Affinage

UNC13B

Protein unc-13 homolog B · UniProt O14795

Length
1591 aa
Mass
180.7 kDa
Annotated
2026-04-28
52 papers in source corpus 30 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UNC13B (Munc13-2) is a presynaptic priming factor that renders docked synaptic vesicles fusion-competent by converting syntaxin from a closed to an open conformation, thereby enabling SNARE complex assembly and neurotransmitter release (PMID:11460165, PMID:10526333). Its activity is regulated by diacylglycerol binding to its C1 domain downstream of the Gαq→PLCβ→DAG signaling cascade, which controls both its membrane association and nanoscale positioning within active zones; DAG binding drives rapid clustering of UNC13 at release sites to potentiate evoked transmission, while inhibitory intramolecular domains (X, C1, C2B) restrain basal activity (PMID:10571228, PMID:31509756, PMID:40833403). The N-terminal C2A domain and active-zone scaffolds (Syd-1/Liprin-α, CLA-1/Clarinet) determine UNC13B's nanoscale distance from calcium channels, tuning release probability, kinetics, and short-term plasticity in a synapse-type-specific manner—Munc13-2 knockout selectively increases facilitation at hippocampal mossy fiber and amygdala synapses (PMID:27526206, PMID:24220508, PMID:19700493, PMID:37186867). Beyond neurons, Munc13-2 mediates constitutive granule priming in airway Clara cells and Rab34-dependent Golgi trafficking in non-neuronal cells (PMID:18258655, PMID:16138900).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1991 High

    Establishing that UNC-13 family members are direct DAG effectors resolved the question of how phorbol ester/DAG second-messenger signaling could modulate vesicle release machinery, identifying the C1 domain as the DAG-responsive element.

    Evidence Recombinant C1 domain expression with radioligand phorbol ester binding and DAG competition assays in vitro

    PMID:1445255 PMID:2062851 PMID:7537738

    Open questions at the time
    • Whether DAG binding is sufficient to activate the full-length protein or only one regulatory input
    • Structural basis of C1 domain selectivity for DAG versus phorbol esters
  2. 1995 High

    Cloning and subcellular localization of mammalian Munc13-2 established that UNC13B is a presynaptic plasma membrane protein enriched in synaptosomes but absent from synaptic vesicles, placing it at the site of vesicle fusion rather than on the vesicles themselves.

    Evidence Molecular cloning, immunolocalization with specific antibodies, and synaptosome fractionation

    PMID:7559667

    Open questions at the time
    • Sub-synaptic localization relative to active zone structures
    • Whether Munc13-2 and Munc13-1 occupy identical or distinct presynaptic positions
  3. 1997 High

    Demonstration that Munc13 family members directly bind syntaxin's N-terminal coiled-coil at a site overlapping the Munc18 binding region provided a molecular link between UNC-13 and the SNARE fusion machinery, suggesting a mechanism involving Munc18 displacement.

    Evidence GST pulldown, co-immunoprecipitation, and yeast two-hybrid for Munc13-1–syntaxin interaction

    PMID:8999968

    Open questions at the time
    • Whether Munc13-2 uses an identical syntaxin-binding interface
    • Whether UNC-13 actively displaces Munc18 or captures an equilibrium intermediate
  4. 1999 High

    Convergent genetic, electrophysiological, and biochemical evidence in C. elegans established that UNC-13 is essential for a post-docking priming step, acts as the downstream DAG effector of the Gαq→PLCβ→DAG pathway, and promotes displacement of UNC-18 from syntaxin to enable vesicle fusion competence.

    Evidence unc-13 null mutants with EM and electrophysiology showing docked but unprimed vesicles; genetic epistasis placing UNC-13 downstream of EGL-30/EGL-8; DAG-binding point mutation and constitutive membrane-tethered rescue; co-IP showing UNC-13/UNC-18/syntaxin complex dynamics

    PMID:10366611 PMID:10526333 PMID:10571228 PMID:10677040

    Open questions at the time
    • Molecular mechanism by which UNC-13 opens syntaxin not yet directly tested
    • Relative contributions of DAG-dependent membrane translocation versus allosteric activation
  5. 2001 High

    The central mechanistic question—how UNC-13 primes vesicles—was resolved by showing that a constitutively open syntaxin mutant fully bypasses the requirement for UNC-13, proving that UNC-13's essential function is converting syntaxin from closed to open conformation.

