Affinage

MCOLN3

Mucolipin-3 · UniProt Q8TDD5

Length
553 aa
Mass
64.2 kDa
Annotated
2026-04-28
34 papers in source corpus 22 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MCOLN3/TRPML3 is a Ca²⁺-permeable, inwardly rectifying cation channel of the mucolipin/TRPML subfamily that functions in endolysosomal ion homeostasis, autophagy, and sensory cell development. The channel is gated by the endolysosomal lipid PtdIns(3,5)P₂ via a unique cytosolic mucolipin domain that acts as a gating pulley, is inhibited by low luminal pH through extracytosolic histidine residues (notably H283), and is blocked by extracytosolic Na⁺ at residue E361; cryo-EM structures in closed, agonist-bound, and pH-inhibited states define the structural basis of these regulatory mechanisms (PMID:29019979, PMID:29106414, PMID:18369318, PMID:22753890). TRPML3 provides Ca²⁺ at multiple stages of autophagy: it is activated by PI3P on phagophores to promote autophagosome biogenesis in concert with GATE16 and RAB33B, and forms a heteromer with TRPML1 that supplies Ca²⁺ for PtdIns4P/SYT5-dependent autophagosome–lysosome fusion; palmitoylation at its C-terminus is required for starvation-induced trafficking to autophagic structures (PMID:36252030, PMID:40855209, PMID:40413756, PMID:30215288). Somatic gain-of-function mutations near the pore (Y391D, F415I, N411_V412delinsI) cause constitutive Ca²⁺ influx in adrenocortical cells and drive aldosterone overproduction, identifying MCOLN3 as a causative gene in primary aldosteronism, while the classical A419P gain-of-function mutation in TM5 causes hair cell degeneration and deafness in varitint-waddler mice through Ca²⁺ overload counteracted by PMCA2 (PMID:40772318, PMID:12403827, PMID:18048323, PMID:19299509).

Mechanistic history

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

    Positional cloning of the varitint-waddler locus established MCOLN3 as a TRP-family channel essential for hair cell maturation and identified the A419P substitution in TM5 as the causative mutation, opening the field to functional characterization.

    Evidence Positional cloning, immunolocalization in hair cells, mouse genetics with dominant Va alleles

    PMID:12403827

    Open questions at the time
    • Channel activity not yet demonstrated electrophysiologically
    • Mechanism by which A419P causes hair cell death unknown
    • Subcellular trafficking and endolysosomal function not explored
  2. 2006 High

    Demonstration that TRPML1–3 form homo- and heteromultimers, with TRPML1/2 redirecting TRPML3 from the ER to lysosomes, established that heteromerization dictates TRPML3 subcellular localization and functional context.

    Evidence Reciprocal co-immunoprecipitation, confocal co-localization, dominant-negative lysosomal targeting

    PMID:16606612

    Open questions at the time
    • Stoichiometry of heteromeric complexes undetermined
    • Functional consequences of heteromerization on channel conductance unknown
  3. 2007 High

    Electrophysiological recordings revealed that TRPML3 is a strongly inward-rectifying cation channel regulated by extracytosolic Na⁺, and that the A419P mutation locks it in a constitutively open state — explaining hair cell death as a gain-of-function Ca²⁺ overload mechanism.

    Evidence Patch-clamp electrophysiology in heterologous cells and native hair cells, proline substitution scan mutagenesis, surface biotinylation

    PMID:17962195 PMID:18048323 PMID:18162548

    Open questions at the time
    • Endogenous regulatory lipids not yet identified
    • Structural basis of TM5 gating not resolved
    • Physiological activator in vivo unknown
  4. 2008 High

    Identification of three extracytosolic histidines (H252, H273, H283) as pH sensors, with H283 serving as the inhibitory switch, established luminal pH as a gating mechanism and showed that A419P bypasses pH regulation — linking TRPML3 activity to the acidic endolysosomal lumen.

