Affinage

Showing UNC13B — UNC13 is a alias.

UNC13B

Protein unc-13 homolog B · UniProt O14795

Length
1591 aa
Mass
180.7 kDa
Annotated
2026-06-10
52 papers in source corpus 31 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UNC13B/Munc13-2 is a presynaptic peripheral membrane protein that serves as an essential synaptic vesicle priming factor, converting morphologically docked but fusion-incompetent vesicles into a release-ready state (PMID:10526333, PMID:10526334, PMID:16885217). Its conserved C1 domain is a stereospecific, zinc- and phospholipid-dependent receptor for diacylglycerol and phorbol esters, coupling it to Gq/PLC signaling that potentiates neurotransmitter release (PMID:2062851, PMID:1445255, PMID:7537738, PMID:10571228). Mechanistically, UNC13B acts upstream of syntaxin: it promotes the open conformation of syntaxin so that a constitutively open syntaxin mutant bypasses the priming requirement, and it transiently displaces Munc18 from syntaxin to license SNARE complex assembly, with Munc18-1 templating fusion downstream (PMID:11460165, PMID:10366611, PMID:28821673). A C-terminal MHD2 domain mediates the direct interaction with syntaxin that is needed for evoked fusion, separable from the priming step (PMID:8999968, PMID:16271476). The protein is intramolecularly autoinhibited by an X region, the C1 domain, and the C2B domain; removing these yields a hyperactive protein with increased release probability and Ca2+ sensitivity (PMID:31509756). Isoform-specific active-zone scaffolds position UNC13B at defined nanoscale distances from Ca2+ channels — the B isoform is recruited by Syd-1/Liprin-α (~120 nm) while the A isoform is positioned by Bruchpilot/RIM-BP (~70 nm) — so that positioning dictates release probability and kinetics, with additional recruitment by CLA-1/UNC-10 and trans-synaptic Elfn1 (PMID:27526206, PMID:37186867, PMID:35221979). In mammals, Munc13-2 sets basal release probability at hippocampal mossy fiber synapses and underlies strain-dependent presynaptic differences, and DAG-driven nanoscale compaction of the protein acutely potentiates release (PMID:19700493, PMID:27798178, PMID:40833403). Beyond neurons, UNC13B functions as an effector of GTP-bound Rab34 through its MHD2 domain to mediate constitutive secretory granule priming and intracellular vesicle/lysosome positioning (PMID:16138900, PMID:18258655, PMID:19641095).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1991 High

    Established the biochemical identity of the UNC-13 lipid-sensing module, answering how the protein could be coupled to second-messenger signaling.

    Evidence Radioligand phorbol ester binding and DAG competition with recombinant C1/C2-region domain

    PMID:1445255 PMID:2062851 PMID:7537738

    Open questions at the time
    • Did not address the cellular consequence of DAG binding
    • Used the C. elegans ortholog, not mammalian UNC13B directly
  2. 1995 Medium

    Identified UNC13B/Munc13-2 as a mammalian UNC-13 homologue and localized it as a peripheral plasma-membrane protein, distinguishing it from synaptic vesicle components.

    Evidence Molecular cloning, Western blot, and synaptosome subcellular fractionation of rat brain

    PMID:7559667

    Open questions at the time
    • Antibody-based localization from a single lab
    • No functional assay of UNC13B in this study
  3. 1997 High

    Defined a direct molecular interaction between the Munc13 family and syntaxin, providing a physical link to the SNARE machinery.

    Evidence Yeast two-hybrid, GST pulldown, and co-IP on Munc13-1/syntaxin

    PMID:8999968

    Open questions at the time
    • Performed on the paralog Munc13-1, not UNC13B directly
    • Functional consequence of the interaction not yet defined
  4. 1999 High

    Defined the core cellular function of UNC-13 as a post-docking priming factor and placed it downstream of a Gq/PLC/DAG signaling cascade requiring DAG binding.