    Evidence Constitutively open syntaxin transgene rescuing unc-13 null phenotype in C. elegans, with electrophysiology

    PMID:11460165

    Open questions at the time
    • Whether UNC-13 directly catalyzes syntaxin opening or acts through an intermediate
    • Structural basis of the closed-to-open transition
  6. 2005 High

    Dissection of the UNC-13/syntaxin interaction via MHD2 mutagenesis revealed that the direct syntaxin-binding interface is required for efficient evoked fusion but not for the priming step itself, separating priming from fusion coupling as distinct UNC-13 functions; separately, an unexpected non-neuronal role as a Rab34 effector in Golgi-lysosome trafficking was identified.

    Evidence MHD2 F1000/K1002 point mutations with electrophysiology at C. elegans NMJ; bacterial two-hybrid, co-IP, and GST pulldown for Rab34–MHD2 interaction with fluorescence microscopy in kidney cells

    PMID:16138900 PMID:16271476

    Open questions at the time
    • Structural model of MHD2–syntaxin versus MHD2–Rab34 interfaces
    • Whether Rab34-dependent trafficking function is conserved across Munc13 isoforms
  7. 2006 High

    Immunogold EM localized UNC-13 within ~100 nm of the dense projection and showed that unc-13 nulls lack membrane-contacting (morphologically primed) vesicles, defining the nanoscale spatial domain where priming occurs.

    Evidence High-pressure freeze fixation with immunogold EM and morphometric analysis in C. elegans

    PMID:16885217

    Open questions at the time
    • Whether the ~100 nm distance reflects UNC-13's direct scaffold association or indirect positioning
    • Resolution insufficient to distinguish Munc13 isoform-specific sub-positions
  8. 2008 High

    Munc13-2 knockout mice revealed a non-neuronal, isoform-specific role: Munc13-2 is required for constitutive (but not agonist-stimulated) mucin granule priming in airway Clara cells, demonstrating that UNC13B priming function extends beyond synapses.

    Evidence Munc13-2 KO mouse with histochemistry, mucin immunostaining, and EM of Clara cell ultrastructure

    PMID:18258655

    Open questions at the time
    • Whether Munc13-2 uses the same syntaxin-opening mechanism in non-neuronal secretory cells
    • Identity of the target syntaxin isoform in Clara cells
  9. 2009 High

    Synapse-type specificity was established: Munc13-2 KO selectively altered release probability and short-term plasticity at hippocampal mossy fiber synapses without affecting other hippocampal synapse types, showing that Munc13-2 expression level is a determinant of synapse-specific release properties.

    Evidence Munc13-2 KO mouse with patch-clamp electrophysiology at hippocampal slices, paired-pulse and frequency facilitation protocols

    PMID:19700493

    Open questions at the time
    • Whether Munc13-1 compensates at non-mossy fiber synapses or is simply absent
    • Transcriptional regulation determining synapse-specific Munc13-2 expression
  10. 2013 High

    The N-terminal C2A domain was identified as the key determinant of UNC-13's proximity to Ca²⁺ entry sites: C2A deletion slowed release kinetics, increased EGTA sensitivity, and abolished spontaneous release, establishing that C2A-mediated positioning tunes release probability.

    Evidence C2A domain deletion mutants with electrophysiology and kinetics analysis at C. elegans NMJ

    PMID:24220508

    Open questions at the time
    • Whether C2A binds a specific scaffold protein or lipid to achieve positioning
    • Ca²⁺ dependence of C2A domain contribution
  11. 2016 High

    Super-resolution imaging resolved the nanoscale architecture: Unc13B localizes ~120 nm from Ca²⁺ channels (recruited by Syd-1/Liprin-α) while Unc13A sits ~70 nm away (recruited by Bruchpilot/RBP), with each isoform independently docking vesicles at its respective distance to create functionally distinct release pools with different coupling efficiencies.

    Evidence STED super-resolution microscopy, isoform-specific null mutants, electrophysiology, and mathematical modeling at Drosophila NMJ

    PMID:27526206

    Open questions at the time
    • Whether mammalian Munc13-2 occupies an analogous distal position relative to Munc13-1
    • Structural basis of Syd-1/Liprin-α recruitment of Unc13B
  12. 2017 High

    The epistatic hierarchy was clarified: UNC-18/Munc18 functions downstream of UNC-13 in SNARE complex templating, as a gain-of-function UNC-18 mutation partially bypasses UNC-13 requirement, and Doc2B acts as a calcium sensor in a priming step that requires interaction with ubMunc13-2.