    Evidence Systematic histidine mutagenesis combined with patch-clamp pH titration

    PMID:18369318

    Open questions at the time
    • Structural mechanism of pH-induced conformational change unresolved
    • Relative contributions of pH vs. Na⁺ block in vivo unclear
  5. 2008 High

    Localization of TRPML3 to the stereocilia ankle-link region and demonstration that Va(J) mutations abolish this localization while reducing mechanotransduction currents provided the first evidence that TRPML3 functions at a specific subcellular site in hair cells.

    Evidence TRPML3-specific immunohistochemistry, MET current recordings, FM1-43 uptake in Va(J) mice

    PMID:18801844

    Open questions at the time
    • Whether TRPML3 is a component of the MET complex or an accessory channel remains unresolved
    • Mechanism of TRPML3 stereociliary targeting unknown
  6. 2009 High

    Functional studies showing that TRPML3 dynamically traffics between the plasma membrane and intracellular compartments, is recruited to autophagosomes upon starvation, and is required for both endocytosis and autophagy established its role as a membrane trafficking regulator beyond hair cells.

    Evidence Gradient fractionation, siRNA knockdown, dominant-negative TRPML3(D458K), autophagy/endocytosis flux assays

    PMID:19522758

    Open questions at the time
    • Ca²⁺-dependent mechanism linking TRPML3 to autophagosome formation unknown
    • Lipid activators of TRPML3 autophagy function not identified
  7. 2009 High

    Genetic epistasis between varitint-waddler and deaf-waddler (PMCA2) mice, combined with Ca²⁺ imaging rescue experiments, established that PMCA2 counteracts TRPML3-mediated Ca²⁺ overload, providing a quantitative model for delayed hair cell death.

    Evidence Double-mutant mouse genetics, HEK293 co-expression, intracellular Ca²⁺ imaging, apoptosis assays

    PMID:19299509

    Open questions at the time
    • Whether other Ca²⁺ clearance mechanisms contribute in vivo is untested
    • Downstream Ca²⁺-dependent death pathways not fully mapped
  8. 2010 High

    Biophysical characterization showed that A419P produces a uniquely expanded pore resistant to Ca²⁺-mediated modulation, and identification of E361 as the critical residue for Na⁺ block refined understanding of extracytosolic gating mechanisms.

    Evidence Inside-out patch clamp with ion substitution, systematic mutagenesis of charged extracellular loop residues

    PMID:20378547 PMID:22753890

    Open questions at the time
    • Atomic-resolution pore structure not yet available
    • Physiological significance of pore plasticity in normal TRPML3 function unclear
  9. 2017 High

    Cryo-EM structures of TRPML3 at near-atomic resolution in multiple states revealed the mucolipin domain as a PtdIns(3,5)P₂-binding gating pulley, defined the agonist-binding site between S5–S6, and showed how the luminal PMD cap and S1 gating rod transduce pH inhibition — providing the first complete structural framework for TRPML gating.

    Evidence Cryo-EM at 2.9–4.65 Å in closed, ML-SA1-activated, and low-pH-inhibited states; mutagenesis with electrophysiology

    PMID:29019979 PMID:29106414

    Open questions at the time
    • No structure of the heteromeric TRPML1–TRPML3 complex
    • Structural basis of Na⁺ block not captured
    • Lipid-bound open-state structure lacking
  10. 2018 High

    Discovery that C-terminal palmitoylation is required for starvation-induced TRPML3 trafficking to autophagic structures and Ca²⁺ release identified a post-translational switch that couples nutrient status to TRPML3 activation.

    Evidence 17-ODYA metabolic labeling, mass spectrometry, 2-bromopalmitate inhibition, Ca²⁺ imaging, autophagy flux assays

    PMID:30215288

    Open questions at the time
    • Palmitoyl transferase(s) responsible not identified
    • Whether depalmitoylation terminates TRPML3 autophagy function untested
  11. 2022 High

    Identification of PI3P as a direct activator of TRPML3 on phagophores, and of TRPML3 as a PI3P effector required for autophagosome biogenesis, resolved how early autophagy lipid signals are transduced into Ca²⁺ release at the phagophore membrane.

