Neurotransmitter release cycle (Bos taurus)

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Description

Neurotransmitter is stored in the synaptic vesicle in the pre-synaptic terminal prior to its release in the synaptic cleft upon depolarization of the pre-synaptic membrane. The release of the neurotransmitter is a multi-step process that is controlled by electrical signals passing through the axons in form of action potential. Neurotransmitters include glutamate, acetylcholine, nor-epinephrine, dopamine and seratonin. Each of the neurotransmitter cycle is independently described.Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=112310

Comments

HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP1871(76832) with a 84.0% conversion rate.

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Bibliography

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  1. Seal RP, Akil O, Yi E, Weber CM, Grant L, Yoo J, Clause A, Kandler K, Noebels JL, Glowatzki E, Lustig LR, Edwards RH.; ''Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.''; PubMed Europe PMC Scholia
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  35. Augustin I, Rosenmund C, Südhof TC, Brose N.; ''Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
140516view04:52, 4 September 2025EgonwMore unicode
140515view04:51, 4 September 2025EgonwMarkdown link
139747view18:47, 2 July 2025EgonwReverted to version '18:39, 2 July 2025' by Egonw
139743view18:44, 2 July 2025EgonwModified description
139742view18:43, 2 July 2025EgonwReverted to version '18:39, 2 July 2025' by Egonw
139741view18:41, 2 July 2025EgonwModified description
139739view18:39, 2 July 2025EgonwWater with unicode
117569view11:21, 21 May 2021EweitzModified title
87908view12:57, 25 July 2016ElisaOntology Term : 'signaling pathway pertinent to the brain and nervous system' added !
87907view12:57, 25 July 2016ElisaOntology Term : 'signaling pathway' added !
80776view15:25, 30 June 2015MkutmonNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
3-Methoxy-4-hydroxyphenylglycolMetaboliteCHEBI:16436 (ChEBI)
5HT

[clathrin-sculpted monoamine transport

vesicle lumen]		MetaboliteCHEBI:28790 (ChEBI)
5HTMetaboliteCHEBI:28790 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
AcChoMetaboliteCHEBI:15355 (ChEBI)
Acetylcholine Loaded Synaptic VesicleComplexREACT_17766 (Reactome)
CHATProteinENSBTAG00000016814 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:P28329
CPLX1Protein
CPLX1 [cytosol]Protein
ChoMetaboliteCHEBI:15354 (ChEBI)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DA

[clathrin-sculpted monoamine transport

vesicle lumen]		MetaboliteCHEBI:18243 (ChEBI)
DAMetaboliteCHEBI:18243 (ChEBI)
Docked Glutamate

Loaded Synaptic

Vesicle		ComplexREACT_12825 (Reactome) Glutamate synaptic vesicle contains Rab3 ( GTPase), synaptobrevin/VAMP ( V-SNARE), VGLUT1 (Glutamate transporter) and synpatotagmin which is beleived to be a Ca2+ sensor and plays a role in the synaptic vesicle fusion process.
Docked Noradrenalin

loaded synaptic

vesicle		ComplexREACT_15843 (Reactome)
Docked acetylcholine

loaded Synaptic

Vesicle		ComplexREACT_17285 (Reactome) Acetylcholine synaptic vesicle contains Rab3 ( GTPase), synaptobrevin/VAMP ( V-SNARE), VGLUT1 (Glutamate transporter) and synpatotagmin which is beleived to be a Ca2+ sensor and plays a role in the synaptic vesicle fusion process.
Docked dopamine

loaded synaptic

vesicle		ComplexREACT_15684 (Reactome)
Docked serotonin

loaded synaptic

vesicle		ComplexREACT_17565 (Reactome)
Dopamine loaded synaptic vesicleComplexREACT_15992 (Reactome)
Empty Acetylcholine Synaptic VesicleComplexREACT_12740 (Reactome)
Empty Glutamate Synaptic VesicleComplexREACT_14482 (Reactome)
FAD [mitochondrial outer membrane]MetaboliteCHEBI:16238 (ChEBI)
GABA synthesis,

