Synaptic vesicle exocytosis (docking, priming, Ca2+-triggered fusion)

The release stage of the synaptic vesicle cycle at the presynaptic active zone. Loaded vesicles are recruited to the active zone by the vesicle GTPase Rab3 and its effector RIM, which together with ELKS scaffolds tether vesicles and position them near voltage-gated Ca2+ channels. Munc13 and Munc18-1 then prime the vesicle by opening syntaxin-1 and templating assembly of the trans-SNARE complex (syntaxin-1 / SNAP-25 / synaptobrevin-2). An action potential opens Cav2 channels; the resulting Ca2+ microdomain is sensed by synaptotagmin-1, which relieves the complexin clamp and drives full SNARE zippering and fusion-pore opening, releasing transmitter. NSF with alpha-SNAP finally disassembles the cis-SNARE complex so the SNAREs can be reused. The inner pair -> fuse -> recycle bundle conforms to the generic MODULE:snare_fusion_cycle motif. Exemplars are human; the machinery is conserved across metazoan chemical synapses. Grounded in GO:0016079 (synaptic vesicle exocytosis).

MODULE:synaptic_vesicle_exocytosisDRAFTCONCRETEBiological Processmodules/synaptic_vesicle_exocytosis.yaml
synaptic vesicle exocytosisGO:0016079
GO:0016079
synaptic vesicle exocytosis
The module is grounded in the GO process for synaptic vesicle exocytosis.
GO:0016082
synaptic vesicle priming
Munc13/Munc18-dependent priming is modeled as a required part.
GO:0099502
calcium-dependent activation of synaptic vesicle fusion
Synaptotagmin-mediated Ca2+ triggering is modeled as the fusion-activating step.
PMID:24183019
Neurotransmitter release: the last millisecond in the life of a synaptic vesicle.
Review framing the docking/priming/Ca2+-triggering/fusion sequence and the roles of RIM, Munc13, Munc18, SNAREs, complexin and synaptotagmin.
PMID:23060190
Molecular machines governing exocytosis of synaptic vesicles.
Review of the SNARE/SM-protein fusion machinery and NSF/SNAP recycling.
PMID:26098518
The Synaptic Vesicle Release Machinery.
Review of the structural mechanism of SNARE assembly templated by Munc18-1 and Munc13-1.
PMID:24274737
Molecular mechanisms for synchronous, asynchronous, and spontaneous neurotransmitter release.
Basis for the release-mode variant set (synchronous vs asynchronous Ca2+ sensors).
PANTHER:PTN000461349
PAINT syntaxin SNARE-complex node
Local PAINT IBD node in PTHR19957 seeded by human syntaxins with propagated terms C:GO:0031201 and P:GO:0006906.
PANTHER:PTN009219507
PAINT Rab3 G protein activity node
Local PAINT IBD node in PTHR47980 seeded by RAB3A with propagated term F:GO:0003925.
PMID:10526333
UNC-13 is required for synaptic vesicle fusion in C. elegans.
C. elegans unc-13 mutants accumulate docked but unprimed vesicles, grounding the worm realization of the priming step.
PMID:12973353
Defects in synaptic vesicle docking in unc-18 mutants.
C. elegans unc-18 mutants show reduced vesicle docking, grounding the worm realization of the Munc18 role.

Human-centric exemplars with family-level descriptors. The obsolete GO term for synaptic vesicle docking is not used; docking is described in prose on the active-zone recruitment node and the RIM annoton carries GO:0010808 (positive regulation of synaptic vesicle priming). Ca2+ channel beta/alpha2delta subunits, bassoon/piccolo, and the dense-core-vesicle pathway are out of scope. Neurotransmitter loading and vesicle retrieval are separate modules (MODULE:synaptic_vesicle_neurotransmitter_loading, MODULE:synaptic_vesicle_endocytosis); MODULE:synaptic_vesicle_cycle is the umbrella. Caenorhabditis elegans orthologs are listed as second representative members (rab-3, unc-10, elks-1, unc-13, unc-18, unc-2, rimb-1, unc-64, ric-4, snb-1, snt-1, cpx-1, nsf-1, snap-1). The worm has a single Cav2 channel and a single fast sensor; no worm member is asserted for the SYT7 asynchronous variant.