    Evidence TRPML3-GCaMP6 targeted Ca²⁺ reporter, lipid binding assays, patch-clamp electrophysiology, TRPML3 KO/KD with autophagy flux rescue

    PMID:36252030

    Open questions at the time
    • How PI3P and PtdIns(3,5)P₂ activation are distinguished structurally unknown
    • Downstream Ca²⁺ effectors at the phagophore not fully defined
  12. 2022 Medium

    Demonstration that TRPML3 senses lysosomal pH elevation (e.g., gefitinib-induced) to trigger lysosomal exocytosis and exosome release linked TRPML3 pH-sensing to drug resistance, while the FGL2–TRPML3 interaction connected TRPML3-dependent Ca²⁺/autophagy to NET formation in viral hepatitis.

    Evidence siRNA knockdown with lysosomal pH/Ca²⁺ imaging and exosome quantification (gefitinib); Co-IP with Ca²⁺ flux and mouse models (FGL2)

    PMID:35926777 PMID:36037747

    Open questions at the time
    • FGL2–TRPML3 interaction awaits reciprocal validation and structural characterization
    • Whether TRPML3-mediated exocytosis occurs in non-cancer contexts untested
    • Direct binding site of FGL2 on TRPML3 unknown
  13. 2025 Medium

    The TRPML1–TRPML3 heteromer was identified as the Ca²⁺ source for PtdIns4P/SYT5-dependent autophagosome–lysosome fusion, establishing that TRPML3 participates in two distinct lipid-gated Ca²⁺ release steps during autophagy (PI3P at the phagophore and PtdIns4P at fusion).

    Evidence Co-immunoprecipitation of TRPML1–TRPML3, Ca²⁺ imaging, PtdIns4P binding assays, KO/KD autophagy flux

    PMID:40413756

    Open questions at the time
    • Stoichiometry and structure of the TRPML1–TRPML3 heteromer unknown
    • Whether SYT5 is the sole Ca²⁺ sensor for this fusion step untested
  14. 2025 Medium

    Mapping of GATE16-specific and RAB33B-specific interaction motifs on TRPML3 defined a TRPML3–GATE16–RAB33B axis at the phagophore, resolving how TRPML3 selectively recruits Golgi-derived RAB33B to promote autophagosome formation.

    Evidence Co-immunoprecipitation, LIR/GIM motif mutagenesis, confocal RAB33B recruitment imaging, autophagy flux assays

    PMID:40855209

    Open questions at the time
    • Direct structural evidence for ternary complex lacking
    • Whether GATE16 selectivity over LC3B has functional consequences for autophagy cargo selection unknown
  15. 2025 High

    Discovery of somatic gain-of-function MCOLN3 mutations (Y391D, F415I, N411_V412delinsI) in aldosterone-producing adenomas established TRPML3 as a driver of primary aldosteronism through constitutive Ca²⁺ influx and CYP11B2 upregulation.

    Evidence Next-generation sequencing of APAs, patch-clamp electrophysiology, fura-2 Ca²⁺ measurements, CYP11B2 expression and aldosterone quantification in HAC15 cells

    PMID:40772318

    Open questions at the time
    • Frequency of MCOLN3 mutations across APA cohorts not established
    • Mechanism by which Ca²⁺ influx activates CYP11B2 transcription not delineated
    • Whether these mutants also affect autophagy in adrenocortical cells unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structure of the TRPML1–TRPML3 heteromeric complex, the identity of palmitoyl transferases regulating TRPML3 autophagy trafficking, the structural basis for PI3P versus PtdIns(3,5)P₂ discrimination, and whether TRPML3's dual role in phagophore biogenesis and autophagosome–lysosome fusion is coordinated by a single regulatory switch.
  • No heteromeric cryo-EM structure
  • Palmitoyl transferase identity unknown
  • PI3P vs PtdIns(3,5)P₂ binding site discrimination unresolved structurally

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 7 GO:0008289 lipid binding 2
Localization
GO:0005764 lysosome 4 GO:0031410 cytoplasmic vesicle 3 GO:0005886 plasma membrane 2 GO:0005929 cilium 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-382551 Transport of small molecules 5 R-HSA-9612973 Autophagy 5 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9709957 Sensory Perception 2
Partners
ATP2B2FGL2GABARAPL2MCOLN1MCOLN2RAB33BSYT5TRPV5
Complex memberships
TRPML1-TRPML3 heteromerTRPML3-TRPV5 heteromer