    Evidence Genetic epistasis and liposome fusion reconstitution in C. elegans/in vitro; Doc2B C2-domain mutagenesis in Munc13-2 KO chromaffin cells with capacitance measurements

    PMID:28821673 PMID:29274147

    Open questions at the time
    • Direct structural evidence for UNC-13 catalyzing Munc18-mediated SNARE templating
    • Stoichiometry of the Doc2B–Munc13-2 interaction
  13. 2019 High

    Systematic domain deletion revealed three intramolecular inhibitory domains (X region, C1, C2B) that suppress UNC-13 activity: removal of all three creates a hyperactive protein with dramatically increased release probability and Ca²⁺ sensitivity, establishing that UNC-13 is tonically autoinhibited and that DAG/Ca²⁺ signals relieve this inhibition.

    Evidence Systematic domain deletion mutagenesis with electrophysiology and genetic epistasis with syntaxin alleles in C. elegans

    PMID:31509756

    Open questions at the time
    • Structural mechanism by which each inhibitory domain suppresses activity
    • Whether autoinhibition is relieved sequentially or cooperatively by DAG and Ca²⁺
  14. 2022 Medium

    During presynaptic homeostatic potentiation, Unc-13 undergoes nanoscale spatial redistribution toward active zone centers without changes in total abundance, identifying spatial reorganization rather than protein level as the plasticity mechanism.

    Evidence Endogenous GFSTF tagging with structured illumination microscopy and HDBSCAN cluster analysis at Drosophila NMJ

    PMID:36589286

    Open questions at the time
    • Molecular trigger for spatial redistribution during PHP
    • Whether Unc13A and Unc13B subclusters redistribute differently
    • Single-lab finding awaiting independent replication
  15. 2023 Medium

    CLA-1/Clarinet was identified as a scaffold that recruits UNC-13 to active zones independently of RIM-binding protein, with cla-1 null mutants showing mislocalized UNC-13 and reduced priming, revealing a parallel active-zone recruitment pathway.

    Evidence Quantitative fluorescence imaging, EM, electrophysiology, and genetic double mutants in C. elegans

    PMID:37186867

    Open questions at the time
    • Direct physical interaction between CLA-1 and UNC-13 not demonstrated biochemically
    • Whether CLA-1 recruits specifically UNC-13L versus UNC-13S isoforms
  16. 2025 Medium

    Live single-molecule imaging showed that Gαq→PLCβ→DAG signaling causes rapid (~1 min) immobilization and compaction of Unc13 into nanoscale synaptic clusters, and a C1-domain point mutation blocking DAG binding abolishes this plasticity-induced enrichment, reduces Ca²⁺ sensitivity, and converts facilitation into depression—directly linking DAG-dependent nanoscale dynamics to short-term plasticity.

    Evidence Endogenous C1-domain knockin point mutation with live single-molecule imaging and electrophysiology at Drosophila NMJ

    PMID:40833403

    Open questions at the time
    • Whether DAG directly immobilizes Unc13 or acts through conformational change affecting scaffold interactions
    • Generalizability to mammalian Munc13-2

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structural model of full-length UNC-13B in its autoinhibited and activated states, and the precise mechanism by which it catalyzes the syntaxin closed-to-open transition in the context of Munc18 and the SNARE complex, remain unresolved.
  • No full-length Munc13-2 structure available
  • Whether Munc13-2 directly templates SNARE complex assembly or solely opens syntaxin for Munc18-mediated templating
  • Mammalian in vivo confirmation of isoform-specific nanoscale positioning observed in Drosophila

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 4 GO:0005794 Golgi apparatus 1
Partners
CLA1DOC2BPPFIA1RAB34STX1ASYD1UNC18
Complex memberships
SNARE priming complex (with syntaxin/Munc18)

