Affinage

MCOLN3

Mucolipin-3 · UniProt Q8TDD5

Length
553 aa
Mass
64.2 kDa
Annotated
2026-06-10
34 papers in source corpus 22 papers cited in narrative 23 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

MCOLN3/TRPML3 is an inwardly rectifying, Ca2+-permeable cation channel that supplies localized Ca2+ to control endolysosomal trafficking and autophagy (PMID:19522758, PMID:36252030). The wild-type channel is strongly regulated by its ionic and lipid environment: extracytosolic Na+ inhibits the channel and its removal activates it, while luminal H+ inhibits via histidines (H252/H273/H283) in the large TM1-TM2 extracytosolic loop and a negatively charged residue (Glu-361) mediates Na+ block (PMID:17962195, PMID:18369318, PMID:22753890). Cryo-EM structures define an architecture in which a voltage sensor-like domain connects to the pore through a cytosolic mucolipin domain that binds PtdIns(3,5)P2 to gate the channel as a 'gating pulley', with a luminal polycystin-mucolipin cap that undergoes conformational changes mediating low-pH inhibition and agonists (ML-SA1) opening the S6 gate (PMID:29019979, PMID:29106414). TRPML3 is dynamically distributed across the plasma membrane, ER, endosomes, lysosomes, and phagophores, and its lysosomal localization is dictated by heteromultimerization with TRPML1/TRPML2; it also forms functional heteromers with TRPV5 (PMID:16606612, PMID:23469151). Beyond its channel activity, TRPML3 acts as a downstream effector of phosphoinositides in autophagy: PI3P directly activates it at the phagophore to release Ca2+ for autophagosome biogenesis, and a MCOLN1-MCOLN3 heteromer acts downstream of PtdIns4P to release Ca2+ decoded by the sensor SYT5 for autophagosome-lysosome fusion; C-terminal palmitoylation controls starvation-induced trafficking to autophagic structures (PMID:30215288, PMID:36252030, PMID:40413756). The gain-of-function A419P mutation, which constitutively opens the channel by a helix-breaking proline kink in TM5, causes Ca2+ overload and hair cell death in varitint-waddler mice, an effect suppressed by the plasma membrane Ca2+ pump PMCA2 (PMID:12403827, PMID:18048323, PMID:19299509). Somatic gain-of-function mutations near the pore drive primary aldosteronism by inducing Ca2+ influx and CYP11B2 upregulation in adrenocortical cells (PMID:40772318).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2002 High

    Established MCOLN3/TRPML3 as a putative six-transmembrane cation channel and linked a specific TM5 mutation (A419P) to the varitint-waddler hair cell degeneration phenotype, defining its disease relevance.

    Evidence Positional cloning, sequence analysis, and immunolocalization in hair cells

    PMID:12403827

    Open questions at the time
    • Did not establish channel function or conductance
    • Mechanism by which A419P causes hair cell death unresolved
  2. 2006 High

    Resolved the subcellular logic of TRPML targeting by showing TRPML3 homomers reside in the ER but are redirected to lysosomes by heteromultimerization with TRPML1/TRPML2, establishing a localization hierarchy.

    Evidence Reciprocal co-immunoprecipitation, subcellular fractionation, and confocal microscopy with targeting mutants

    PMID:16606612

    Open questions at the time
    • Functional consequence of heteromer assembly on conductance not defined
    • Stoichiometry of heteromers unknown
  3. 2007 High

    Defined wild-type TRPML3 biophysics and proved the A419P mutation is gain-of-function, locking an inwardly rectifying channel open via a TM5 helix-breaking kink and causing lethal Ca2+ overload.

    Evidence Whole-cell and single-channel patch-clamp with proline-scan mutagenesis in heterologous and native hair cells

    PMID:17962195 PMID:18048323 PMID:18162548

    Open questions at the time
    • Physiological activating ligand of the wild-type channel not yet identified
    • Mechanism coupling Na+ sensing to gating unresolved
  4. 2008 High

    Identified luminal H+ as a regulator acting through three histidines in the TM1-TM2 loop and showed this regulation communicates with TM5, mechanistically linking the extracytosolic loop to pore gating.