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 MCOLN3/TRPML3 is a putative six-transmembrane-domain ion channel protein with sequence and motif similarities to TRP channels; it localizes to cytoplasmic compartments of hair cells and the plasma membrane of stereocilia, and plays an essential role during early hair cell maturation acting cell-autonomously. The Va allele A419P substitution in TM5 causes the varitint-waddler phenotype. Positional cloning, immunolocalization, mouse genetics (dominant mutant alleles) Proceedings of the National Academy of Sciences of the United States of America High 12403827
2006 TRPML1, TRPML2, and TRPML3 interact to form homo- and heteromultimers. TRPML3 homomultimers localize to the ER, but TRPML3 is redirected to lysosomes when co-expressed with TRPML1 or TRPML2, demonstrating a hierarchy in which TRPML1 and TRPML2 dictate TRPML3 subcellular localization. Co-immunoprecipitation, confocal co-localization, dominant-negative lysosomal targeting mutants The Journal of biological chemistry High 16606612
2007 The varitint-waddler A419P mutation in TM5 renders TRPML3 constitutively active as a cation channel; a proline substitution scan showed the inner third of TM5 is highly susceptible to proline-based kinks that constitutively open the channel, causing hair cell death and deafness. Electrophysiology (patch clamp in heterologous cells and native hair cells), proline substitution scan mutagenesis 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+; preincubating the extracytosolic face in Na+-free medium is required for channel activation. The A419P mutation locks the channel in an open, unregulated state (gain-of-function), affects channel glycosylation, and causes cell death. The I362T mutation results in an inactive channel but reduces surface expression and current density of the A419P background. Patch-clamp electrophysiology (excised inside-out patches), mutagenesis, surface biotinylation The Journal of biological chemistry High 17962195
2007 Wild-type TRPML3 forms cation channels with ~50–70 pS conductance that are blocked by Gd3+ and rectify outwardly; the A419P (and I362T/A419P) mutations generate a constitutive inwardly rectifying current that depolarizes cells. Cells expressing A419P TRPML3 die and are extruded from the epithelium, mimicking hair cell degeneration. Patch-clamp electrophysiology (heterologous LLC-PK1-CL4 cells), cell death assays 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+ through three histidines (H252, H273, H283) in the large extracytosolic loop between TM1 and TM2. H283 is the inhibitory residue; H283A mimics A419P gain-of-function, while H283R inactivates the channel. The A419P mutation eliminates H+-mediated regulation by disrupting communication between the extracytosolic loop and TM5 pore gating. Patch-clamp electrophysiology, site-directed mutagenesis of histidine residues, pH titration The EMBO journal High 18369318
2008 TRPML3 localizes to the base of stereocilia near the ankle-link position in postnatal hair cells. The Va(J) mutations (I362T/A419P) abolish this stereociliary localization, reduce mechano-electrical transducer (MET) currents, and decrease FM1-43/gentamicin uptake; outer hair cells of Va(J) homozygotes additionally show an inwardly rectifying leak current causing depolarization. Immunohistochemistry with TRPML3-specific antibody, electrophysiology (MET current recordings), FM1-43 uptake, [3H]gentamicin accumulation The Journal of physiology High 18801844
2009 TRPML3 is a regulator of endocytosis, membrane trafficking, and autophagy. It dynamically localizes to the plasma membrane and multiple intracellular compartments; its plasma membrane accumulation increases upon endocytosis inhibition and it is recruited to autophagosomes upon autophagy induction. Overexpression reduces endocytosis and increases autophagy; siRNA knockdown and dominant-negative TRPML3(D458K) reduce both endocytosis and autophagy. Gradient fractionation, confocal localization, siRNA knockdown, dominant-negative overexpression, autophagy/endocytosis assays Traffic (Copenhagen, Denmark) High 19522758