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 The UNC-13 protein contains a cysteine-rich C1 domain that binds phorbol esters in a phospholipid- and calcium-dependent manner, and diacylglycerol competitively inhibits phorbol ester binding, identifying UNC-13/Munc13-2 as a DAG-binding protein in the diacylglycerol second-messenger pathway. Recombinant domain expression in E. coli, radioligand phorbol ester binding assay, competitive inhibition with diacylglycerol Proceedings of the National Academy of Sciences of the United States of America High 1445255 2062851 7537738
1995 Mammalian Munc13-2 (UNC13B) is a brain-expressed peripheral membrane protein enriched in synaptosomes and localized to presynaptic plasma membranes but absent from synaptic vesicles, containing conserved C1 and C2 domains consistent with roles in diacylglycerol and calcium signaling during neurotransmitter release. Molecular cloning, specific antibody immunolocalization, subcellular fractionation/synaptosome preparation The Journal of biological chemistry High 7559667
1997 Munc13-1 (the rat UNC-13 homolog most closely related to Munc13-2/UNC13B) directly interacts with the N-terminal coiled-coil domain of syntaxin via its C-terminus, and through this interaction associates with a subpopulation of the exocytotic core complex (syntaxin/SNAP-25/synaptobrevin); the syntaxin-binding site overlaps with the Munc18 binding site. Three independent methods: GST pulldown, co-immunoprecipitation, and yeast two-hybrid; the interaction was demonstrated for Munc13-1 but directly relevant to the Munc13 family mechanism conserved in Munc13-2/UNC13B The Journal of biological chemistry High 8999968
1999 UNC-13 is required for synaptic vesicle priming (the step after docking that renders vesicles fusion-competent): unc-13 null mutants in C. elegans have morphologically docked vesicles that are not competent for evoked release or for release by hyperosmotic saline, indicating a post-docking, pre-fusion priming role. Whole-cell voltage-clamp electrophysiology at C. elegans NMJ, electron microscopy, genetic null alleles Nature neuroscience High 10526333
1999 Neurotransmitter release at C. elegans NMJs is facilitated by a presynaptic pathway: Gqα (EGL-30) → PLCβ (EGL-8) → DAG → DAG binding to UNC-13. A mutation eliminating phorbol ester/DAG binding to UNC-13 blocks this facilitation, and a constitutively membrane-tethered UNC-13 rescues PLCβ mutants, placing UNC-13 as the downstream DAG effector in this pathway. Genetic epistasis, phorbol ester binding site point mutation, constitutively membrane-bound UNC-13 transgenic rescue, acetylcholine release assays in C. elegans Neuron High 10571228
1999 Serotonin inhibits synaptic transmission by activating Gα0 (GOA-1) and diacylglycerol kinase (DGK-1) to decrease DAG levels, which reduces the abundance of UNC-13 at presynaptic release sites; loss of GOA-1 causes abnormally high accumulation of UNC-13 at nerve terminals. Genetic epistasis in C. elegans, immunostaining of UNC-13 at synapses in pathway mutants, aldicarb sensitivity assay for acetylcholine release Neuron High 10677040
1999 UNC-13 transiently interacts with the UNC-18–syntaxin complex and promotes displacement of UNC-18 from syntaxin, providing a biochemical mechanism for UNC-13's role in regulating the priming step of synaptic vesicle exocytosis. Co-immunoprecipitation, in vitro binding assay, genetic double mutant analysis in C. elegans The Journal of neuroscience Medium 10366611
2001 UNC-13 primes synaptic vesicles for fusion by promoting the open conformation of syntaxin: an engineered open-conformation syntaxin bypasses the requirement for UNC-13 in vesicle priming at C. elegans NMJs, demonstrating that the mechanistic function of UNC-13 is to convert syntaxin from closed to open. Constitutively open syntaxin mutant transgenic rescue of unc-13 null, electrophysiology, genetic epistasis in C. elegans Nature High 11460165
2003 In Drosophila, the synaptic abundance of DUNC-13 (UNC13B ortholog) is regulated by antagonistic G-protein pathways (GαS/cAMP/PKA increases, Gαq/PLC/DAG also increases abundance) through proteasome-mediated protein degradation, rather than translocation or transport. Immunostaining of DUNC-13 at NMJ boutons in pathway mutants, pharmacological modulation of cAMP and DAG, proteasome inhibitor experiments in Drosophila Journal of neurobiology Medium 12532395
2005 The UNC-13/syntaxin interaction (via MHD2 domain residues F1000/K1002) is required for nerve-evoked vesicle fusion at C. elegans synapses but not for synaptic vesicle priming per se, as MHD2 double mutants have normal primed vesicle pools but reduced evoked EPSCs. Site-directed mutagenesis of MHD2, electrophysiology at C. elegans NMJ, transgenic rescue of unc-13 mutants Current biology : CB High 16271476