release, reuptake

and degradation		PathwayWP2685 (WikiPathways) GABA is a major inhibitory neurotransmitter in the mammalian central nervous system. GABA modulates neuronal excitability throughout the nervous system. Disruption of GABA neurotransmission leads to many neurological diseases including epilepsy and a general anxiety disorder. GABA is synthesized by two distinct enzymes GAD67 and GAD65 that differ in their cellular localization, functional properties and co-factor requirements. GABA synthesized by GAD65 is used for neurotransmission whereas GABA synthesized by GAD67 is used for processes other than neurotransmission such as synaptogenesis and protection against neuronal injury. GABA is loaded into synaptic vesicle with the help of vesicular inhibitory amino acid transporter or VGAT. GAD65 and VGAT are functionally linked at the synaptic vesicle membrane and GABA synthesized by GAD65 is preferentially loaded into the synaptic vesicle over GABA synthesized in cytoplasm by GAD67.The GABA loaded synaptic vesicles are docked at the plasma membrane with the help of the SNARE complexes and primed by interplay between various proteins including Munc18, complexin etc. Release of GABA loaded synaptic vesicle is initiated by the arrival of action potential at the presynaptic bouton and opening of N or P/Q voltage gated Ca2+ channels. Ca2+ influx results in Ca2+ binding by synaptobrevin, which is a part of the SNARE complex that also includes SNAP25 and syntaxin, leading to synaptic vesicle fusion. Release of GABA in the synaptic cleft leads to binding of GABA by the GABA receptors and post ligand binding events.
GLS dimersREACT_21656 (Reactome)
Glu

[clathrin-sculpted glutamate transport

vesicle lumen]		MetaboliteCHEBI:16015 (ChEBI)
GluMetaboliteCHEBI:16015 (ChEBI)
Glutamate loaded synaptic vesicleComplexREACT_12769 (Reactome)
H+MetaboliteCHEBI:15378 (ChEBI)
H₂OMetaboliteCHEBI:15377 (ChEBI)
H₂O₂MetaboliteCHEBI:16240 (ChEBI)
L-GlnMetaboliteCHEBI:18050 (ChEBI)
L-GluMetaboliteCHEBI:16015 (ChEBI)
MAOA-FAD complexComplexREACT_5113 (Reactome)
MAOAProteinENSBTAG00000016206 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:P21397
NAd

[clathrin-sculpted glutamate transport

vesicle lumen]		MetaboliteCHEBI:18357 (ChEBI)
NAdMetaboliteCHEBI:18357 (ChEBI)
NH3MetaboliteCHEBI:16134 (ChEBI)
NH4+MetaboliteCHEBI:28938 (ChEBI)
Na+MetaboliteCHEBI:29101 (ChEBI)
Neuronal EAATsREACT_14035 (Reactome)
Noradrenalin loaded synaptic vesicleComplexREACT_17964 (Reactome)
O-acetylcholine

