in INS-1 insulinoma cells; chromatin IP; reporter gene assays The Journal of biological chemistry High 21257751
2014 TRPM3 promotes oncogenic autophagy in clear cell renal cell carcinoma by driving Ca2+ influx that activates CAMKK2→AMPK→ULK1 and phagophore formation; TRPM3 Ca2+/Zn2+ fluxes also inhibit miR-214, which directly targets LC3A and LC3B; VHL suppresses TRPM3 via miR-204 (encoded within TRPM3 intron 6) and indirectly via CAV1. shRNA knockdown, dominant-negative mutant, pharmacological inhibition (MFA), signaling pathway analysis in ccRCC cells Cancer cell High 25517751
2014 Steroid activation of TRPM3 requires a chiral binding site: the natural enantiomer of PS is more efficacious than its mirror image; a negative charge at position C3 of the steroid is required; nifedipine and PS act at distinct binding sites (supra-additive activation; different structural analogs have opposite effects); weak TRPM3 activators act as partial agonists at the PS binding site. Patch-clamp and Ca2+ imaging with systematic steroid analogs and enantiomers in transfected HEK293 cells British journal of pharmacology High 24251620
2020 Two disease-associated TRPM3 mutations (V837M/V990M in S4-S5 linker; P937Q/P1090Q at S6-pore loop boundary) render the channel overactive via distinct mechanisms: V990M primarily increases basal activity and agonist sensitivity at room temperature; P1090Q predominantly enhances heat activation; V990M additionally enables large inward currents through the non-canonical pore in response to PS. Both mutants are inhibited by primidone. Whole-cell patch-clamp and Ca2+ imaging in HEK293 cells expressing human disease mutants vs. wild-type eLife / eLife High 32343227 32427099
2021 ATF4 interacts directly with TRPM3 and is required for KIF17-mediated plasma membrane trafficking of TRPM3 in DRG neurons; loss of ATF4 reduces TRPM3 current amplitude and surface expression, selectively impairing heat nociception without affecting other sensory modalities. Co-IP, KIF17 knockdown, live-cell trafficking assays, patch-clamp in ATF4 conditional-knockout DRG neurons Nature communications High 33658516
2021 TRPM3 controls basal and temperature-driven spontaneous glutamate release onto NTS neurons from vagal afferents; genetic deletion of TRPM3 eliminated temperature-sensitive spontaneous release but did not alter synchronous or asynchronous release, establishing TRPM3 as the thermosensitive Ca2+ conductance controlling spontaneous vesicle fusion at these synapses. Patch-clamp recording of synaptic currents in brainstem slice, Ca2+ imaging, pharmacological blockade and Trpm3−/− genetic deletion Journal of neurophysiology High 33296617
2021 CK2 phosphorylates TRPM3α2 at serine residue 1172; CK2 inhibition or S1172A mutation enhances TRPM3-mediated Ca2+ entry in HEK293 cells and INS-1 β-cells, while CK2 overexpression reduces it, establishing CK2 as a negative regulator of TRPM3 channel activity through direct phosphorylation. In vitro kinase assays, site-directed mutagenesis (S1172A), Fura-2 Ca2+ imaging, CK2 overexpression/inhibition (CX-4945) International journal of molecular sciences High 34884938
2019 TRPM3 expression in mesenteric resistance arteries is restricted to perivascular nerves (not vascular smooth muscle); PS-induced TRPM3 activation in these neurons triggers CGRP release, which subsequently dilates arteries via CGRP receptor and K+ channel activation in VSMCs; this vasodilatory pathway is absent in Trpm3−/− mice. Immunofluorescence, qPCR, patch-clamp in isolated VSMCs, pressure myography, CGRP receptor antagonist, Trpm3−/− genetic controls Journal of molecular and cellular cardiology High 30853321
2019 The TRPP2-dependent large-conductance channel in primary cilia of renal epithelial cells requires TRPM3 as a subunit: CRISPR/Cas9 knockout of TRPM3 eliminates the ciliary channel; TRPM3 knockdown does not alter TRPP2 protein levels in cilia, excluding a trafficking effect. Single-channel electrophysiology in primary cilia, CRISPR/Cas9 knockout, immunofluorescence for TRPP2 protein PloS one High 30883612