    Evidence Null-mutant electrophysiology and EM in C. elegans and Drosophila, plus genetic epistasis with EGL-30/EGL-8 and DAG-binding-dead rescue

    PMID:10366611 PMID:10526333 PMID:10526334 PMID:10571228 PMID:10677040

    Open questions at the time
    • Molecular nature of the priming reaction not resolved
    • How DAG binding mechanistically alters priming activity unknown
  5. 2001 High

    Resolved the molecular target of priming by showing UNC-13 acts to open syntaxin, since constitutively open syntaxin bypasses the UNC-13 requirement.

    Evidence Genetic epistasis with engineered open-syntaxin mutations in C. elegans, electrophysiology and behavior

    PMID:11460165

    Open questions at the time
    • Direct structural mechanism of syntaxin opening not demonstrated
    • Did not separate priming from later fusion steps
  6. 2005 High

    Separated UNC-13's priming function from its fusion function and mapped vesicle priming to membrane-contacting vesicles within ~100 nm of dense projections.

    Evidence MHD2 mutagenesis with electrophysiology, and quantitative immunogold EM in C. elegans null mutants

    PMID:16271476 PMID:16885217

    Open questions at the time
    • Distinct biochemical activities of priming vs fusion steps not reconstituted
    • How MHD2-syntaxin contact drives the fusion step unclear
  7. 2005 High

    Extended UNC13B function beyond neurons by identifying it as a DAG-activated effector of GTP-bound Rab34 at the Golgi.

    Evidence Bacterial two-hybrid, co-IP, nucleotide-state GST pulldown, GTP overlay, and MHD2 deletion

    PMID:16138900

    Open questions at the time
    • Single lab
    • Downstream consequences of Rab34 binding for vesicle positioning not yet shown in this study
  8. 2008 High

    Demonstrated an isoform-specific, non-neuronal role: Munc13-2 is required for constitutive/baseline secretory granule priming distinct from agonist-regulated Munc13-4 secretion.

    Evidence Munc13-2 knockout mouse histology, EM, qPCR, and agonist stimulation in airway epithelium

    PMID:18258655

    Open questions at the time
    • Did not establish whether Rab34 mediates the airway secretion phenotype
    • Molecular priming step in mucin granules not dissected
  9. 2009 Medium

    Linked the Rab34 interaction to a quantitative secretory output and to disease-relevant high-glucose signaling.

    Evidence siRNA knockdown of munc13-2/rab34 and MHD2-deletion with VSVG-GFP and fibronectin secretion assays in mesangial/HeLa cells

    PMID:19641095

    Open questions at the time
    • Single lab
    • Mechanism connecting high glucose to UNC13B upregulation not defined
  10. 2009 High

    Established the mammalian neuronal phenotype: Munc13-2 sets basal release probability at a specific synapse type (mossy fibers).

    Evidence Knockout mouse patch-clamp electrophysiology with paired-pulse, frequency facilitation, and LTP protocols

    PMID:19700493

    Open questions at the time
    • Why the requirement is restricted to mossy fibers not explained
    • No molecular readout of priming defect
  11. 2013 High

    Assigned the N-terminal C2A domain a role in active-zone localization, release probability, and spontaneous release, tying spatial proximity to Ca2+ entry to release kinetics.

    Evidence C2A deletion/mutagenesis with voltage-clamp electrophysiology and localization in C. elegans

    PMID:24220508

    Open questions at the time
    • Binding partners of C2A at the active zone not fully identified here
    • Spontaneous vs evoked mechanistic separation incomplete
  12. 2016 High

    Showed that isoform-specific active-zone scaffolds position UNC13B at defined nanoscale distances from Ca2+ channels, with positioning determining release probability and kinetics.