    Evidence Whole-cell patch-clamp with site-directed mutagenesis and pH manipulation

    PMID:18369318

    Open questions at the time
    • Structural path of allosteric coupling between loop and TM5 not visualized
    • In vivo relevance of pH gating untested at this stage
  5. 2008 Medium

    Challenged the constitutive-activity model of deafness by showing TRPML3 mutations reduce mechano-electrical transducer currents and disrupt stereocilia ankle-link localization, implicating a hair-bundle developmental role.

    Evidence MET current recordings, FM1-43 and gentamicin uptake assays, and immunohistochemistry in cochlear hair cells

    PMID:18801844

    Open questions at the time
    • Single lab; relative contribution of MET loss vs Ca2+ overload to deafness unresolved
    • Direct role of TRPML3 in MET channel complex not established
  6. 2009 Medium

    Connected TRPML3 to endocytosis and autophagy regulation, and established PMCA2 as a genetic and functional suppressor of TRPML3(A419P)-induced Ca2+ overload, linking channel activity to cell-death control.

    Evidence siRNA knockdown, dominant-negative expression, trafficking/autophagy assays, Ca2+ imaging, and double-mutant mouse genetics

    PMID:19299509 PMID:19522758

    Open questions at the time
    • Molecular target organelle for TRPML3 Ca2+ delivery in trafficking unclear
    • Direct interaction between TRPML3 and PMCA2 not demonstrated
  7. 2010 Medium

    Showed via clean conditional knockout that TRPML3 loss-of-function alone does not cause auditory/vestibular phenotypes, indicating the varitint-waddler disease arises from gain-of-function rather than absence of channel.

    Evidence Conditional knockout mouse with auditory brainstem response testing and behavioral analysis

    PMID:21179200

    Open questions at the time
    • Possible redundancy with TRPML1/TRPML2 not tested
    • Phenotypes under stress conditions not examined
  8. 2010 Medium

    Characterized pharmacological and pore dynamics, identifying synthetic agonists synergizing with low Na+ and a unique A419P pore expansion, while finding native hair cells/melanocytes lack plasma-membrane activator responses.

    Evidence High-throughput fluorescence screen, single-channel and whole-cell electrophysiology, and native cell testing

    PMID:20189104 PMID:20378547

    Open questions at the time
    • Endogenous agonist not identified
    • Native localization of TRPML3 outside plasma membrane not directly mapped
  9. 2012 Medium

    Mapped Glu-361 in the second extracellular loop as critical for Na+-mediated block, refining the gating model and revealing shared activation mechanisms with TRPML2.

    Evidence Site-directed mutagenesis with whole-cell patch-clamp and pharmacology

    PMID:22753890

    Open questions at the time
    • Structural basis of Na+ sensing not resolved at this stage
    • Physiological Na+ sensing in intact organelles untested
  10. 2013 Medium

    Expanded the heteromeric repertoire by demonstrating a TRPML3-TRPV5 heteromeric channel with distinct single-channel properties, indicating combinatorial channel assembly beyond the TRPML family.

    Evidence Co-immunoprecipitation, single-channel patch-clamp, and pharmacology

    PMID:23469151

    Open questions at the time
    • Physiological context and tissue where the heteromer forms unknown
    • Stoichiometry only partially defined
  11. 2017 High

    Provided high-resolution structural mechanism, revealing the mucolipin/gating-pulley domain as the PtdIns(3,5)P2 sensor and capturing closed, agonist-open, and low-pH inhibited states to explain lipid, agonist, and pH gating.

    Evidence Cryo-EM structures of marmoset and human TRPML3 with functional mutagenesis and electrophysiology

    PMID:29019979 PMID:29106414

    Open questions at the time
    • Structures of heteromeric assemblies not determined
    • Dynamics of conformational transitions in membrane environment not captured
  12. 2018 Medium

    Identified C-terminal palmitoylation as the switch enabling starvation-induced trafficking of TRPML3 to autophagic structures, dissociating trafficking regulation from intrinsic channel activity.

    Evidence Mass spectrometry site mapping, palmitoylation inhibitor and hydroxylamine studies, Ca2+ imaging, and autophagy flux assays

    PMID:30215288

    Open questions at the time
    • Palmitoyltransferase responsible not identified
    • Single lab
  13. 2022 High

    Established TRPML3 as a direct PI3P effector at the phagophore that releases Ca2+ to drive autophagosome biogenesis, and identified an FGL2-MCOLN3 axis triggering autophagy-dependent NET formation in neutrophils.