[clathrin-sculpted acetylcholine transport vesicle

lumen]		MetaboliteCHEBI:15355 (ChEBI)
OCT2ProteinThis CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
O₂MetaboliteCHEBI:15379 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
RAB3AProteinENSBTAG00000010635 (Ensembl)
  • Rab3A, located in the synaptic vesicle membrane, interacts with RIM ( Rab3A interacting Molecule) and with Doc2. These interactions are beleived to initiate the process of priming which precedes the fuison of the synaptic vesicle with the plasma membrane.
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:P20336
RIMS1ProteinENSBTAG00000020238 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q86UR5
Rab3-RIM complexComplexREACT_13268 (Reactome) Rab3A, located in the synaptic vesicle membrane, interacts with RIM ( Rab3A interacting Molecule) and with Doc2. These interactions are beleived to initiate the process of priming which precedes the fuison of the synaptic vesicle with the plasma membrane.
SLC17A7ProteinENSBTAG00000007036 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q9P2U7
SLC18A2ProteinENSBTAG00000004739 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q05940
SLC18A3ProteinENSBTAG00000014990 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q16572
SLC22A2ProteinENSBTAG00000009583 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:O15244
SLC38A2ProteinENSBTAG00000011105 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q96QD8
SLC5A7ProteinENSBTAG00000004352 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q9GZV3
SNAP25ProteinENSBTAG00000008323 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:P60880
SNARE complexComplexREACT_12700 (Reactome)
STX1AProteinENSBTAG00000017075 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q16623
STXBP1-1ProteinMunc 18 interacts with syntaxin in the plasma membrane, with Mint (Munc 18 interacting) which in turn interacts with CASK and neurexins. Munc18 also interacts with granulophilin. Granulophilin is interacts simultaneously with syntaxin and Munc18. These interactions are believed to be involved in the docking of the synaptic vesicle to the plasma membrane. However, the sequence of events is unclear.
STXBP1-1 [cytosol]ProteinMunc 18 interacts with syntaxin in the plasma membrane, with Mint (Munc 18 interacting) which in turn interacts with CASK and neurexins. Munc18 also interacts with granulophilin. Granulophilin is interacts simultaneously with syntaxin and Munc18. These interactions are believed to be involved in the docking of the synaptic vesicle to the plasma membrane. However, the sequence of events is unclear.
SYT1ProteinENSBTAG00000034693 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:P21579
Serotonin loaded synaptic vesicleComplexREACT_16110 (Reactome)
SynapsinProtein
UNC13BProteinENSBTAG00000011397 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:O14795
VAMP2ProteinENSBTAG00000003891 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:P63027

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
3-Methoxy-4-hydroxyphenylglycolArrowREACT_15390 (Reactome)
5HTArrowREACT_15486 (Reactome)
5HTArrowREACT_15503 (Reactome)
5HTREACT_15486 (Reactome)
ADPArrowREACT_13770 (Reactome)
ADPArrowREACT_15379 (Reactome)
ATPREACT_13770 (Reactome)
ATPREACT_15379 (Reactome)
Ac-CoAREACT_15484 (Reactome)
AcChoArrowREACT_15404 (Reactome)
AcChoArrowREACT_15484 (Reactome)
AcChoREACT_15317 (Reactome)
Acetylcholine Loaded Synaptic VesicleArrowREACT_15317 (Reactome)
Acetylcholine Loaded Synaptic VesicleREACT_15483 (Reactome)
Acetylcholine Loaded Synaptic Vesiclemim-catalysisREACT_15483 (Reactome)
CHATmim-catalysisREACT_15484 (Reactome)
CPLX1ArrowREACT_12411 (Reactome)
CPLX1ArrowREACT_15404 (Reactome)
CPLX1ArrowREACT_15448 (Reactome)
CPLX1ArrowREACT_15503 (Reactome)
CPLX1ArrowREACT_15533 (Reactome)
CPLX1REACT_12617 (Reactome)
CPLX1REACT_15338 (Reactome)
CPLX1REACT_15411 (Reactome)
CPLX1REACT_15483 (Reactome)
CPLX1REACT_15517 (Reactome)
ChoArrowREACT_15552 (Reactome)
ChoREACT_15484 (Reactome)
ChoREACT_15552 (Reactome)
CoA-SHArrowREACT_15484 (Reactome)
DAArrowREACT_15524 (Reactome)
DAArrowREACT_15533 (Reactome)
DAREACT_15524 (Reactome)
Docked Glutamate