    Evidence Super-resolution imaging, electrophysiology, EGTA chelation, and modeling with isoform-specific Drosophila nulls

    PMID:27526206

    Open questions at the time
    • Mammalian conservation of the two-isoform positioning logic not tested
    • Direct binding interfaces with Syd-1/Liprin-α vs Bruchpilot/RIM-BP not mapped biochemically
  13. 2016 High

    Demonstrated that quantitative differences in Munc13-2 abundance drive natural variation in presynaptic release and short-term plasticity.

    Evidence In vivo shRNA knockdown, electrophysiology, protein quantification, and BXD QTL analysis in mouse amygdala

    PMID:27798178

    Open questions at the time
    • Upstream regulator setting strain-specific Munc13-2 levels unidentified
    • Single brain region examined
  14. 2017 High

    Placed UNC13B upstream of Munc18-1 in a priming sequence in which Munc18 templates SNARE assembly, refining the order of the priming reaction.

    Evidence Genetic epistasis, electrophysiology, and liposome fusion reconstitution with gain-of-function Munc18 mutants

    PMID:28821673

    Open questions at the time
    • Structural basis of the UNC13B-to-Munc18 handoff not resolved
    • Role of Tomosyn synergy in physiological priming unclear
  15. 2017 Medium

    Identified Doc2B and synaptotagmin-1 as functional partners requiring ubMunc13-2 for downstream dense-core vesicle priming in chromaffin cells.

    Evidence Doc2B mutagenesis with capacitance measurements and Ca2+ uncaging in Munc13-2 and synaptotagmin-1 deletion backgrounds

    PMID:29274147

    Open questions at the time
    • Single lab
    • Direct physical interaction of Doc2B with ubMunc13-2 not demonstrated
  16. 2019 High

    Defined the autoinhibitory architecture of UNC13B, showing that the X region, C1, and C2B domains suppress release and that their removal hyperactivates via increased syntaxin opening.

    Evidence Systematic domain deletion, electrophysiology, Ca2+ sensitivity assays, and epistasis with open-syntaxin mutants in C. elegans

    PMID:31509756

    Open questions at the time
    • Physiological signals relieving each inhibitory domain not all defined
    • Structural conformation of the autoinhibited state unresolved
  17. 2021 Medium

    Placed a synaptotagmin-7-mediated membrane-approach step upstream of Munc13-2-dependent dense-core vesicle priming.

    Evidence Synaptotagmin-7 knockout/overexpression with capacitance, TIRF vesicle-distance measurements, and Munc13-2 epistasis in chromaffin cells

    PMID:33749593

    Open questions at the time
    • Single lab
    • Whether synaptotagmin-7 physically delivers vesicles to Munc13-2 not shown directly
  18. 2022 Medium

    Showed active-zone recruitment of UNC13B is governed by trans-synaptic and scaffold cues (Elfn1, CLA-1/UNC-10) and that Munc13-1 can be sufficient at some low-Pr synapses.

    Evidence Conditional knockout, paired recordings, immunofluorescence in mouse hippocampus, and EM/imaging epistasis with cla-1/unc-10 in C. elegans

    PMID:35221979 PMID:37186867

    Open questions at the time
    • Direct binding of UNC13B to Elfn1 or CLA-1 not biochemically established
    • Functional non-redundancy of Munc13-1 vs UNC13B incompletely mapped across synapse types
  19. 2022 Medium

    Revealed that UNC13B undergoes nanoscale spatial reorganization during presynaptic homeostatic potentiation without changes in total protein level.

    Evidence Endogenous GFSTF tagging, SIM/localization microscopy with HDBSCAN clustering, and voltage-clamp electrophysiology in Drosophila

    PMID:36589286

    Open questions at the time
    • Single lab
    • Molecular trigger driving subcluster movement during PHP not identified
  20. 2024 Low

    Reported a non-neuronal lysosomal role linking UNC13B to lysosome formation and drug resistance in tumor cells.