2005 DAG-activated Munc13-2 (hmunc13/UNC13B) translocates to the Golgi and interacts with GTP-bound Rab34 via its MHD2 domain, functioning as an effector of Rab34 in intracellular lysosome-Golgi trafficking in kidney cells. Bacterial two-hybrid screen, co-immunoprecipitation, GST pulldown with GTPase mutants (Q111L/T66N), subcellular localization by fluorescence microscopy Traffic (Copenhagen, Denmark) Medium 16138900
2006 UNC-13 localizes to the presynaptic plasma membrane within ~100 nm of the dense projection (active zone) at C. elegans NMJs, and in unc-13 null mutants, synaptic vesicle contacts with the plasma membrane are dramatically reduced, identifying morphologically primed vesicles and defining the priming domain. High-pressure freeze fixation, immunogold electron microscopy, morphometric analysis in C. elegans The Journal of neuroscience High 16885217
2007 hMunc13-4 (UNC13D) mediates priming of cytotoxic granule exocytosis in cytotoxic T lymphocytes and NK cells by independently facilitating the assembly of Rab11+ recycling endosomes and Rab27+ late endosomal vesicles, and by priming cytotoxic granule fusion through interaction with active Rab27a. Genetic deficiency models, co-immunoprecipitation, subcellular fractionation, fluorescence imaging of organelle trafficking in primary lymphocytes Nature immunology Medium 17237785
2008 Munc13-2 (UNC13B) is required for baseline/constitutive priming of a specific population of secretory granules in airway Clara cells; Munc13-2-deficient mouse airways accumulate Muc5b mucin in Clara cells, while agonist-stimulated secretion via Munc13-4 remains intact, demonstrating isoform-specific priming of distinct granule pools. Munc13-2 knockout mouse, histochemistry (AB/PAS staining), mucin immunostaining, electron microscopy of Clara cell ultrastructure, BAL cell counts The Journal of physiology High 18258655
2009 High glucose-induced upregulation of munc13-2 (UNC13B) increases constitutive protein secretion in mesangial cells through interaction with GTP-bound Rab34 via the MHD2 domain; siRNA knockdown of munc13-2 or Rab34 abolishes high-glucose-stimulated fibronectin secretion, and an MHD2-deleted mutant fails to stimulate secretion. siRNA knockdown, domain deletion mutant transfection, VSVG-GFP secretion assay, fibronectin secretion assay in rat mesangial cells American journal of physiology. Cell physiology Medium 19641095
2009 Munc13-2 (UNC13B) is essential for normal release probability at hippocampal mossy fiber synapses; Munc13-2-deficient mice show strongly increased paired-pulse and frequency facilitation at mossy fiber synapses but unaffected transmission at other hippocampal synapse types, demonstrating synapse-type specific roles. Munc13-2 knockout mouse, patch-clamp electrophysiology at hippocampal slices, paired-pulse and frequency facilitation protocols Cerebral cortex High 19700493
2013 The N-terminal C2A domain of UNC-13 regulates the probability of evoked release and precise active zone localization in C. elegans; C2A-domain-mediated proximity of UNC-13 to Ca2+ entry sites accelerates neurotransmitter release kinetics, and the C2A domain is specifically required for spontaneous release. C2A domain deletion mutants, electrophysiology at C. elegans NMJ, kinetics analysis, EGTA sensitivity assays eLife High 24220508
2015 NLP-12 neuropeptide potentiates tonic ACh release specifically through DAG binding to UNC-13L (the long isoform), via a pathway independent of EGL-30 Gαq and EGL-8 PLCβ; evoked release potentiation uses both short and long UNC-13 isoforms through the canonical Gαq→PLCβ→DAG pathway, demonstrating isoform-specific signal integration. Genetic epistasis with isoform-specific mutants, aldicarb assays and electrophysiology in C. elegans, DAG-binding domain mutants The Journal of neuroscience High 25609620
2016 At Drosophila glutamatergic synapses, Unc13B isoform is recruited to nascent active zones by scaffolding proteins Syd-1 and Liprin-α and localizes ~120 nm from Ca2+ channels, while Unc13A is positioned ~70 nm from Ca2+ channels by Bruchpilot and Rim-binding protein. Unc13A is responsible for docking SVs at the closer distance and mediates efficient, fast release; Unc13A null mutants show inefficient, delayed, EGTA-supersensitive release. Super-resolution STED microscopy, intravital two-photon imaging, isoform-specific null mutants, electrophysiology, mathematical modeling at Drosophila NMJ Nature neuroscience High 27526206