Loaded Synaptic

Vesicle		ArrowREACT_12617 (Reactome)
Docked Glutamate

Loaded Synaptic

Vesicle		REACT_12411 (Reactome)
Docked Glutamate

Loaded Synaptic

Vesicle		mim-catalysisREACT_12411 (Reactome)
Docked Noradrenalin

loaded synaptic

vesicle		ArrowREACT_15411 (Reactome)
Docked Noradrenalin

loaded synaptic

vesicle		REACT_15448 (Reactome)
Docked Noradrenalin

loaded synaptic

vesicle		mim-catalysisREACT_15448 (Reactome)
Docked acetylcholine

loaded Synaptic

Vesicle		ArrowREACT_15483 (Reactome)
Docked acetylcholine

loaded Synaptic

Vesicle		REACT_15404 (Reactome)
Docked acetylcholine

loaded Synaptic

Vesicle		mim-catalysisREACT_15404 (Reactome)
Docked dopamine

loaded synaptic

vesicle		ArrowREACT_15517 (Reactome)
Docked dopamine

loaded synaptic

vesicle		REACT_15533 (Reactome)
Docked dopamine

loaded synaptic

vesicle		mim-catalysisREACT_15533 (Reactome)
Docked serotonin

loaded synaptic

vesicle		ArrowREACT_15338 (Reactome)
Docked serotonin

loaded synaptic

vesicle		REACT_15503 (Reactome)
Docked serotonin

loaded synaptic

vesicle		mim-catalysisREACT_15503 (Reactome)
Dopamine loaded synaptic vesicleREACT_15517 (Reactome)
Dopamine loaded synaptic vesiclemim-catalysisREACT_15517 (Reactome)
Empty Acetylcholine Synaptic VesicleREACT_15317 (Reactome)
Empty Glutamate Synaptic VesicleREACT_12503 (Reactome)
Empty Glutamate Synaptic Vesiclemim-catalysisREACT_12503 (Reactome)
GLS dimersmim-catalysisREACT_1700 (Reactome)
GluArrowREACT_12411 (Reactome)
GluArrowREACT_1700 (Reactome)
GluREACT_13574 (Reactome)
GluREACT_13790 (Reactome)
Glutamate loaded synaptic vesicleArrowREACT_12503 (Reactome)
Glutamate loaded synaptic vesicleREACT_12617 (Reactome)
Glutamate loaded synaptic vesiclemim-catalysisREACT_12617 (Reactome)
H+ArrowREACT_13770 (Reactome)
H+ArrowREACT_15317 (Reactome)
H+ArrowREACT_15379 (Reactome)
H+REACT_13770 (Reactome)
H+REACT_15317 (Reactome)
H+REACT_15379 (Reactome)
H₂OREACT_15390 (Reactome)
H₂OREACT_1700 (Reactome)
H₂O₂ArrowREACT_15390 (Reactome)
L-GlnArrowREACT_13703 (Reactome)
L-GlnArrowREACT_13763 (Reactome)
L-GlnREACT_13703 (Reactome)
L-GlnREACT_13763 (Reactome)
L-GlnREACT_1700 (Reactome)
L-GluArrowREACT_13574 (Reactome)
L-GluArrowREACT_13790 (Reactome)
L-GluREACT_12503 (Reactome)
MAOA-FAD complexmim-catalysisREACT_15390 (Reactome)
NAdArrowREACT_15448 (Reactome)
NAdArrowREACT_15472 (Reactome)
NAdREACT_15390 (Reactome)
NAdREACT_15472 (Reactome)
NH3ArrowREACT_15390 (Reactome)
NH4+ArrowREACT_1700 (Reactome)
Na+ArrowREACT_13763 (Reactome)
Na+ArrowREACT_15552 (Reactome)
Na+REACT_13763 (Reactome)
Na+REACT_15552 (Reactome)
Neuronal EAATsmim-catalysisREACT_13574 (Reactome)
Noradrenalin loaded synaptic vesicleREACT_15411 (Reactome)
Noradrenalin loaded synaptic vesiclemim-catalysisREACT_15411 (Reactome)
OCT2mim-catalysisREACT_15472 (Reactome)
O₂REACT_15390 (Reactome)
PiArrowREACT_15379 (Reactome)
RAB3AArrowREACT_15338 (Reactome)
RAB3AArrowREACT_15503 (Reactome)
RAB3AArrowREACT_15533 (Reactome)
REACT_12411 (Reactome) Once vesicles are docked, primed and ready to be released fusion of the synaptic vesicle with the plasma membrane can be triggered by an influx of Ca2+ through the voltage gated Ca2+ channels (N, P/Q and R type). Ca2+ influx initiates a cascade of events in which the Ca2+ sensing protein, synaptotagmin-1 (sty-1) is central. Sty-1 promotes the membrane fusion between the synaptic vesicle and the plasma membrane by Ca2+ dependant induction of membrane curvature. Synaptotagmin competes with SNARE complex binding in a Ca2+ dependent manner thereby displacing complexin-1 and causing membrane curvature and fusion of the synaptic vesicle with the plasma membrane. The fusion is characterized by the formation of a trans SNARE complex in which SNAP 25, syntaxin and synaptobrevin along with VGLUT1, the glutamate transporter, synaptotagmin, and Rab3a either become a part of the plasma membrane or membrane delimited in the vesicular membrane. Vesicle fusion ultimately results in the release of the glutamate into the synaptic cleft.
REACT_12503 (Reactome) Nascent synaptic vesicles are loaded with glutamate by VGLUT1 to form glutamate containing synaptic vesicles. This process occurs while the synaptic vesicle is in the cytosol.
REACT_12617 (Reactome) Docking occurs once the synaptic vesicle has moved from the cytoplasm to a region apposed to the plasma membrane. The vesicle is held in close apposition to the plasma membrane by several proteins that bridge the synaptic vesicle to the plasma membrane. Some of these proteins are in the plasma membrane while others are in the synaptic vesicle. Vesicle fusion is preceded by a priming event where molecular interactions between the docked vesicle and the plasma membrane undergo changes. The molecules in the docking and the priming process are known, however, the exact sequence and the precise molecular changes involved in docking and priming are not well dissected. In this reaction the process of docking and priming has been condensed. It is known that Munc18 along with its interactors is critical for membrane docking and fusion events while Munc 13 along with its interacting proteins is central to priming. Munc 13 could act as a positive regulator for the priming recation. Finally the primed fusion complex is clamped in the pre-fusion form by a Complexin. Complexins are Ca2+ independent cytosolic proteins that bind to partly or fully assembled SNARE complexes. Complexins play both a positive and a negative role in the release process.