    Evidence shRNA knockdown, Lyso-Tracker staining, viability and apoptosis assays in Wilms' tumor cells

    PMID:39091580

    Open questions at the time
    • Correlative knockdown only; mechanism not dissected beyond association
    • Single lab and single cell model
    • Relationship to the Rab34 effector function not tested
  21. 2025 High

    Demonstrated that DAG signaling acutely drives C1-dependent immobilization and nanocluster compaction of endogenous UNC13B to potentiate evoked release, directly linking the founding lipid-binding activity to fast plasticity.

    Evidence Live single-molecule imaging of endogenously tagged Unc13, CRISPR C1-domain point mutation, electrophysiology, and phorbol ester pharmacology in Drosophila

    PMID:40833403

    Open questions at the time
    • Molecular partners anchoring the compacted nanocluster not identified
    • Whether mammalian UNC13B uses the same C1-driven mechanism not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the neuronal priming/syntaxin-opening activity and the non-neuronal Rab34-effector/lysosomal functions are integrated within a single protein, and the structural basis of autoinhibition relief and nanocluster assembly, remain unresolved.
  • No unified structural model of the autoinhibited vs active state
  • Mammalian conservation of isoform-specific Ca2+-channel positioning untested
  • Mechanistic basis of the lysosomal/tumor phenotype undefined

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 2 GO:0005794 Golgi apparatus 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-162582 Signal Transduction 2
Partners
DOC2BELFN1RAB34RIMS1STX1ASTXBP1SYT1SYT7
Complex memberships
presynaptic active zone