2016 Munc13-2 (UNC13B) expression level determines release probability and short-term plasticity phenotype at basolateral amygdala glutamatergic synapses: B6 mice expressing higher Munc13-2 show lower release probability and more facilitation; shRNA knockdown of Munc13-2 in B6 mice recapitulates the D2 presynaptic phenotype. shRNA knockdown in vivo, patch-clamp electrophysiology, phorbol ester sensitivity assays, Western blot, strain comparison (B6 vs D2) The Journal of neuroscience High 27798178
2017 Doc2B acts as a calcium sensor in vesicle priming in a step that requires interaction with ubMunc13-2 (UNC13B): Doc2B C2B-domain Ca2+-binding and interaction with ubMunc13-2 are required for a downstream priming step, as shown by Ca2+-coordinating aspartate mutations and Munc13-2-deficient chromaffin cells. C2-domain point mutations, overexpression in chromaffin cells, Munc13-2 KO mouse cells, capacitance measurements of exocytosis eLife Medium 29274147
2017 UNC-18/Munc18-1 primes synaptic vesicle fusion downstream of UNC-13/Munc13-1; a gain-of-function UNC-18(P334A) mutation partially bypasses the requirement for UNC-13, and this bypass is synergistically enhanced by loss of TOM-1/Tomosyn, placing UNC-13 upstream of UNC-18-mediated SNARE complex templating. Genetic epistasis in C. elegans, electrophysiology, liposome fusion assay, SNARE complex assembly assay with Munc18-1(P335A) The Journal of neuroscience High 28821673
2018 Ethanol binds to the C1 domain of Munc13-1/Dunc13 and reduces diacylglycerol binding; in Drosophila, sedating concentrations of ethanol reduce synaptic vesicle release in olfactory neurons without affecting membrane depolarization or Ca2+ influx, and Dunc13 haploinsufficiency confers resistance to ethanol-induced presynaptic inhibition and sedation. In vitro C1-domain DAG binding competition assay with ethanol, two-photon calcium imaging, electrophysiology, Dunc13 haploinsufficient mutants, RNAi, Munc13-1 transgenic rescue in Drosophila eNeuro Medium 29911175
2019 UNC-13L has three inhibitory domains (X region between C2A and C1, C1, and C2B) that suppress synaptic vesicle exocytosis; deleting all three produces hyperactive UNC-13 with dramatically increased release, Ca2+ sensitivity, and release probability. The hyperactive form enhances tonic release by increasing syntaxin open probability and has additional functions in evoked release. Systematic domain deletion mutagenesis, electrophysiology at C. elegans NMJ, genetic double mutant analysis with syntaxin alleles Cell reports High 31509756
2021 Synaptotagmin-7 promotes Ca2+-dependent priming and inhibits depriming by placing dense-core vesicles within 6 nm of the plasma membrane, and this priming effect requires ubMunc13-2 (UNC13B) and phorbol ester-dependent pathways; without synaptotagmin-7, vesicles accumulate 20–40 nm from the membrane, out of reach of the fusion complex. TIRF microscopy with EGFP-tagged vesicle markers, synaptotagmin-7 KO in mouse chromaffin cells, Munc13-2 KO chromaffin cells, capacitance and amperometry measurements eLife Medium 33749593
2022 Endogenous Unc-13 in Drosophila undergoes nanoscale reorganization at active zones during presynaptic homeostatic potentiation (PHP): super-resolution microscopy reveals Unc-13 subclusters move toward the active zone center during PHP with unaltered total protein levels, indicating spatial redistribution rather than abundance change as the plasticity mechanism. MiMIC-based endogenous GFSTF tagging, structured illumination microscopy, HDBSCAN cluster analysis, TEVC electrophysiology at Drosophila NMJ Frontiers in cellular neuroscience Medium 36589286
2023 CLA-1 (Clarinet) recruits UNC-13 to active zones through a RIMB-1-independent mechanism in C. elegans; cla-1 null mutants show mislocalized UNC-13 and reduced priming, while CLA-1 acts in concert with UNC-10/RIM to organize the active zone scaffold. Quantitative fluorescence imaging, electron microscopy, electrophysiology at C. elegans NMJ, genetic double mutants Proceedings of the National Academy of Sciences of the United States of America Medium 37186867
2025 Monoamine/octopamine signaling via Gαq→PLCβ→DAG causes rapid (within ~1 minute) nanoscale immobilization and compaction of Unc13A into synaptic clusters, potentiating evoked neurotransmitter release; a point mutation in the C1 (DAG-binding) domain of Unc13 blocks plasticity-induced nanoscale enrichment and synaptic potentiation, and also reduces calcium sensitivity and causes short-term depression. Live single-molecule imaging of endogenously tagged Unc13 at Drosophila NMJ, C1-domain point mutation (endogenous knockin), electrophysiology, phorbol ester pharmacology Proceedings of the National Academy of Sciences of the United States of America Medium 40833403