REACT_13574 (Reactome) Excess L-Glutamate released by the pre-synaptic neuron in the synaptic cleft is cleared by high affinity transporters called the excitatory amino acid transporters (EAATs) to terminate synaptic actions of the neurotransmitter and to recycle these molecules. Five types of EAATs have been identified EAAT1-EAAT5 in the mammalian CNS. EAAT1 and EAAT2 are mainly expressed by astrocytes whereas EAAT3 and EAAT4 are predominantly neuronal. EAAT3 are expressed throughout the CNS however, EAAT4 is predominantly localized to purkinje cells. EAAT5 are expressed rod photoreceptor and bipolar cells of retina. Astrocytic EAATs are expressed in astrocytes in close apposition to the synapses and neuronal EAATs are expressed in the extra-synaptic or peri-synaptic locations on the neurons. Astrocytic EAATs are responsible for majority of the glutamate uptake, neuronal transporters are responsible for glutamate clearance in specialized synapses in cerebellum where the spatial relationship between the glutamate receptors and EAATs is altered and glutamate receptors are expressed in the peri-synaptic region.
REACT_13703 (Reactome) Glutamine in neurons is transported into mitochondrial matrix by an unknown transporter. Because this enzyme is not yet identified, it is represented as a black box event.
REACT_13763 (Reactome) Glutamine uptake in neurons is carried out by Na+-dependant system A neutral amino acid transporter (Melone et al. 2006).
REACT_13770 (Reactome) The proton gradient for the acetylcholine uptake is provided by vH+ type ATPase pump located in the acetylcholine vesicular membrane.
REACT_13790 (Reactome) Glutamate from the mitochondrial matrix is transported back into the cytosol, to be loaded into synaptic vesicles. Solute carrier 25 is a mitochondrial glutamate transporter known to transport glutamate, but it is unclear if this protein is involved in the transport of glutamate in neurons.
REACT_15317 (Reactome) Acetylcholine is actively transported from the cytosol to the lumen of the clathrin sculpted synaptic vesicle by vesicular acetylcholine transporter. Two protons are exchanged for 1 molecule of acetylcholine. The vesicular acetylcholine transporter is located in the membrane of the clathrin sculpted synaptic vesicle.
REACT_15338 (Reactome) Serotonin loaded synaptic vesicles are docked, inside the synapse in the presynaptic cell, close to the plasmamembrane. The docking brings the vesicles in close proximity to the release site to fascilitate the release of serotonin. Some of the molecules involved in the docking process are Munc 18, Rab3a, Rab 3 interacting molecule (RIM). The priming reaction brings docked but unprimed synaptic vesicles into a releaseable pool. Priming involes formation of the trimeric SNARE complex between two plasmamembrane proteins SNAP25 and Syntaxin and vesicular membrane protein, VAMP2.
REACT_15379 (Reactome) Loading of the monoamine vesicle is preceded by acidifcation of the vesicle by ATPAse.
REACT_15390 (Reactome) Noradrenaline is degraded by Monoamine oxidase A, which contains FAD as a cofactor. Monoamine oxidase is located in the outer mitochondrial membrane facing the cytoplasmic site. Monoamine xoidase functions as a monomer and is functional both is astrocyes and neurons.
REACT_15404 (Reactome) Once vesicles are docked, primed and ready to be released fusion of the synaptic vesicle with the plasma membrane can be triggered by an influx of Ca2+ through the voltage gated Ca2+ channels (N, P/Q and R type). Ca2+ influx initiates a cascade of events in which the Ca2+ sensing protein, synaptotagmin-1 (sty-1) is central. Sty-1 promotes the membrane fusion between the synaptic vesicle and the plasma membrane by Ca2+ dependant induction of membrane curvature. Synaptotagmin competes with SNARE complex binding in a Ca2+ dependent manner thereby displacing complexin-1 and causing membrane curvature and fusion of the synaptic vesicle with the plasma membrane. The fusion is characterized by the formation of a trans SNARE complex in which SNAP 25, syntaxin and synaptobrevin along with VGLUT1, the glutamate transporter, synaptotagmin, and Rab3a either become a part of the plasma membrane or membrane delimited in the vesicular membrane. Vesicle fusion ultimately results in the release of the acetylcholine into the synaptic cleft.
REACT_15411 (Reactome) Docking and priming of clathrin sculpted Noradrenaline loaded transport vesicle occurs once the synaptic vesicle has moved from the cytoplasm to a region apposed to the plasma membrane. The details of the docking and priming recation have been worked out using synaptic vesicle loaded with glutamate and similar reactions may occur during the transport cycle of noradrenaline. The vesicle is held in close apposition to the plasma membrane by several proteins that bridge the synaptic vesicle to the plasma membrane. Some of these proteins are in the plasma membrane while others are in the synaptic vesicle. Vesicle fusion is preceded by a priming event where molecular interactions between the docked vesicle and the plasma membrane undergo changes. The molecules in the docking and the priming process are known, however, the exact sequence and the precise molecular changes involved in docking and priming are not well dissected. In this reaction the process of docking and priming has been condensed. It is known that Munc18 along with its interactors is critical for membrane docking and fusion events while Munc 13 along with its interacting proteins is central to priming. Munc 13 could act as a positive regulator for the priming recation. Finally the primed fusion complex is clamped in the pre-fusion form by a Complexin. Complexins are Ca2+ independent cytosolic proteins that bind to partly or fully assembled SNARE complexes. Complexins play both a positive and a negative role in the release process.