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 The C1/C2-like domain region of UNC-13 (C. elegans ortholog) binds phorbol esters with high affinity in a zinc- and phospholipid-dependent, stereospecific manner, and diacylglycerol competitively inhibits this binding, establishing UNC-13 as a DAG/phorbol ester receptor. Recombinant protein expression in E. coli, radioligand binding assay with [3H]phorbol ester, competitive inhibition with diacylglycerol Proceedings of the National Academy of Sciences of the United States of America High 1445255 2062851 7537738
1995 Munc13-2 (UNC13B) is a mammalian homologue of C. elegans UNC-13 expressed in rat brain; it is a brain-specific large protein with conserved C1- and C2-domains and is enriched as a peripheral membrane protein in synaptosomes localized to plasma membranes but absent from synaptic vesicles. Molecular cloning, Western blot with specific antibodies, subcellular fractionation of rat brain synaptosomes The Journal of biological chemistry Medium 7559667
1997 Munc13-1 (the closest paralog, but the interaction paradigm is the founding mechanism for Munc13 family including Munc13-2/UNC13B) directly interacts with the N-terminal coiled-coil domain of syntaxin via its C terminus; through this interaction it associates with a subpopulation of the SNARE core complex (synaptobrevin/SNAP-25/syntaxin) but not with other syntaxin-interacting proteins. Yeast two-hybrid, in vitro GST pulldown, co-immunoprecipitation — three independent methods on Munc13-1/syntaxin interaction; the binding site in syntaxin overlaps with Munc18 binding site The Journal of biological chemistry High 8999968
1999 UNC-13 (C. elegans) is required for a post-docking priming step of synaptic vesicle exocytosis: null mutants have morphologically docked vesicles but these are not competent for fusion as shown by absent evoked release and failure to release with hyperosmotic saline or in calcium-free solution. Whole-cell voltage-clamp electrophysiology at C. elegans NMJ, hyperosmotic saline stimulation, calcium-free recording, electron microscopy of synapse morphology Nature neuroscience High 10526333
1999 Neurotransmitter release at C. elegans NMJs is facilitated by a presynaptic Gqα (EGL-30) → PLCβ (EGL-8) → DAG pathway, and this effect requires DAG binding to UNC-13: a mutation abolishing phorbol ester/DAG binding to UNC-13 blocks the stimulatory effect of phorbol esters on acetylcholine release. Genetic epistasis in C. elegans, phorbol ester pharmacology, constitutively membrane-targeted UNC-13 rescue, confocal imaging of UNC-13 localization Neuron High 10571228
1999 Serotonin inhibits acetylcholine release at C. elegans NMJs via GOA-1 (Gα0) and DGK-1 (DAG kinase), and this inhibition correlates with decreased abundance of UNC-13 at release sites; loss of GOA-1 leads to abnormally high levels of UNC-13 at nerve terminals. Aldicarb sensitivity assay in intact C. elegans, immunofluorescence quantification of UNC-13 at synapses, genetic epistasis with goa-1 and dgk-1 mutants Neuron Medium 10677040
1999 UNC-13 transiently interacts with the UNC-18–syntaxin complex and causes rapid displacement of UNC-18 from syntaxin, providing a mechanism by which UNC-13 modulates SNARE complex availability. Co-immunoprecipitation, GST pulldown (biochemical), genetic epistasis in C. elegans unc-13/unc-18/unc-64 double mutants The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 10366611
1999 Drosophila UNC-13 (Dunc-13) is essential for synaptic transmission at a post-docking priming step: null mutants accumulate docked vesicles at release sites but have no evoked or hyperosmotic-saline-evoked release. Electrophysiology (EJPs, miniature EJPs), hyperosmotic saline stimulation, electron microscopy of presynaptic terminals in Dunc-13 null Drosophila Nature neuroscience High 10526334
2001 UNC-13 primes synaptic vesicles by promoting the open conformation of syntaxin: an open-form syntaxin mutant (constitutively open) bypasses the requirement for UNC-13 in synaptic vesicle priming in C. elegans, placing UNC-13 upstream of syntaxin opening in the exocytic pathway. Genetic epistasis — engineered open-form syntaxin mutations introduced into C. elegans unc-13 null background; electrophysiology and behavioral rescue assays Nature High 11460165
2003 Synaptic levels of Drosophila UNC-13 (Dunc-13) are regulated by proteasome-mediated degradation downstream of both GαS/cAMP/PKA and Gαq/PLC/DAG pathways; both pathways converge to control synaptic UNC-13 abundance by modulating the rate of proteasomal degradation rather than translocation. Immunofluorescence quantification of Dunc-13 at NMJ boutons, pharmacological manipulation of cAMP/PKA and PLC/DAG pathways, proteasome inhibitor treatment in Drosophila Journal of neurobiology Medium 12532395