10Nodes
7Parts
1Variant Sets
2Variants
14Annotons
6Connections

Derived QC

Recommended-field compliance

87.5% recommended fields populated
  • knowledge_gaps[1] · provenance (0/1)
  • knowledge_gaps[2] · provenance (0/1)

Module deep research

✗ none found

No MODULE:synaptic_vesicle_exocytosis deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

2 conformance issue(s):

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

  • active_zone_recruitment → vesicle_priming [NOT_CHECKED]
    Protein-mediated vesicle state transitions, not metabolite chaining.
  • vesicle_priming → calcium_triggered_snare_fusion [NOT_CHECKED]
    Protein-mediated vesicle state transitions, not metabolite chaining.

Gene-review completeness (16/31 grounded genes reviewed)

11 complete review(s) · 16 with deep research · 15 missing review · 0 reviewed but lacking deep research

Gene Review Complete Deep research
cpx-1 Q9GUM7 ✓ ✓ ✓
elks-1 O44490 ✓ ✓ ✓
ERC1 Q8IUD2 ✓ 36/37 ✓
nsf-1 Q94392 ✓ ✓ ✓
CACNA1A (Homo sapiens) O00555 ✗ — —
CPLX1 (Homo sapiens) O14810 ✗ — —
SYT7 (Homo sapiens) O43581 ✗ — —
RAB3A (Homo sapiens) P20336 ✗ — —
SYT1 (Homo sapiens) P21579 ✗ — —
NSF (Homo sapiens) P46459 ✗ — —
NAPA (Homo sapiens) P54920 ✗ — —
SNAP25 (Homo sapiens) P60880 ✗ — —
STXBP1 (Homo sapiens) P61764 ✗ — —
VAMP2 (Homo sapiens) P63027 ✗ — —
CACNA1B (Homo sapiens) Q00975 ✗ — —
STX1A (Homo sapiens) Q16623 ✗ — —
RIMS1 (Homo sapiens) Q86UR5 ✗ — —
SYT2 (Homo sapiens) Q8N9I0 ✗ — —
UNC13A (Homo sapiens) Q9UPW8 ✗ — —
rab-3 Q94986 ✓ 22/23 ✓
ric-4 A5PEW5 ✓ ✓ ✓
rimb-1 Q9N415 ✓ ✓ ✓
RIMBP2 O15034 ✓ 5/6 ✓
snap-1 Q18921 ✓ ✓ ✓
snb-1 O02495 ✓ ✓ ✓
snt-1 P34693 ✓ ✓ ✓
unc-10 Q22366 ✓ ✓ ✓
unc-13 P27715 ✓ ✓ ✓
unc-18 P34815 ✓ 19/21 ✓
unc-2 G5EFB0 ✓ 25/27 ✓
unc-64 O16000 ✓ ✓ ✓

Details

Context
metazoaNCBITaxon:33208
presynaptic active zoneGO:0048786 synaptic vesicle membraneGO:0030672
Active-zone recruitment -> priming -> Ca2+ influx -> SNARE fusionBiological Processsynaptic_vesicle_exocytosis
synaptic vesicle exocytosisGO:0016079
Context
metazoaNCBITaxon:33208
presynaptic active zoneGO:0048786 synaptic vesicle membraneGO:0030672

Connections

Docked vesicles are primed by RIM-recruited Munc13 and Munc18-1.
Priming yields the partially zippered trans-SNARE complex that Ca2+ then triggers.
The Cav2 Ca2+ microdomain is the trigger sensed by synaptotagmin.
RIM/RIM-BP tether Cav2 channels to docked vesicles, tightening Ca2+-release coupling.
Part 1: active-zone recruitment and docking
Rab3/RIM/ELKS recruitment of vesicles to the active zoneRegulatory Stepactive_zone_recruitment

GTP-bound Rab3 on the vesicle binds RIM at the active zone; RIM and the ELKS scaffold hold the vesicle at the release site and, via RIM-BP, near Ca2+ channels. This is the docking/tethering step that precedes priming.

Annotons

Rab3 vesicle GTPase
rab3_vesicle_gtpase
Participant: Family: Rab3 (RAB3A/B/C/D) family
Family:
Rab3 (RAB3A/B/C/D) familyPANTHER:PTHR47980
Representative Members: RAB3A (Homo sapiens)UniProtKB:P20336 rab-3 (Caenorhabditis elegans)UniProtKB:Q94986

Function

G protein activityGO:0003925

Locations

synaptic vesicle membraneGO:0030672

GTP-bound Rab3 on the vesicle recruits RIM (and rabphilin) and is switched off by Rab3-GAP after fusion.