REACT_15448 (Reactome) Once vesicles are docked, primed and ready to be released fusion of the synaptic vesicle with the plasma membrane can be triggered by an influx of Ca2+ through the voltage gated Ca2+ channels (N, P/Q and R type). Ca2+ influx initiates a cascade of events in which the Ca2+ sensing protein, synaptotagmin-1 (sty-1) is central. Sty-1 promotes the membrane fusion between the synaptic vesicle and the plasma membrane by Ca2+ dependant induction of membrane curvature. Synaptotagmin competes with SNARE complex binding in a Ca2+ dependent manner thereby displacing complexin-1 and causing membrane curvature and fusion of the synaptic vesicle with the plasma membrane. The fusion is characterized by the formation of a trans SNARE complex in which SNAP 25, syntaxin and synaptobrevin along with VGLUT1, the glutamate transporter, synaptotagmin, and Rab3a either become a part of the plasma membrane or membrane delimited in the vesicular membrane. Vesicle fusion ultimately results in the release of the noradrenalin into the synaptic cleft.
REACT_15472 (Reactome) Noradrenaline is cleared from the synaptic cleft by Noaradrenaline uptake transporter. This reaction is carried out by neurons as well as astrocytes.
REACT_15483 (Reactome) Docking and priming of clathrin sculpted acetylcholine loaded transport vesicle occurs once the synaptic vesicle has moved from the cytoplasm to a region apposed to the plasma membrane. The details of the docking and priming reaction have been worked out using synaptic vesicles loaded with glutamate and similar reactions may occur during the transport cycle of acetylcholine. The vesicle is held in close apposition to the plasma membrane by several proteins that bridge the synaptic vesicle to the plasma membrane. Some of these proteins are in the plasma membrane while others are in the synaptic vesicle. Vesicle fusion is preceded by a priming event where molecular interactions between the docked vesicle and the plasma membrane undergo changes. The molecules in the docking and the priming process are known, however, the exact sequence and the precise molecular changes involved in docking and priming are not well dissected. In this reaction the process of docking and priming has been condensed. It is known that Munc18 along with its interactors is critical for membrane docking and fusion events while Munc 13 along with its interacting proteins is central to priming. Munc 13 could act as a positive regulator for the priming recation. Finally the primed fusion complex is clamped in the pre-fusion form by a Complexin. Complexins are Ca2+ independent cytosolic proteins that bind to partly or fully assembled SNARE complexes. Complexins play both a positive and a negative role in the release process.