2009 PMCA2 (plasma membrane Ca2+-ATPase 2) rescues the cytosolic Ca2+ overload and apoptosis caused by constitutively active TRPML3(A419P); reducing PMCA2 activity (deaf-waddler allele) exacerbates hair cell loss and vestibular/auditory defects in varitint-waddler mice, providing a molecular basis for delayed hair cell death. Heterologous co-expression in HEK293 cells, intracellular Ca2+ imaging, apoptosis assays, mouse double-mutant genetics The Journal of biological chemistry High 19299509
2010 The TRPML3 pore is dynamic during Ca2+ conduction, with conductance and permeability modulated by Ca2+ trapping within the pore; strong depolarization or Na+ conduction restores pore properties. The A419P mutation produces a stably expanded pore with altered permeability that cannot be modulated by Ca2+, a mechanism specific to A419P and not shared by A419G, H283A, or other TM5 proline mutations. Patch-clamp electrophysiology (inside-out patches), ion substitution experiments, mutagenesis The Journal of biological chemistry High 20378547
2010 TRPML3 constitutive activity in low/no extracellular Na+ is sodium-independent intracellularly; Glu-361 in the second extracellular loop is critical for sodium-mediated block of TRPML3. TRPML2 shares similar activation by low extracellular sodium and responds to a subset of TRPML3 activating small molecules, suggesting conserved gating mechanisms. Mutagenesis of negatively charged extracellular loop residues, patch-clamp electrophysiology, small molecule pharmacology The Journal of biological chemistry High 22753890
2010 A high-throughput screen identified 53 small molecule activators of TRPML3 from nine chemical scaffolds. These activators synergize with low extracytosolic Na+ to potentiate TRPML3 activation, revealing distinct and cooperative activation mechanisms. Native hair cell or melanocyte TRPML3 did not respond to activators, suggesting plasma membrane absence or heteromeric channel formation in native cells. High-throughput electrophysiology screen, cheminformatics, native cell recordings Chemistry & biology Medium 20189104
2013 TRPML3 associates with TRPV5 to form a novel heteromeric ion channel with pharmacological similarity to TRPML3 homomers and requiring functional versions of both subunits; single-channel analysis revealed distinct features and potentially different stoichiometric configurations compared to homomers. Co-immunoprecipitation, patch-clamp electrophysiology (single-channel), mutagenesis of both subunits PloS one Medium 23469151
2017 Cryo-EM structure of full-length TRPML3 at 2.9 Å resolution reveals a unique cytosolic 'mucolipin domain' linking the voltage sensor-like domain to the pore; this domain is responsible for PtdIns(3,5)P2 binding and acts as a 'gating pulley' for lipid-dependent channel gating. The structure also reveals the molecular basis of ion conduction. Cryo-electron microscopy (2.9 Å), functional electrophysiology, mutagenesis of PtdIns(3,5)P2 binding residues Nature High 29019979
2017 Cryo-EM structures of human TRPML3 in closed (4.06 Å), agonist-activated (3.62 Å), and low-pH-inhibited (4.65 Å) states reveal that the agonist ML-SA1 lodges between S5 and S6 to open the S6 gate; S1 extends into a luminal PMD cap as a 'gating rod' connected to a luminal pore loop that changes conformation at low pH; S2 extends intracellularly as a 'gating knob'. These features define pH- and PIP2-dependent TRPML3 gating. Cryo-EM (three conformational states), electrophysiology (ML-SA1 and pH experiments), mutagenesis Nature structural & molecular biology High 29106414
2018 MCOLN3/TRPML3 undergoes palmitoylation at its C-terminal region; palmitoylation is required for dynamic trafficking of TRPML3 to autophagic structures and for its function as a Ca2+ channel supporting autophagy, but does not affect intrinsic channel properties or localization/function of intracellular TRPML3. Nutrient starvation increases TRPML3 palmitoylation and Ca2+ release; disruption of palmitoylation abolishes starvation-induced TRPML3 activation. 17-ODYA metabolic labeling, 2-bromopalmitate inhibition, hydroxylamine treatment, mass spectrometry, Ca2+ imaging, autophagy flux assays Autophagy High 30215288