RIM Rab3 effector
rim_active_zone_effector
Participant: Family: RIM (RIMS1/2) active-zone protein family
Family:
RIM (RIMS1/2) active-zone protein familyPANTHER:PTHR12157
Representative Members: RIMS1 (Homo sapiens)UniProtKB:Q86UR5 unc-10 (Caenorhabditis elegans)UniProtKB:Q22366

Function

small GTPase binding (Rab3-GTP effector)GO:0031267

Processes

positive regulation of synaptic vesicle primingGO:0010808

Locations

presynaptic active zoneGO:0048786

Binds Rab3-GTP to dock the vesicle, recruits Munc13 to prime it, and binds RIM-BP to tether Ca2+ channels.

ELKS/CAST active-zone scaffold
elks_active_zone_scaffold
Participant: Family: ELKS/CAST (ERC1/2) family
Family:
ELKS/CAST (ERC1/2) familyPANTHER:PTHR18861
Representative Members: ERC1 (Homo sapiens)UniProtKB:Q8IUD2 elks-1 (Caenorhabditis elegans)UniProtKB:O44490

Function

structural constituent of presynaptic active zoneGO:0098882

Locations

presynaptic active zone cytoplasmic componentGO:0098831

Structural scaffold that holds RIM, RIM-BP and Ca2+ channels at the release site.

file:human/ERC1/ERC1-ai-review.yaml
Gene review accepts GO:0098882 as the core presynaptic function of ERC1.
Part 2: priming
Munc13/Munc18-1 priming and SNARE assembly templatingRegulatory Stepvesicle_priming

Munc13 (recruited by RIM) and Munc18-1 convert the docked vesicle into a release-ready state: Munc18-1 holds syntaxin-1 in its closed conformation and, with Munc13, templates the correct assembly of the trans-SNARE complex.

synaptic vesicle primingGO:0016082

Annotons

Munc13 priming factor
munc13_priming_factor
Participant: Family: Munc13 (UNC13A/B/C) family
Family:
Munc13 (UNC13A/B/C) familyPANTHER:PTHR10480
Representative Members: UNC13A (Homo sapiens)UniProtKB:Q9UPW8 unc-13 (Caenorhabditis elegans)UniProtKB:P27715

Function

syntaxin-1 bindingGO:0017075

Processes

synaptic vesicle primingGO:0016082

Locations

presynaptic active zoneGO:0048786

MUN domain opens syntaxin-1 and bridges the vesicle to the plasma membrane; C1/C2B domains confer DAG and Ca2+/PIP2 regulation of release probability.

Munc18-1 SM protein
munc18_sm_protein
Participant: Family: Munc18-1 / UNC-18 orthologs in the Sec1/Munc18 SM-protein family
Family:
Munc18-1 / UNC-18 orthologs in the Sec1/Munc18 SM-protein familyPANTHER:PTHR11679
Representative Members: STXBP1 (Homo sapiens)UniProtKB:P61764 unc-18 (Caenorhabditis elegans)UniProtKB:P34815

Function

syntaxin-1 bindingGO:0017075

Processes

SNARE complex assemblyGO:0035493

Locations

presynaptic active zoneGO:0048786

Binds closed syntaxin-1, then templates syntaxin-1/synaptobrevin pairing so that the SNARE complex assembles in the correct register.

Part 3: presynaptic Ca2+ influx
Action-potential-gated Ca2+ entry through Cav2 channelsTransport Steppresynaptic_calcium_influx

Depolarisation opens P/Q-type (Cav2.1) and N-type (Cav2.2) channels tethered to the active zone by RIM and RIM-BP, producing the local Ca2+ microdomain that triggers fusion.

Annotons

Cav2 voltage-gated Ca2+ channel alpha1 subunit
cav2_calcium_channel
Participant: Family: Cav2 (CACNA1A/B/E) voltage-gated Ca2+ channel alpha1 subunits
Family:
Cav2 (CACNA1A/B/E) voltage-gated Ca2+ channel alpha1 subunitsPANTHER:PTHR45628
Representative Members: CACNA1A (Homo sapiens)UniProtKB:O00555 CACNA1B (Homo sapiens)UniProtKB:Q00975 unc-2 (Caenorhabditis elegans)UniProtKB:G5EFB0

Function

voltage-gated calcium channel activity involved in regulation of presynaptic cytosolic calcium levelsGO:0099626

Processes

regulation of presynaptic cytosolic calcium ion concentrationGO:0099509

Locations

presynaptic active zone membraneGO:0048787

Supplies the Ca2+ transient that synaptotagmin senses.