Source papers

Stage 0 corpus · 52 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 UNC-13 is required for synaptic vesicle fusion in C. elegans. Nature neuroscience 498 10526333
1995 Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins. The Journal of biological chemistry 329 7559667
2001 An open form of syntaxin bypasses the requirement for UNC-13 in vesicle priming. Nature 322 11460165
1999 Facilitation of synaptic transmission by EGL-30 Gqalpha and EGL-8 PLCbeta: DAG binding to UNC-13 is required to stimulate acetylcholine release. Neuron 273 10571228
1999 Serotonin inhibition of synaptic transmission: Galpha(0) decreases the abundance of UNC-13 at release sites. Neuron 263 10677040
1999 Drosophila UNC-13 is essential for synaptic transmission. Nature neuroscience 254 10526334
1997 Direct interaction of the rat unc-13 homologue Munc13-1 with the N terminus of syntaxin. The Journal of biological chemistry 237 8999968
1991 A phorbol ester/diacylglycerol-binding protein encoded by the unc-13 gene of Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America 225 2062851
2007 Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4. Nature immunology 206 17237785
2000 Regulation of transmitter release by Unc-13 and its homologues. Current opinion in neurobiology 178 10851170
2016 Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling. Nature neuroscience 165 27526206
2006 UNC-13 and UNC-10/rim localize synaptic vesicles to specific membrane domains. The Journal of neuroscience : the official journal of the Society for Neuroscience 128 16885217
2005 UNC-13 interaction with syntaxin is required for synaptic transmission. Current biology : CB 115 16271476
1999 Regulation of the UNC-18-Caenorhabditis elegans syntaxin complex by UNC-13. The Journal of neuroscience : the official journal of the Society for Neuroscience 103 10366611
2008 Munc13-2-/- baseline secretion defect reveals source of oligomeric mucins in mouse airways. The Journal of physiology 91 18258655
1995 Characterization of the cysteine-rich region of the Caenorhabditis elegans protein Unc-13 as a high affinity phorbol ester receptor. Analysis of ligand-binding interactions, lipid cofactor requirements, and inhibitor sensitivity. The Journal of biological chemistry 86 7537738
2000 Expression of multiple UNC-13 proteins in the Caenorhabditis elegans nervous system. Molecular biology of the cell 72 11029047
1992 The Caenorhabditis elegans unc-13 gene product is a phospholipid-dependent high-affinity phorbol ester receptor. The Biochemical journal 71 1445255
2013 Position of UNC-13 in the active zone regulates synaptic vesicle release probability and release kinetics. eLife 69 24220508
2021 UNC13B variants associated with partial epilepsy with favourable outcome. Brain : a journal of neurology 56 33876820
2003 Synaptic Drosophila UNC-13 is regulated by antagonistic G-protein pathways via a proteasome-dependent degradation mechanism. Journal of neurobiology 45 12532395
2009 Munc13-2 differentially affects hippocampal synaptic transmission and plasticity. Cerebral cortex (New York, N.Y. : 1991) 35 19700493
2017 UNC-18 and Tomosyn Antagonistically Control Synaptic Vesicle Priming Downstream of UNC-13 in Caenorhabditis elegans. The Journal of neuroscience : the official journal of the Society for Neuroscience 33 28821673
2008 G/T substitution in intron 1 of the UNC13B gene is associated with increased risk of nephropathy in patients with type 1 diabetes. Diabetes 32 18633107
2017 Doc2B acts as a calcium sensor for vesicle priming requiring synaptotagmin-1, Munc13-2 and SNAREs. eLife 27 29274147
2021 Synaptotagmin-7 places dense-core vesicles at the cell membrane to promote Munc13-2- and Ca2+-dependent priming. eLife 24 33749593
2022 Endogenous tagging of Unc-13 reveals nanoscale reorganization at active zones during presynaptic homeostatic potentiation. Frontiers in cellular neuroscience 22 36589286