2005 UNC-13 interaction with syntaxin is required for nerve-evoked synaptic vesicle fusion but not for vesicle priming: a double mutation in MHD2 (F1000A/K1002A) that disrupts the UNC-13/syntaxin interaction reduces evoked EPSCs but leaves the primed vesicle pool normal, indicating UNC-13 regulates multiple steps of the vesicle cycle. Site-directed mutagenesis of UNC-13 MHD2 domain, whole-cell electrophysiology at C. elegans NMJ, behavioral rescue assays Current biology : CB High 16271476
2005 Diacylglycerol-activated Hmunc13 (UNC13B) translocates to the Golgi and binds GTP-bound Rab34 via its MHD2 domain; this interaction requires the GTP-loaded form of Rab34, establishing UNC13B as an effector of Rab34 in intracellular vesicle/lysosome positioning. Bacterial two-hybrid screen, co-immunoprecipitation from cell lysates, GST pulldown with GTP/GDP-loaded Rab34 mutants (Q111L, T66N), radioactive GTP overlay assay, deletion mutagenesis of MHD2 Traffic (Copenhagen, Denmark) High 16138900
2006 UNC-13 localizes to the plasma membrane within ~100 nm of dense projections at C. elegans NMJs; in unc-13 null mutants, synaptic vesicles that normally contact the plasma membrane are nearly absent, identifying membrane-contacting vesicles as morphological correlates of primed vesicles and defining UNC-13's spatial domain for priming. Rapid physical fixation, immunogold electron microscopy, high-resolution morphometric analysis at C. elegans NMJ The Journal of neuroscience : the official journal of the Society for Neuroscience High 16885217
2008 Munc13-2 (UNC13B) knockout mice show accumulation of mucins (Muc5b) in Clara cells and goblet cells of multiple mucosal tissues, demonstrating that Munc13-2 is required for constitutive/baseline priming and secretion of a specific population of secretory granules; agonist-regulated secretion via Munc13-4 is preserved, revealing isoform-specific priming requirements. Munc13-2 knockout mouse histology (AB/PAS staining), BAL cell counts, qPCR, electron microscopy of Clara cells, agonist stimulation (ATP/UTP) in Munc13-2−/− airways The Journal of physiology High 18258655
2009 Munc13-2 (UNC13B) upregulation by high glucose in mesangial cells increases constitutive protein secretion via Rab34 interaction; siRNA knockdown of munc13-2 or rab34 abolishes high-glucose-induced VSVG-GFP secretion and fibronectin secretion; deletion of MHD2 abolishes the effect, confirming the MHD2–Rab34 interaction as the mechanistic basis. siRNA knockdown in rat mesangial cells, VSVG-GFP secretion assay, fibronectin secretion assay, MHD2-deletion mutant transfection in HeLa 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 knockout mice show strongly increased paired-pulse and frequency facilitation at mossy fiber synapses, consistent with reduced basal release probability, while mossy fiber LTP is unaffected; other hippocampal synapse types are unaffected. Munc13-2 knockout mouse electrophysiology — patch-clamp recordings of mossy fiber synapses, paired-pulse and frequency facilitation protocols, LTP induction Cerebral cortex (New York, N.Y. : 1991) High 19700493
2013 The N-terminal C2A domain of UNC-13 regulates active zone localization of UNC-13, release probability of evoked release, and is specifically required for spontaneous release; proximity of UNC-13 to Ca2+ entry sites mediated by the C2A-containing N-terminus accelerates neurotransmitter release kinetics. C2A domain deletion and mutagenesis in C. elegans, whole-cell voltage-clamp electrophysiology, kinetic analysis of synaptic vesicle release, immunofluorescence localization eLife High 24220508
2015 NLP-12 neuropeptide potentiates tonic ACh release through a Gαq/PLCβ-independent DAG pathway requiring DAG binding to UNC-13L (but not UNC-13S), while potentiation of evoked release uses both UNC-13 isoforms via the Gαq/PLCβ/DAG pathway, demonstrating isoform-specific and pathway-specific roles of UNC-13 in tonic versus evoked release. Genetic epistasis in C. elegans (egl-30, egl-8 mutants combined with unc-13 isoform-specific mutants), aldicarb sensitivity assay, electrophysiology The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 25609620
2016 The Drosophila 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/RIM-binding protein complexes and is responsible for docking SVs at that distance; Unc13A null mutants show inefficient, delayed, and EGTA-supersensitive release, demonstrating that isoform positioning defines release probability and kinetics. Super-resolution microscopy (STORM/STED), intravital imaging in Drosophila, electrophysiology (TEVC), EGTA chelation, mathematical modeling, isoform-specific null mutants Nature neuroscience High 27526206