2020 Inflammation upregulates Trpm3 mRNA levels in DRG neurons innervating inflamed tissue and augments TRPM3-mediated Ca2+ responses in cell bodies and peripheral endings; pharmacological TRPM3 inhibition dampens co-expressed TRPV1- and TRPA1-mediated responses specifically in nociceptors innervating inflamed paw, establishing TRPM3 upregulation as a mechanism for inflammatory heat hyperalgesia. Single-molecule FISH, Ca2+ imaging in intact nerve endings, retrograde labeling, pharmacological inhibition eLife High 32880575
2020 Pharmacological properties of TRPM3 isoforms are determined by pore loop length: all short-pore variants (α2–α6) are activated by PS and nifedipine, while the long-pore variant (α1) is insensitive to both but robustly activated by clotrimazole; mutants with intermediate pore loop lengths show graded pharmacological responses, directly linking pore loop length to ligand sensitivity. Ca2+ imaging, patch-clamp, site-directed mutagenesis creating pore loops of intermediate length British journal of pharmacology High 32780479
2017 TRPM3 is localized to primary cilia of renal epithelial cells; ciliary TRPM3 is required for the maximal osmotic stress response: TRPM3 agonism attenuated osmotic response gene induction only in ciliated cells, and TRPM3 knockout attenuated Akr1b3 induction, establishing a cilia-dependent mechanistic role. Immunofluorescence, electrophysiology, TRPM3 knockout, agonist/antagonist treatment in ciliated vs. non-ciliated renal cell lines American journal of physiology. Renal physiology Medium 28722715
2020 TRPM3 is required for glucose-induced insulin release in pancreatic β-cells: CRISPR/Cas9 deletion of Trpm3 in INS-1 cells eliminates PS-induced Ca2+ signals and insulin release, and strongly reduces glucose-induced Ca2+ signals and insulin release; β-cell-specific Trpm3-deficient mice show impaired glucose clearance in tolerance tests. CRISPR/Cas9 knockout in INS-1 cells, Fura-2 Ca2+ imaging, electrophysiology, insulin immunoassay, glucose tolerance test in β-cell-specific KO mice Cellular physiology and biochemistry High 33166100
2023 Seven additional TRPM3 missense variants causing neurodevelopmental disorders all exhibit gain-of-function, characterized by increased basal activity, cellular Ca2+ overload, and enhanced responses to PS when co-expressed with wild-type TRPM3; primidone reduced the increased basal activity of all mutant channels. Ca2+ imaging and patch-clamp in mammalian cells expressing disease mutants; pharmacological inhibition with primidone eLife High 36648066

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 TRPM3 is a nociceptor channel involved in the detection of noxious heat. Neuron 465 21555074
2003 Molecular and functional characterization of the melastatin-related cation channel TRPM3. The Journal of biological chemistry 276 12672799
2005 Alternative splicing switches the divalent cation selectivity of TRPM3 channels. The Journal of biological chemistry 170 15824111
2014 TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma. Cancer cell 160 25517751
2010 Pregnenolone sulphate- and cholesterol-regulated TRPM3 channels coupled to vascular smooth muscle secretion and contraction. Circulation research 121 20360246
2015 Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release. Proceedings of the National Academy of Sciences of the United States of America 120 25733887
2004 Activation of the melastatin-related cation channel TRPM3 by D-erythro-sphingosine [corrected]. Molecular pharmacology 120 15550678
2013 Flavanones that selectively inhibit TRPM3 attenuate thermal nociception in vivo. Molecular pharmacology 117 24006495
2017 Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels. eLife 93 28826482
2011 Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3. British journal of pharmacology 86 21198543
2017 G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons. eLife 84 28826490
2013 Citrus fruit and fabacea secondary metabolites potently and selectively block TRPM3. British journal of pharmacology 83 23190005
2017 Primidone inhibits TRPM3 and attenuates thermal nociception in vivo. Pain 81 28106668