    Evidence Targeted GCaMP6 Ca2+ reporter imaging, electrophysiology, lipid-binding assays, autophagy assays, and co-IP with knockdown/in vivo models

    PMID:35926777 PMID:36252030

    Open questions at the time
    • Structural basis of PI3P binding distinct from PtdIns(3,5)P2 not resolved
    • FGL2 interaction lacks reciprocal structural validation
  14. 2025 Medium

    Defined the autophagosome-lysosome fusion machinery in which a MCOLN1-MCOLN3 heteromer acts downstream of PtdIns4P to release Ca2+ decoded by SYT5, and integrated TRPML3 with GATE16/RAB33B in autophagosome formation.

    Evidence Co-immunoprecipitation, Ca2+ imaging, autophagy flux assays, KO and dominant-negative constructs, and lipid-binding assays

    PMID:40413756 PMID:40855209

    Open questions at the time
    • Stoichiometry of MCOLN1-MCOLN3 heteromer at fusion sites undefined
    • Single lab for each interaction
  15. 2025 Medium

    Established MCOLN3 as a driver gene for primary aldosteronism, showing pore-region somatic gain-of-function mutations induce Ca2+ influx and CYP11B2 upregulation in adrenocortical cells.

    Evidence NGS of aldosterone-producing adenomas, electrophysiology, fura-2 Ca2+ measurements, gene expression and steroid quantification in transfected cells

    PMID:40772318

    Open questions at the time
    • In vivo causation in animal models not demonstrated
    • Single lab; frequency of these mutations across cohorts unestablished

Open questions

Synthesis pass · forward-looking unresolved questions
  • The endogenous physiological activator and the in vivo tissue-specific functions of native TRPML3 channels (beyond autophagy and hair cells) remain incompletely defined.
  • No single endogenous agonist accounting for all native activation defined
  • Heteromer composition in specific tissues not mapped
  • Mechanism connecting Ca2+ release to specific downstream sensors only partially resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0140299 molecular sensor activity 3 GO:0008289 lipid binding 2
Localization
GO:0005764 lysosome 2 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 2 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-1643685 Disease 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
FGL2GATE16MCOLN1MCOLN2PMCA2RAB33BSYT5TRPV5
Complex memberships
TRPML1-TRPML3 heteromeric channelTRPML1/TRPML2-TRPML3 heteromultimersTRPML3-TRPV5 heteromeric channel