RIM-BP channel tether
rim_bp_channel_tether
Participant: Family: RIM-binding protein (RIMBP1/2) family
Family:
RIM-binding protein (RIMBP1/2) familyPANTHER:PTHR14234
Representative Members: RIMBP2 (Homo sapiens)UniProtKB:O15034 rimb-1 (Caenorhabditis elegans)UniProtKB:Q9N415

Function

structural constituent of presynaptic active zoneGO:0098882

Locations

presynaptic active zoneGO:0048786

SH3 domains bind the Cav2 C-terminus and RIM, coupling channels to docked vesicles for tight Ca2+-release coupling.

file:human/RIMBP2/RIMBP2-ai-review.yaml
Gene review accepts GO:0098882 and positive regulation of synaptic vesicle priming for RIMBP2.
Part 4: Ca2+-triggered SNARE fusion and SNARE recycling
SNARE pairing -> Ca2+-triggered fusion -> NSF disassemblyTransport Stepcalcium_triggered_snare_fusion

The concrete synaptic realization of the generic SNARE fusion cycle: syntaxin-1/SNAP-25/synaptobrevin-2 form the trans-SNARE complex, synaptotagmin-1 senses Ca2+ to trigger full zippering and fusion-pore opening (with complexin clamping the primed state), and NSF/alpha-SNAP disassemble the cis-SNARE complex afterwards.

Connections

Partial trans-SNARE zippering sets up the Ca2+-triggerable fusion intermediate.
Disassembly regenerates free SNAREs for the next round of pairing.
Part 1: trans-SNARE pairing
Syntaxin-1 / SNAP-25 / synaptobrevin-2 trans-SNARE complexReactiontrans_snare_assembly

The Qa (syntaxin-1), Qbc (SNAP-25) and R (synaptobrevin-2/VAMP2) SNARE motifs zipper from the N-terminus into a four-helix bundle bridging vesicle and plasma membrane.

Annotons

Synaptic SNARE complex
synaptic_snare_complex
Participant: Protein Complex: synaptic (syntaxin-1 / SNAP-25 / VAMP2) SNARE complex
Protein Complex:
synaptic (syntaxin-1 / SNAP-25 / VAMP2) SNARE complexGO:0031201
Active units:
Qa-SNARE syntaxin-1
Participant: Family: syntaxin-1 (STX1A/STX1B) family
Family:
syntaxin-1 (STX1A/STX1B) familyPANTHER:PTHR19957
Representative Members: STX1A (Homo sapiens)UniProtKB:Q16623 unc-64 (Caenorhabditis elegans)UniProtKB:O16000
Role: Plasma-membrane Qa-SNARE; contributes one helix.
Function:
SNAP receptor activityGO:0005484
Qbc-SNARE SNAP-25
Participant: Family: SNAP-25 (SNAP25/SNAP23) family
Family:
SNAP-25 (SNAP25/SNAP23) familyPANTHER:PTHR19305
Representative Members: SNAP25 (Homo sapiens)UniProtKB:P60880 ric-4 (Caenorhabditis elegans)UniProtKB:A5PEW5
Role: Palmitoylated plasma-membrane Qbc-SNARE; contributes two helices.
Function:
SNAP receptor activityGO:0005484
R-SNARE synaptobrevin-2 (VAMP2)
Participant: Family: synaptobrevin (VAMP1/2/3) family
Family:
synaptobrevin (VAMP1/2/3) familyPANTHER:PTHR45701
Representative Members: VAMP2 (Homo sapiens)UniProtKB:P63027 snb-1 (Caenorhabditis elegans)UniProtKB:O02495
Role: Vesicle R-SNARE; contributes one helix.
Function:
SNAP receptor activityGO:0005484

Function

SNAP receptor activityGO:0005484

Processes

SNARE complex assemblyGO:0035493

Locations

presynaptic active zone membraneGO:0048787

Forms the fusogenic trans-SNARE complex between vesicle and active-zone membrane.

Part 2: Ca2+ sensing and membrane fusion
Synaptotagmin Ca2+ sensing, complexin clamp release, fusion-pore openingTransport Stepcalcium_sensing_and_fusion

Ca2+ binding to the synaptotagmin C2 domains drives their insertion into the plasma membrane and displaces the complexin clamp, completing SNARE zippering and opening the fusion pore.