2017 Circular RNAs promote TRPM3 expression by inhibiting hsa-miR-130a-3p in coronary artery disease patients. Oncotarget 77 28947970
2014 TRPM3. Handbook of experimental pharmacology 76 24756716
2020 circPRRC2A promotes angiogenesis and metastasis through epithelial-mesenchymal transition and upregulates TRPM3 in renal cell carcinoma. Theranostics 73 32292503
2010 TRPM3 channels provide a regulated influx pathway for zinc in pancreatic beta cells. Pflugers Archiv : European journal of physiology 73 20401728
2017 Transient receptor potential TRPM3 channels: Pharmacology, signaling, and biological functions. Pharmacological research 67 28720517
2015 TRPM3 in temperature sensing and beyond. Temperature (Austin, Tex.) 65 27227024
1997 gon-2, a gene required for gonadogenesis in Caenorhabditis elegans. Genetics 65 9383054
2010 TRPM3 is expressed in sphingosine-responsive myelinating oligodendrocytes. Journal of neurochemistry 64 20163522
2011 Signal transduction of pregnenolone sulfate in insulinoma cells: activation of Egr-1 expression involving TRPM3, voltage-gated calcium channels, ERK, and ternary complex factors. The Journal of biological chemistry 61 21257751
2012 Alternative splicing of a protein domain indispensable for function of transient receptor potential melastatin 3 (TRPM3) ion channels. The Journal of biological chemistry 60 22961981
2021 TRPM3 Channels Play Roles in Heat Hypersensitivity and Spontaneous Pain after Nerve Injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 59 33478988
2015 Regulation of the transient receptor potential channel TRPM3 by phosphoinositides. The Journal of general physiology 58 26123194
2011 Pregnenolone sulphate-independent inhibition of TRPM3 channels by progesterone. Cell calcium 58 22000496
2022 Structural and functional analyses of a GPCR-inhibited ion channel TRPM3. Neuron 56 36283409
2019 De novo substitutions of TRPM3 cause intellectual disability and epilepsy. European journal of human genetics : EJHG 55 31278393
2011 Rapid and contrasting effects of rosiglitazone on transient receptor potential TRPM3 and TRPC5 channels. Molecular pharmacology 53 21406603
2014 Structural requirements of steroidal agonists of transient receptor potential melastatin 3 (TRPM3) cation channels. British journal of pharmacology 51 24251620
2011 Activation of steroid-sensitive TRPM3 channels potentiates glutamatergic transmission at cerebellar Purkinje neurons from developing rats. Journal of neurochemistry 51 21955047
2016 Direct modulation of TRPM4 and TRPM3 channels by the phospholipase C inhibitor U73122. British journal of pharmacology 50 27328745
2020 Disease-associated mutations in the human TRPM3 render the channel overactive via two distinct mechanisms. eLife 49 32343227
2020 Functional expression and pharmacological modulation of TRPM3 in human sensory neurons. British journal of pharmacology 47 31985045
2010 Cis-isomerism and other chemical requirements of steroidal agonists and partial agonists acting at TRPM3 channels. British journal of pharmacology 47 20735426
2020 Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy. eLife 46 32427099
2012 Calmodulin and S100A1 protein interact with N terminus of TRPM3 channel. The Journal of biological chemistry 46 22451665
2018 Sensing the heat with TRPM3. Pflugers Archiv : European journal of physiology 45 29305649
2014 Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma. PloS one 44 25090642
2008 Production of a specific extracellular inhibitor of TRPM3 channels. British journal of pharmacology 44 18604232
2014 Activation and inhibition of transient receptor potential TRPM3-induced gene transcription. British journal of pharmacology 41 24895737
2020 Upregulation of TRPM3 in nociceptors innervating inflamed tissue. eLife 40 32880575
2021 TRPM3 in Brain (Patho)Physiology. Frontiers in cell and developmental biology 39 33732703
2018 Puerarin inhibits TRPM3/miR-204 to promote MC3T3-E1 cells proliferation, differentiation and mineralization. Phytotherapy research : PTR 39 29368357
2020 TRPM3_miR-204: a complex locus for eye development and disease. Human genomics 38 32070426