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 MCOLN3/TRPML3 encodes a putative six-transmembrane-domain cation channel protein; the Va allele carries an Ala419Pro substitution in the fifth transmembrane domain causing the varitint-waddler phenotype, while the Va(J) allele has an additional Ile362Thr substitution that partially rescues it. TRPML3 localizes to cytoplasmic compartments of hair cells and plasma membrane of stereocilia, with hair cell defects apparent by embryonic day 17.5. Positional cloning, sequence analysis, immunolocalization in hair cells Proceedings of the National Academy of Sciences of the United States of America High 12403827
2007 The Va mutation A419P in TRPML3 generates a constitutively active cation channel (gain-of-function) by a helix-breaking proline substitution in TM5. Proline substitution scan showed the inner third of TM5 is highly susceptible to proline-based kinks causing constitutive activity; the constitutively active channel was detected as a distinct inwardly rectifying current in native varitint-waddler hair cells. Patch-clamp electrophysiology in heterologous expression and native hair cells; proline substitution scan of TM5 Proceedings of the National Academy of Sciences of the United States of America High 18048323
2007 Wild-type TRPML3 is a strongly inward rectifying cation channel regulated by extracytosolic Na+: pre-incubation in Na+-free medium activates the channel, which then slowly inactivates upon Na+ re-addition. The A419P mutation locks the channel in an open, unregulated state (gain-of-function), affects channel glycosylation, and causes massive cell death. The A419G mutation similarly destabilizes TM5 alpha-helix and produces gain-of-function. I362T results in an inactive channel but does not fully suppress A419P in the double mutant. Whole-cell patch-clamp electrophysiology, site-directed mutagenesis, cell viability assays in heterologous expression system The Journal of biological chemistry High 17962195
2007 Wild-type TRPML3 forms channels with conductance of 50–70 pS, opens at very positive potentials (outward rectification). The A419P mutant generates an additional constitutive inwardly rectifying current that depolarizes cells. Cells expressing TRPML3(A419P) or TRPML3(I362T+A419P) die and are extruded from the epithelium, resembling degeneration of Va hair cells. Single-channel and whole-cell patch-clamp in LLC-PK1-CL4 epithelial cells; immunolocalization Proceedings of the National Academy of Sciences of the United States of America High 18162548
2008 TRPML3 is a Ca2+-permeable channel uniquely regulated by extracytosolic (luminal) H+ via three histidines (H252, H273, H283) in the large extracytosolic loop between TM1 and TM2. H283A mutation locks the channel open (mimics A419P), while H283R inactivates it. The A419P mutation abolishes H+ regulation, suggesting that the extracytosolic loop communicates with TM5 orientation to control pore opening. Whole-cell patch-clamp electrophysiology, site-directed mutagenesis, pH manipulation The EMBO journal High 18369318
2006 TRPML proteins form homo- and heteromultimers. TRPML1 and TRPML2 homomultimers are lysosomal, whereas TRPML3 homomultimers localize to the endoplasmic reticulum. However, TRPML3 is redirected to lysosomes when coexpressed with TRPML1 or TRPML2, demonstrating a hierarchy in which TRPML1 and TRPML2 dictate TRPML3 lysosomal localization but not vice versa. Co-immunoprecipitation, subcellular fractionation, confocal microscopy with dominant-negative and lysosomal-targeting mutants The Journal of biological chemistry High 16606612
2008 TRPML3 mutations (I362T/A419P) cause reduced mechano-electrical transducer (MET) currents in cochlear hair cells, reduced FM1-43 and gentamicin uptake, and loss of TRPML3 localization at the base of stereocilia near ankle links. The study argues TRPML3 plays a critical role at the ankle-link region during hair-bundle growth and that impaired MET is the main cause of hearing loss in Va(J) heterozygotes, rather than constitutive channel activity. Electrophysiological recordings of MET currents, FM1-43 and [3H]gentamicin uptake assays, immunohistochemistry with TRPML3-specific antibody The Journal of physiology Medium 18801844