2016 Munc13-2 (UNC13B) level differences between C57BL/6J and DBA/2J mice underlie strain-dependent differences in presynaptic release probability, vesicle recycling, and short-term plasticity at BLA glutamatergic synapses; shRNA knockdown of Munc13-2 in B6 mice recapitulates the DBA/2J presynaptic phenotype. shRNA knockdown in vivo, electrophysiology (paired-pulse, frequency facilitation), biochemical quantification of presynaptic proteins, BXD recombinant inbred strain in silico QTL analysis The Journal of neuroscience : the official journal of the Society for Neuroscience High 27798178
2017 Munc18-1/UNC-18 primes vesicle fusion downstream of Munc13-1/UNC-13 by templating SNARE complex assembly; a gain-of-function UNC-18(P334A) mutation partially bypasses the requirement for UNC-13, and this bypass is synergistically enhanced by loss of Tomosyn/TOM-1; Munc18-1(P335A) shows enhanced SNARE complex formation and partially bypasses Munc13-1 requirement in liposome fusion assays. Genetic epistasis in C. elegans, electrophysiology (C. elegans and mammalian neurons), liposome fusion reconstitution assay, biochemical SNARE complex formation assay The Journal of neuroscience : the official journal of the Society for Neuroscience High 28821673
2017 Doc2B requires interaction with ubMunc13-2 (a ubiquitous isoform of UNC13B/Munc13-2) for its downstream vesicle priming function in chromaffin cells: Doc2B Ca2+-binding mutations and SNARE-binding mutations block distinct priming steps, and the downstream priming step is dependent on both ubMunc13-2 and synaptotagmin-1. Overexpression and mutagenesis of Doc2B in mouse chromaffin cells, capacitance measurements, Ca2+ uncaging, genetic deletion of synaptotagmin-1 and Munc13-2 eLife Medium 29274147
2019 UNC-13L has three inhibitory domains (X region between C2A and C1, C1 domain, and C2B domain) that suppress synaptic vesicle exocytosis; removing all three produces a hyperactive UNC-13 with dramatically increased neurotransmitter release, Ca2+ sensitivity, and release probability, and this hyperactivity increases syntaxin open probability to enhance tonic release. Domain deletion mutagenesis in C. elegans, electrophysiology, Ca2+ sensitivity assay, synaptic recovery/replenishment kinetics, double mutant epistasis with syntaxin open-form mutants Cell reports High 31509756
2021 Synaptotagmin-7 promotes ubMunc13-2- and phorbol ester-dependent priming of dense-core vesicles, especially at low resting Ca2+; without synaptotagmin-7, vesicles accumulate 20–40 nm from the membrane rather than in close (<6 nm) apposition, indicating synaptotagmin-7 mediates a membrane-approach step upstream of Munc13-2-dependent priming. Synaptotagmin-7 knockout and overexpression in mouse chromaffin cells, capacitance measurements, TIRF microscopy with vesicle distance measurements, phorbol ester stimulation, genetic epistasis with Munc13-2 eLife Medium 33749593
2022 Endogenously tagged Unc-13 (all isoforms) in Drosophila undergoes nanoscale reorganization during presynaptic homeostatic potentiation (PHP): localization microscopy shows Unc-13 subclusters move toward the active zone center during PHP without changes in total Unc-13 protein levels. MiMIC-based endogenous GFSTF tagging of all Unc-13 isoforms, structured-illumination microscopy, localization microscopy with HDBSCAN clustering, two-electrode voltage-clamp electrophysiology Frontiers in cellular neuroscience Medium 36589286
2022 Munc13-2 (UNC13B) is selectively enriched at presynaptic active zones of hippocampal pyramidal cell synapses onto mGluR1α+ interneurons via Elfn1-dependent trans-synaptic recruitment; conditional deletion of Munc13-2 from CA1 pyramidal cells does not affect unitary EPSC amplitude or short-term facilitation at this connection, indicating Munc13-1 alone is sufficient for low release probability at these synapses. Conditional Munc13-2 knockout in CA1 pyramidal cells, paired whole-cell recordings, immunofluorescence quantification of Munc13-2 and mGluR7 at identified synapses, Elfn1 knockout comparison Frontiers in synaptic neuroscience Medium 35221979
2023 CLA-1 (Clarinet) recruits the priming factor UNC-13 to active zones via a RIMB-1-independent mechanism in C. elegans; CLA-1 acts in concert with UNC-10/RIM to regulate UNC-13 localization and presynaptic neurotransmitter release. Electrophysiology (C. elegans NMJ), electron microscopy, quantitative fluorescence imaging of UNC-13 localization in cla-1 and unc-10 null and double mutants Proceedings of the National Academy of Sciences of the United States of America Medium 37186867