2015 Voriconazole, an antifungal triazol that causes visual side effects, is an inhibitor of TRPM1 and TRPM3 channels. Investigative ophthalmology & visual science 35 25650413
2013 Signal transduction via TRPM3 channels in pancreatic β-cells. Journal of molecular endocrinology 35 23511953
2018 TRPM3/TRPV4 regulates Ca2+-mediated RANKL/NFATc1 expression in osteoblasts. Journal of molecular endocrinology 34 30328352
2015 Transient receptor potential melastatin-3 (TRPM3)-induced activation of AP-1 requires Ca2+ ions and the transcription factors c-Jun, ATF2, and ternary complex factor. Molecular pharmacology 34 25576487
2003 The promotion of gonadal cell divisions by the Caenorhabditis elegans TRPM cation channel GON-2 is antagonized by GEM-4 copine. Genetics 34 14573470
2001 The C. elegans gon-2 gene encodes a putative TRP cation channel protein required for mitotic cell cycle progression. Gene 34 11290424
2023 Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders. eLife 33 36648066
2023 TRPM3 as a novel target to alleviate acute oxaliplatin-induced peripheral neuropathic pain. Pain 33 37079852
2021 Mutation of the TRPM3 cation channel underlies progressive cataract development and lens calcification associated with pro-fibrotic and immune cell responses. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 33484482
2021 ATF4 selectively regulates heat nociception and contributes to kinesin-mediated TRPM3 trafficking. Nature communications 32 33658516
2018 Mutations in the voltage-sensing domain affect the alternative ion permeation pathway in the TRPM3 channel. The Journal of physiology 32 29604058
2011 A family with autism and rare copy number variants disrupting the Duchenne/Becker muscular dystrophy gene DMD and TRPM3. Journal of neurodevelopmental disorders 32 21484199
2010 TRPM3 channel stimulated by pregnenolone sulphate in synovial fibroblasts and negatively coupled to hyaluronan. BMC musculoskeletal disorders 32 20525329
2007 TRPM3. Handbook of experimental pharmacology 31 17217062
2017 Primary cilia regulate the osmotic stress response of renal epithelial cells through TRPM3. American journal of physiology. Renal physiology 30 28122715
2015 CREB, AP-1, ternary complex factors and MAP kinases connect transient receptor potential melastatin-3 (TRPM3) channel stimulation with increased c-Fos expression. British journal of pharmacology 30 26493679
2015 Stimulation-dependent gating of TRPM3 channel in planar lipid bilayers. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 26655382
2012 PtdIns(4,5)P2 interacts with CaM binding domains on TRPM3 N-terminus. Channels (Austin, Tex.) 29 22989896
2015 TRPM3 expression in mouse retina. PloS one 27 25679224
2022 Migraine-relevant sex-dependent activation of mouse meningeal afferents by TRPM3 agonists. The journal of headache and pain 25 35012445
2019 Activation of the cation channel TRPM3 in perivascular nerves induces vasodilation of resistance arteries. Journal of molecular and cellular cardiology 25 30853321
2017 Autoantibodies in Melanoma-Associated Retinopathy Recognize an Epitope Conserved Between TRPM1 and TRPM3. Investigative ophthalmology & visual science 24 28549093
2016 Diclofenac, a nonsteroidal anti-inflammatory drug, is an antagonist of human TRPM3 isoforms. Pharmacology research & perspectives 24 27433342
2015 Hypotonic stress induces RANKL via transient receptor potential melastatin 3 (TRPM3) and vaniloid 4 (TRPV4) in human PDL cells. Journal of dental research 24 25595364
2022 Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients. Journal of translational medicine 23 35172836
2021 TRPM3 Is Expressed in Afferent Bladder Neurons and Is Upregulated during Bladder Inflammation. International journal of molecular sciences 23 35008533
2019 The TRPP2-dependent channel of renal primary cilia also requires TRPM3. PloS one 23 30883612
2017 Extracellular Signal-Regulated Protein Kinase, c-Jun N-Terminal Protein Kinase, and Calcineurin Regulate Transient Receptor Potential M3 (TRPM3) Induced Activation of AP-1. Journal of cellular biochemistry 23 28112420