2009 TRPML3 is a prominent regulator of endocytosis, membrane trafficking, and autophagy. Overexpression of TRPML3 reduces constitutive and regulated endocytosis and increases autophagy. Knockdown of TRPML3 by siRNA or expression of a channel-dead dominant-negative TRPML3(D458K) reduces both endocytosis and autophagy. Upon autophagy induction, TRPML3 is dynamically recruited to autophagosomes, suggesting it controls Ca2+ in the vicinity of cellular organelles needed for these events. Gradient fractionation, confocal localization, siRNA knockdown, dominant-negative expression, endocytosis and autophagy assays Traffic (Copenhagen, Denmark) Medium 19522758
2009 PMCA2 (plasma membrane calcium ATPase 2) significantly reduces [Ca2+]i increase and apoptosis in HEK293 cells expressing constitutively active TRPML3(A419P). Genetic epistasis in mice: combining heterozygous Va (TRPML3 A419P) with heterozygous deaf-waddler (PMCA2 G283S) alleles causes severe hair bundle defects and increased hair cell loss compared to single mutants, establishing PMCA2 as a functional suppressor of TRPML3(A419P)-induced Ca2+ overload. Ca2+ imaging, apoptosis assays in HEK293 cells; double-mutant mouse genetics with auditory brainstem responses The Journal of biological chemistry High 19299509
2010 The TRPML3 pore is dynamic during Ca2+ conduction: it changes conductance and permeability, apparently by trapping Ca2+ within the pore, and can be restored by strong depolarization or Na+ conduction. The A419P mutation results in an expanded channel pore with altered permeability that limits Ca2+-mediated pore modulation; this effect is specific to A419P and is not reproduced by other gain-of-function mutations (A419G, H283A, or other TM5 prolines). Whole-cell and single-channel patch-clamp electrophysiology, site-directed mutagenesis The Journal of biological chemistry Medium 20378547
2010 Genetic inactivation (conditional knockout) of Trpml3 in mice does not lead to hearing loss, vestibular impairment, or circling behavior, establishing that TRPML3 loss-of-function alone is not sufficient to cause auditory/vestibular phenotypes under normal conditions. Conditional knockout mouse, auditory brainstem response testing, behavioral observation PloS one Medium 21179200
2010 TRPML3 can be activated by low extracytosolic sodium and by diverse small molecules identified in a high-throughput screen. Agonists synergize with low extracytosolic [Na+], revealing distinct cooperative activation mechanisms. Testing on native sensory hair cells and melanocytes shows absence of activator-responsive channels, suggesting TRPML3 is absent from the plasma membrane in these native cells or is part of nonresponsive heteromeric channels. High-throughput fluorescence-based screen, electrophysiology, cheminformatics, native cell testing Chemistry & biology Medium 20189104
2012 Glu-361 in the second extracellular loop of TRPML3 is critical for sodium-mediated block; mutating this negatively charged residue significantly reduces the sodium inhibition of TRPML3. TRPML2 is also activated by lowering extracellular sodium concentration and by a subset of TRPML3 agonists, suggesting similar gating mechanisms for both channels. Site-directed mutagenesis, whole-cell patch-clamp electrophysiology, pharmacological screening The Journal of biological chemistry Medium 22753890
2013 TRPML3 and TRPV5 physically associate to form a novel heteromeric ion channel with pharmacological properties similar to TRPML3 but distinct single-channel features from either homomeric channel. The heteromer requires functional TRPML3 and functional TRPV5, and occurs in potentially distinct stoichiometric configurations. Co-immunoprecipitation, single-channel patch-clamp electrophysiology, pharmacology PloS one Medium 23469151
2017 Cryo-EM structure of full-length marmoset TRPML3 at 2.9 Å resolution reveals: (1) a unique architecture where the voltage sensor-like domain is linked to the pore via a cytosolic 'mucolipin domain'; (2) the mucolipin domain is responsible for PtdIns(3,5)P2 binding and channel activation; (3) it acts as a 'gating pulley' for lipid-dependent channel gating. Conserved basic residues at the N-terminus mediate PtdIns(3,5)P2 activation and PtdIns(4,5)P2 inhibition. Cryo-EM structure determination, functional electrophysiology with mutagenesis of basic residues Nature High 29019979