2024 UNC13B localizes within cellular vesicles and positively regulates lysosome formation in Wilms' tumor cells; UNC13B knockdown reduces lysosome levels and increases doxorubicin-induced apoptosis, demonstrating a role for UNC13B in lysosomal regulation that confers drug resistance. shRNA-mediated knockdown, Lyso-Tracker staining, immunofluorescence localization, CCK-8 viability assay, flow cytometry for apoptosis, Western blot Oncology letters Low 39091580
2025 Octopamine-induced DAG signaling causes rapid (within one minute) immobilization and nanoscale compaction of Unc13 into synaptic nanoclusters to potentiate evoked release; a point mutation in the C1 DAG-binding domain of endogenous Unc13 blocks plasticity-induced nanoscopic enrichment, phorbol ester-induced potentiation, and reduces Ca2+ sensitivity of release. Live single-molecule imaging of endogenously tagged Unc13 at Drosophila NMJ, endogenous C1-domain point mutation via CRISPR, electrophysiology (TEVC), phorbol ester pharmacology, presynaptic knockdown Proceedings of the National Academy of Sciences of the United States of America High 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 504 10526333
1995 Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins. The Journal of biological chemistry 330 7559667
2001 An open form of syntaxin bypasses the requirement for UNC-13 in vesicle priming. Nature 323 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 275 10571228
1999 Serotonin inhibition of synaptic transmission: Galpha(0) decreases the abundance of UNC-13 at release sites. Neuron 265 10677040
1999 Drosophila UNC-13 is essential for synaptic transmission. Nature neuroscience 255 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 226 2062851
2007 Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4. Nature immunology 208 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 168 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 129 16885217
2005 UNC-13 interaction with syntaxin is required for synaptic transmission. Current biology : CB 117 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 74 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 70 24220508
2021 UNC13B variants associated with partial epilepsy with favourable outcome. Brain : a journal of neurology 57 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) 36 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 33 18633107
2017 Doc2B acts as a calcium sensor for vesicle priming requiring synaptotagmin-1, Munc13-2 and SNAREs. eLife 28 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
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 21 25609620
2005 Diacylglycerol-activated Hmunc13 serves as an effector of the GTPase Rab34. Traffic (Copenhagen, Denmark) 21 16138900
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 19 26990377
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
2018 Ethanol Regulates Presynaptic Activity and Sedation through Presynaptic Unc13 Proteins in Drosophila. eNeuro 18 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 18 27798178
2017 Ethanol Mediated Inhibition of Synaptic Vesicle Recycling at Amygdala Glutamate Synapses Is Dependent upon Munc13-2. Frontiers in neuroscience 15 28785200
2023 Role of the UNC13 family in human diseases: A literature review. AIMS neuroscience 13 38188011
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
1997 Genetic analysis of sterile mutants in the dpy-5 unc-13 (I) genomic region of Caenorhabditis elegans. Molecular & general genetics : MGG 10 9230900
2022 Selective Enrichment of Munc13-2 in Presynaptic Active Zones of Hippocampal Pyramidal Cells That Innervate mGluR1α Expressing Interneurons. Frontiers in synaptic neuroscience 8 35221979
2018 De novo UNC13B mutation identified in a bipolar disorder patient increases a rare exon-skipping variant. Neuropsychopharmacology reports 8 30117296
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
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 5 37186867
2022 UNC13B Promote Arsenic Trioxide Resistance in Chronic Lymphoid Leukemia Through Mitochondria Quality Control. Frontiers in oncology 5 35707364
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 4 40833403
2022 Differential Expression of Presynaptic Munc13-1 and Munc13-2 in Mouse Hippocampus Following Ethanol Drinking. Neuroscience 3 35167938
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

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