2005 Diacylglycerol-activated Hmunc13 serves as an effector of the GTPase Rab34. Traffic (Copenhagen, Denmark) 21 16138900
2015 NLP-12 engages different UNC-13 proteins to potentiate tonic and evoked release. The Journal of neuroscience : the official journal of the Society for Neuroscience 20 25609620
1999 UNC-13 and neurotransmitter release. Nature neuroscience 19 10526324
2019 A Hyperactive Form of unc-13 Enhances Ca2+ Sensitivity and Synaptic Vesicle Release Probability in C. elegans. Cell reports 18 31509756
2016 Rare UNC13B variations and risk of schizophrenia: Whole-exome sequencing in a multiplex family and follow-up resequencing and a case-control study. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 18 26990377
2018 Ethanol Regulates Presynaptic Activity and Sedation through Presynaptic Unc13 Proteins in Drosophila. eNeuro 17 29911175
2016 Differential Expression of Munc13-2 Produces Unique Synaptic Phenotypes in the Basolateral Amygdala of C57BL/6J and DBA/2J Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 17 27798178
2017 Ethanol Mediated Inhibition of Synaptic Vesicle Recycling at Amygdala Glutamate Synapses Is Dependent upon Munc13-2. Frontiers in neuroscience 14 28785200
2009 Rab34 and its effector munc13-2 constitute a new pathway modulating protein secretion in the cellular response to hyperglycemia. American journal of physiology. Cell physiology 11 19641095
2001 Synaptic exocytosis and nervous system development impaired in Caenorhabditis elegans unc-13 mutants. Neuroscience 11 11377834
2023 Role of the UNC13 family in human diseases: A literature review. AIMS neuroscience 10 38188011
1997 Genetic analysis of sterile mutants in the dpy-5 unc-13 (I) genomic region of Caenorhabditis elegans. Molecular & general genetics : MGG 10 9230900
2018 De novo UNC13B mutation identified in a bipolar disorder patient increases a rare exon-skipping variant. Neuropsychopharmacology reports 8 30117296
2022 Selective Enrichment of Munc13-2 in Presynaptic Active Zones of Hippocampal Pyramidal Cells That Innervate mGluR1α Expressing Interneurons. Frontiers in synaptic neuroscience 7 35221979
2020 Unc-13 homolog D mediates an antiviral effect of the chromosome 19 microRNA cluster miR-517a. Journal of cell science 6 33093239
2019 The Association of UNC13B Gene Polymorphisms and Diabetic Kidney Disease in a Chinese Han Population. Medical science monitor : international medical journal of experimental and clinical research 6 31713534
2022 UNC13B Promote Arsenic Trioxide Resistance in Chronic Lymphoid Leukemia Through Mitochondria Quality Control. Frontiers in oncology 5 35707364
2023 C. elegans Clarinet/CLA-1 recruits RIMB-1/RIM-binding protein and UNC-13 to orchestrate presynaptic neurotransmitter release. Proceedings of the National Academy of Sciences of the United States of America 4 37186867
2022 Differential Expression of Presynaptic Munc13-1 and Munc13-2 in Mouse Hippocampus Following Ethanol Drinking. Neuroscience 3 35167938
2025 Monoamine-induced diacylglycerol signaling rapidly accumulates Unc13 in nanoclusters for fast presynaptic potentiation. Proceedings of the National Academy of Sciences of the United States of America 2 40833403
2024 UNC13B regulates the sensitivity of Wilms' tumor cells to doxorubicin by modulating lysosomes. Oncology letters 2 39091580
2006 Synaptic protein UNC-13 interacts with an F-box protein that may target it for degradation by proteasomes. Acta biochimica Polonica 2 16496042
2007 Synaptic neurotransmission protein UNC-13 affects RNA interference in neurons. Biochemical and biophysical research communications 1 17276405
2025 Inhibiting UNC13B Suppresses Cell Proliferation by Upregulating the Apoptotic Pathway in Multiple Myeloma. Biomedicines 0 41007649
2024 Aberrant Positions of the Chemosensory Neurons in the Neurotransmitter-Release Mutant unc-13. International journal of molecular sciences 0 39684665