2017 Cryo-EM structures of human TRPML3 in closed, agonist-activated (ML-SA1 bound), and low-pH-inhibited states. The agonist ML-SA1 lodges between S5 and S6 and opens the S6 gate. A polycystin-mucolipin domain (PMD) forms a luminal cap; S1 extends into this cap as a 'gating rod' connected to a luminal pore loop that undergoes dramatic conformational changes at low pH. S2 extends intracellularly forming a 'gating knob'. Low pH induces inhibition by changing S1 and S2 conformations. PIP2 regulation also acts through S1 and S2 conformational changes. Cryo-EM structure determination at 3.62–4.65 Å, electrophysiology, agonist binding studies Nature structural & molecular biology High 29106414
2018 MCOLN3/TRPML3 undergoes palmitoylation at its C-terminal region. Palmitoylation is required for dynamic trafficking of MCOLN3 to autophagic structures and for MCOLN3's function in autophagosome formation, but not for channel properties or localization/function of intracellular MCOLN3. Nutrient starvation activates MCOLN3 and increases its palmitoylation level; disruption of palmitoylation abolishes starvation-induced channel activation without affecting intrinsic channel activity. Mass spectrometry for palmitoylation site identification, 2-BP inhibitor studies, hydroxylamine treatment, Ca2+ imaging, autophagy flux assays, shRNA knockdown Autophagy Medium 30215288
2022 TRPML3 localizes in phagophores and is a downstream effector of phosphatidylinositol-3-phosphate (PI3P). PI3P directly activates TRPML3 current and Ca2+ release from the phagophore to promote autophagosome biogenesis. TRPML3 physically interacts with PI3P; disruption of this interaction abolishes both PI3P-dependent activation and the increase in autophagy. Inhibition of TRPML3 suppresses autophagy even in the presence of excess PI3P. TRPML3-GCaMP6 targeted reporter Ca2+ imaging, patch-clamp electrophysiology, lipid-binding assays, autophagy flux assays, KO and activation studies Proceedings of the National Academy of Sciences of the United States of America High 36252030
2022 FGL2 (fibrinogen-like protein 2) directly interacts with mucolipin 3 (MCOLN3/TRPML3) in neutrophils, regulating calcium influx and initiating autophagy that leads to neutrophil extracellular trap (NET) formation. This FGL2-MCOLN3-autophagy axis drives NET-mediated liver injury in fulminant viral hepatitis. Co-immunoprecipitation (direct interaction), adoptive transfer experiments, siRNA/shRNA knockdown, calcium flux assays Cellular and molecular gastroenterology and hepatology Medium 35926777
2025 Somatic gain-of-function mutations in MCOLN3 (p.Y391D, p.F415I, p.N411_V412delinsI), located near the ion pore and selectivity filter, cause membrane depolarization and calcium influx in adrenocortical HAC15 cells, triggering increased CYP11B2 (aldosterone synthase) expression and aldosterone production, establishing MCOLN3 as a driver gene for primary aldosteronism. Next-generation sequencing of APAs, electrophysiology, fura-2 calcium measurements, gene expression assays, steroid quantification in transfected adrenocortical cells Hypertension (Dallas, Tex. : 1979) Medium 40772318
2025 MCOLN1/TRPML1 and MCOLN3/TRPML3 form a heteromeric channel that acts downstream of PtdIns4P to release Ca2+ from autophagosomes for autophagosome-lysosome fusion. The Ca2+ signal is decoded by the Ca2+ sensor SYT5 (synaptotagmin 5), which binds both Ca2+ and PtdIns4P to form a fusion complex. Disruption of the MCOLN1-MCOLN3 heteromer or the MCOLN3-SYT5 interaction inhibits autophagosome-lysosome fusion. Co-immunoprecipitation, Ca2+ imaging, autophagy flux assays, KO cells, dominant-negative constructs, lipid-binding assays Autophagy Medium 40413756
2025 TRPML3 specifically interacts with the mammalian ATG8 homolog GATE16 (but not LC3B) through single amino acid motifs in both proteins that determine interaction specificity. RAB33B, a Golgi-resident GTPase, also functionally interacts with TRPML3 and contains an LIR motif that specifically binds GATE16. Upon autophagy induction, RAB33B is recruited from the Golgi to the phagophore in an LIR-dependent manner, enhancing the RAB33B-TRPML3 interaction and promoting autophagosome formation. Co-immunoprecipitation, site-directed mutagenesis, fluorescence microscopy, autophagy flux assays Scientific reports Medium 40855209
2025 Alkaline extracellular pH elevates lysosomal pH, which activates the lysosomal Ca2+ channel TRPML3. This TRPML3 activation enhances RNF13 E3 ubiquitin ligase activity, which in turn drives ARL8B degradation and promotes perinuclear lysosomal positioning (retrograde transport). Lysosomal pH measurements, Ca2+ imaging, TRPML3 channel activity assays, RNF13 activity assays, lysosomal positioning quantification bioRxivpreprint Low