2025 Molecular basis of neurosteroid and anticonvulsant regulation of TRPM3. Nature structural & molecular biology 22 39809942
2015 Regulation of autophagy by two products of one gene: TRPM3 and miR-204. Molecular & cellular oncology 22 27308495
2021 The newest TRP channelopathy: Gain of function TRPM3 mutations cause epilepsy and intellectual disability. Channels (Austin, Tex.) 21 33853504
2014 Gene regulation by PAX6: structural-functional correlations of missense mutants and transcriptional control of Trpm3/miR-204. Molecular vision 21 24623969
2019 Transient receptor potential channels in the context of nociception and pain - recent insights into TRPM3 properties and function. Biological chemistry 20 30844758
2021 A Chinese patient with developmental and epileptic encephalopathies (DEE) carrying a TRPM3 gene mutation: a paediatric case report. BMC pediatrics 19 34074259
2020 Control of Insulin Release by Transient Receptor Potential Melastatin 3 (TRPM3) Ion Channels. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 19 33166100
2022 Phenotypic spectrum of the recurrent TRPM3 p.(Val837Met) substitution in seven individuals with global developmental delay and hypotonia. American journal of medical genetics. Part A 18 35146895
2021 Partial Agonistic Actions of Sex Hormone Steroids on TRPM3 Function. International journal of molecular sciences 18 34948452
2020 Pharmacological properties of TRPM3 isoforms are determined by the length of the pore loop. British journal of pharmacology 18 32780479
2020 TRPM3 expression and control of glutamate release from primary vagal afferent neurons. Journal of neurophysiology 18 33296617
2023 Primidone improves symptoms in TRPM3-linked developmental and epileptic encephalopathy with spike-and-wave activation in sleep. Epilepsia 17 36929095
2020 The TRPM3 ion channel mediates nociception but not itch evoked by endogenous pruritogenic mediators. Biochemical pharmacology 17 33130130
2018 Ca2+-dependent regulation and binding of calmodulin to multiple sites of Transient Receptor Potential Melastatin 3 (TRPM3) ion channels. Cell calcium 17 29880196
2017 Stimulation of transient receptor potential M3 (TRPM3) channels increases interleukin-8 gene promoter activity involving AP-1 and extracellular signal-regulated protein kinase. Cytokine 15 28982580
2021 The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP2 and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients. Journal of translational medicine 14 34266470
2020 Orofacial Antinociceptive Effect of Nifedipine in Rodents Is Mediated by TRPM3, TRPA1, and NMDA Processes. Journal of oral & facial pain and headache 14 32255583
2019 Identification and classification of a new TRPM3 variant (γ subtype). The journal of physiological sciences : JPS 14 31011981
2016 Transient Receptor Potential Melastatin-3 (TRPM3) Mediates Nociceptive-Like Responses in Hydra vulgaris. PloS one 14 26974325
2024 Neurodevelopmental disorders caused by variants in TRPM3. Biochimica et biophysica acta. Molecular cell research 13 38522727
2022 TRPM3-mediated dynamic mitochondrial activity in nerve growth factor-induced latent sensitization of chronic low back pain. Pain 13 35384915
2020 The Impact of Steroid Activation of TRPM3 on Spontaneous Activity in the Developing Retina. eNeuro 13 32238415
2020 Volatile anaesthetics inhibit the thermosensitive nociceptor ion channel transient receptor potential melastatin 3 (TRPM3). Biochemical pharmacology 12 31987857
2024 Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone. Journal of translational medicine 11 38970055
2021 Control of TRPM3 Ion Channels by Protein Kinase CK2-Mediated Phosphorylation in Pancreatic β-Cells of the Line INS-1. International journal of molecular sciences 11 34884938
2008 Gem-1 encodes an SLC16 monocarboxylate transporter-related protein that functions in parallel to the gon-2 TRPM channel during gonad development in Caenorhabditis elegans. Genetics 11 19087963
2024 TRPM3, TRPM4, and TRPM5 as thermo-sensitive channels. The journal of physiological sciences : JPS 9 39294615

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