2022 TRPML3 localizes in phagophores and is a direct effector of PI3P; PI3P binds TRPML3 and directly activates its current and Ca2+ release from the phagophore to promote autophagosome biogenesis. Inhibition of TRPML3 blocks autophagy even with excess PI3P; TRPML3 also interacts with the ATG8 homolog GATE16. TRPML3-GCaMP6 targeted Ca2+ reporter, lipid binding assays, patch-clamp electrophysiology, autophagy flux assays, TRPML3 KO/KD Proceedings of the National Academy of Sciences of the United States of America High 36252030
2022 FGL2 directly interacts with MCOLN3/mucolipin 3, triggering calcium influx and initiating autophagy that leads to neutrophil extracellular trap (NET) formation and liver injury in fulminant viral hepatitis. Co-immunoprecipitation (FGL2-MCOLN3 interaction), Ca2+ flux assay, adoptive transfer, mouse model Cellular and molecular gastroenterology and hepatology Medium 35926777
2022 TRPML3 senses elevation of lysosomal pH (caused by gefitinib) to trigger lysosomal Ca2+ release, lysosomal trafficking and exocytosis, and exosomal release, promoting drug resistance in NSCLC; TRPML3 deficiency enhances gefitinib-mediated cell death. TRPML3 KD (siRNA), lysosomal pH measurement, Ca2+ imaging, exosome quantification, drug sensitivity assays Biochemical and biophysical research communications Medium 36037747
2025 MCOLN1/TRPML1 and MCOLN3/TRPML3 form a heteromer that acts as the Ca2+ provider for autophagosome-lysosome fusion downstream of PtdIns4P. The Ca2+ signal is decoded by Ca2+ sensor SYT5 (synaptotagmin 5), whose binding to both Ca2+ and PtdIns4P is critical for assembling the fusion complex. Co-immunoprecipitation (TRPML1-TRPML3 heteromer), Ca2+ imaging, PtdIns4P binding assays, autophagy flux assays, KO/KD experiments Autophagy Medium 40413756
2025 TRPML3 specifically interacts with the ATG8 homolog GATE16 (but not LC3B) via single amino acid motifs in both proteins; RAB33B, a Golgi-resident GTPase, also interacts with TRPML3 through an LIR motif that specifically binds GATE16, and is recruited from the Golgi to the phagophore upon autophagy induction to promote autophagosome formation. Co-immunoprecipitation, mutagenesis of interaction motifs, confocal imaging of RAB33B recruitment, autophagy flux assays Scientific reports Medium 40855209
2025 Somatic gain-of-function mutations in MCOLN3 (p.Y391D, p.F415I, p.N411_V412delinsI), located near the ion pore and selectivity filter, cause cell membrane depolarization and calcium influx in adrenocortical cells, leading to increased aldosterone synthase (CYP11B2) expression and aldosterone production, identifying MCOLN3 as a driver of primary aldosteronism. Next-generation sequencing of APAs, patch-clamp electrophysiology, fura-2 Ca2+ measurements, gene expression (CYP11B2), steroid quantification in HAC15 cells Hypertension (Dallas, Tex. : 1979) High 40772318
2025 Alkaline extracellular pH elevates lysosomal pH and activates the lysosomal Ca2+ channel TRPML3, which in turn activates RNF13 (an E3 ubiquitin ligase) to drive perinuclear lysosomal repositioning via ARL8B degradation. Lysosomal Ca2+ measurements, TRPML3 pharmacological activation/inhibition, lysosomal positioning imaging, RNF13 activity assays 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) 134 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 97 29019979
2007 Gain-of-function mutation in TRPML3 causes the mouse Varitint-Waddler phenotype. The Journal of biological chemistry 97 17962195
2008 A novel mode of TRPML3 regulation by extracytosolic pH absent in the varitint-waddler phenotype. The EMBO journal 81 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 35 35926777
2012 Constitutive activity of TRPML2 and TRPML3 channels versus activation by low extracellular sodium and small molecules. The Journal of biological chemistry 28 22753890
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 25 39096542
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
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 Somatic Mutations in MCOLN3 Are Associated With Aldosterone-Producing Adenomas. Hypertension (Dallas, Tex. : 1979) 6 40772318
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