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice. Proceedings of the National Academy of Sciences of the United States of America 179 12403827
2009 The Ca(2+) channel TRPML3 regulates membrane trafficking and autophagy. Traffic (Copenhagen, Denmark) 136 19522758
2007 A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse. Proceedings of the National Academy of Sciences of the United States of America 133 18048323
2006 Lysosomal localization of TRPML3 depends on TRPML2 and the mucolipidosis-associated protein TRPML1. The Journal of biological chemistry 123 16606612
2007 The varitint-waddler (Va) deafness mutation in TRPML3 generates constitutive, inward rectifying currents and causes cell degeneration. Proceedings of the National Academy of Sciences of the United States of America 107 18162548
2010 Small molecule activators of TRPML3. Chemistry & biology 104 20189104
2017 Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3. Nature 98 29019979
2007 Gain-of-function mutation in TRPML3 causes the mouse Varitint-Waddler phenotype. The Journal of biological chemistry 98 17962195
2008 A novel mode of TRPML3 regulation by extracytosolic pH absent in the varitint-waddler phenotype. The EMBO journal 82 18369318
2017 Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states. Nature structural & molecular biology 74 29106414
2018 Palmitoylation controls trafficking of the intracellular Ca2+ channel MCOLN3/TRPML3 to regulate autophagy. Autophagy 52 30215288
2008 TRPML3 mutations cause impaired mechano-electrical transduction and depolarization by an inward-rectifier cation current in auditory hair cells of varitint-waddler mice. The Journal of physiology 48 18801844
2008 The varitint-waddler mouse phenotypes and the TRPML3 ion channel mutation: cause and consequence. Pflugers Archiv : European journal of physiology 42 18504603
2022 FGL2-MCOLN3-Autophagy Axis-Triggered Neutrophil Extracellular Traps Exacerbate Liver Injury in Fulminant Viral Hepatitis. Cellular and molecular gastroenterology and hepatology 40 35926777
2024 Baicalin induces cell death of non-small cell lung cancer cells via MCOLN3-mediated lysosomal dysfunction and autophagy blockage. Phytomedicine : international journal of phytotherapy and phytopharmacology 30 39096542
2012 Constitutive activity of TRPML2 and TRPML3 channels versus activation by low extracellular sodium and small molecules. The Journal of biological chemistry 28 22753890
2011 Expression and vesicular localization of mouse Trpml3 in stria vascularis, hair cells, and vomeronasal and olfactory receptor neurons. The Journal of comparative neurology 25 21344404
2007 TRPML3 and hearing loss in the varitint-waddler mouse. Biochimica et biophysica acta 24 17329082
2022 The intracellular Ca2+ channel TRPML3 is a PI3P effector that regulates autophagosome biogenesis. Proceedings of the National Academy of Sciences of the United States of America 22 36252030
2010 Genetic inactivation of Trpml3 does not lead to hearing and vestibular impairment in mice. PloS one 22 21179200
2013 A novel ion channel formed by interaction of TRPML3 with TRPV5. PloS one 21 23469151
2010 Properties of the TRPML3 channel pore and its stable expansion by the Varitint-Waddler-causing mutation. The Journal of biological chemistry 21 20378547
2009 Life and death of sensory hair cells expressing constitutively active TRPML3. The Journal of biological chemistry 20 19299509
2014 TRPML3. Handbook of experimental pharmacology 17 24756725
2011 The TRPML3 channel: from gene to function. Advances in experimental medicine and biology 12 21290299
2022 TRPML3 enhances drug resistance in non-small cell lung cancer cells by promoting Ca2+-mediated lysosomal trafficking. Biochemical and biophysical research communications 11 36037747
2025 Somatic Mutations in MCOLN3 Are Associated With Aldosterone-Producing Adenomas. Hypertension (Dallas, Tex. : 1979) 8 40772318
2022 Whole-body analysis of TRPML3 (MCOLN3) expression using a GFP-reporter mouse model reveals widespread expression in secretory cells and endocrine glands. PloS one 8 36520788
2025 Targeting TRPML3 inhibits proliferation and invasion, and enhances doxorubicin sensitivity by disrupting lysosomal acidification and mitochondrial function in triple-negative breast cancer. Biochimica et biophysica acta. Molecular cell research 1 40348344
2025 TRPML3‑mediated lysosomal Ca2+ release enhances drug sequestration and biogenesis, promoting osimertinib resistance in non‑small cell lung cancer. Oncology reports 1 40682834
2025 TRP channels in hepatocellular carcinoma: integrative Mendelian randomization and multi-omics analyses highlight MCOLN3/TRPV4 as candidate dual-effect biomarkers. Human genomics 1 40775364
2024 Somatic Mutations in MCOLN3 in Aldosterone-Producing Adenomas cause Primary Aldosteronism. bioRxiv : the preprint server for biology 1 39484451
2025 MCOLN1/TRPML1-MCOLN3/TRPML3 heteromer and its coupling to Ca2+ sensor SYT5 regulates autophagosome-lysosome fusion in a PtdIns4P-dependent manner. Autophagy 0 40413756
2025 Two specific interactions of GATE16 with TRPML3 and RAB33B regulate autophagy. Scientific reports 0 40855209

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