Annotons

Synaptotagmin Ca2+ sensor
synaptotagmin_calcium_sensor
Participant: Family: synaptotagmin family
Family:
synaptotagmin familyPANTHER:PTHR10024
Representative Members: SYT1 (Homo sapiens)UniProtKB:P21579 snt-1 (Caenorhabditis elegans)UniProtKB:P34693

Function

calcium ion sensor activityGO:0061891

Processes

calcium-dependent activation of synaptic vesicle fusionGO:0099502 synaptic vesicle fusion to presynaptic active zone membraneGO:0031629

Locations

synaptic vesicle membraneGO:0030672

Ca2+-dependent phospholipid and SNARE binding converts the Ca2+ transient into fusion within a fraction of a millisecond.

Complexin clamp / facilitator
complexin_clamp
Participant: Family: complexin (CPLX1/2) family
Family:
complexin (CPLX1/2) familyPANTHER:PTHR16705
Representative Members: CPLX1 (Homo sapiens)UniProtKB:O14810 cpx-1 (Caenorhabditis elegans)UniProtKB:Q9GUM7

Function

SNARE bindingGO:0000149

Processes

regulation of synaptic vesicle exocytosisGO:2000300

Binds the partially zippered SNARE complex, clamping spontaneous fusion and facilitating synchronous Ca2+-triggered release.

Variant set: Ca2+ sensor by release mode by release kinetics (One Or More)

Fast synchronous release uses the low-affinity, fast sensors SYT1/SYT2; slower asynchronous release uses the high-affinity sensor SYT7. Both modes coexist at most synapses.

Synchronous release (SYT1/SYT2)Regulatory Stepsynchronous_release_sensor

Fast, synchronous Ca2+-dependent exocytosis triggered by synaptotagmin-1 or -2.

Annotons

Fast synchronous Ca2+ sensor
syt1_syt2_fast_sensor
Participant: Family: synaptotagmin family (SYT1/SYT2 fast sensors)
Family:
synaptotagmin family (SYT1/SYT2 fast sensors)PANTHER:PTHR10024
Representative Members: SYT1 (Homo sapiens)UniProtKB:P21579 snt-1 (Caenorhabditis elegans)UniProtKB:P34693 SYT2 (Homo sapiens)UniProtKB:Q8N9I0

Function

calcium ion sensor activityGO:0061891

Processes

fast, calcium ion-dependent exocytosis of neurotransmitterGO:0098746

Triggers release within ~1 ms of the Ca2+ transient.

Asynchronous release (SYT7)Regulatory Stepasynchronous_release_sensor

Slower asynchronous release driven by the high-affinity sensor synaptotagmin-7.

Annotons

Slow asynchronous Ca2+ sensor
syt7_slow_sensor
Participant: Family: synaptotagmin-7 (SYT7) subfamily
Family:
synaptotagmin-7 (SYT7) subfamilyPANTHER:PTHR10024:SF344
Representative Members: SYT7 (Homo sapiens)UniProtKB:O43581

Function

calcium ion sensor activityGO:0061891

Processes

slow, calcium ion-dependent exocytosis of neurotransmitterGO:0098747

Sustains release over tens to hundreds of milliseconds after the Ca2+ transient.

Part 3: NSF/alpha-SNAP cis-SNARE disassembly
NSF / alpha-SNAP disassembly of the cis-SNARE complexReactioncis_snare_disassembly

After fusion the SNAREs sit in the same membrane as a stable cis-complex; alpha-SNAP binds it and recruits the AAA+ ATPase NSF, whose ATP hydrolysis pries the bundle apart for reuse.

Annotons

NSF AAA+ ATPase
nsf_disassembly_atpase
Participant: Family: NSF vesicle-fusing ATPase family
Family:
NSF vesicle-fusing ATPase familyPANTHER:PTHR23078
Representative Members: NSF (Homo sapiens)UniProtKB:P46459 nsf-1 (Caenorhabditis elegans)UniProtKB:Q94392

Function

ATP hydrolysis activityGO:0016887
Substrates: ATP
Products: ADP + phosphate

Processes

SNARE complex disassemblyGO:0035494

Locations

presynaptic cytosolGO:0099523

Uses ATP hydrolysis to unwind the cis-SNARE four-helix bundle.

alpha-SNAP adaptor
alpha_snap_adaptor
Participant: Family: alpha/gamma-SNAP (NAPA/NAPG) family
Family:
alpha/gamma-SNAP (NAPA/NAPG) familyPANTHER:PTHR13768
Representative Members: NAPA (Homo sapiens)UniProtKB:P54920 snap-1 (Caenorhabditis elegans)UniProtKB:Q18921

Function

soluble NSF attachment protein activityGO:0005483

Processes

SNARE complex disassemblyGO:0035494

Binds the cis-SNARE complex and recruits/activates NSF.