REACT_15484 (Reactome) In the cytosol, choline O-acetyltransferase (CHAT) acetylates choline (Cho) to produce acetylcholine (AcCho) (Toussaint 1992).

AcCho is synthesised in the cytoplasm of cholinergic neurons from acetyl-CoA and Cho by CHAT enzyme.
REACT_15486 (Reactome) Serotonin is loaded into the clathrin sculpted monoamine transport vesicle by vesicular monoamine transporter.
REACT_15503 (Reactome) The trimeric complex formed between V-SNARE (VAMP) and the T-SNAREs (syntaxin and SNAP 25) after priming step is called transSNARE complex because the members of each group lie on the opposide side of the membrane, plasmamembrane side and the vesicular membrane side. Ca2+ influx through the Voltage gated Calcium Channels (VGCC) initaites the process of fusion of the synaptic vesicle in the presynaptic cell. The rise in Ca2+ leads to the activation of Protein Kinase A through rise in cAMP. Synaptotagmin, a Ca2+ sensor proetin also plays a role in the fusion process. Following fusion the members of V and T SNARES lie on the same membrane formin the cis-SNARES. The fusion of release causes the release of the neurotransmitter into the synaptic cleft.
REACT_15517 (Reactome) Dopamine loaded synaptic vesicles are docked, inside the synapse in the presynaptic cell, close to the plasmamembrane. The docking brings the vesicles in close proximity to the release site to fascilitate the release of dopamine. Some of the molecules involved in the docking process are Munc 18, Rab3a, Rab 3 interacting molecule (RIM). The priming reaction brings docked but unprimed synaptic vesicles into a releaseable pool. Priming involes formation of the trimeric SNARE complex between two plasmamembrane proteins SNAP25 and Syntaxin and vesicular membrane protein, VAMP2.
REACT_15524 (Reactome) Dopamine is transported from the cytosol into the reacidified clathrin sculpted monoamine transport vesicle by membranous vesicular monoamine transporter
REACT_15533 (Reactome) The trimeric complex formed between V-SNARE (VAMP) and the T-SNAREs (syntaxin and SNAP 25) after priming step is called transSNARE complex because the members of each group lie on the opposide side of the membrane, plasmamembrane side and the vesicular membrane side. Ca2+ influx through the Voltage gated Calcium Channels (VGCC) initaites the process of fusion of the synaptic vesicle in the presynaptic cell. The rise in Ca2+ leads to the activation of Protein Kinase A through rise in cAMP. Synaptotagmin, a Ca2+ sensor proetin also plays a role in the fusion process. Following fusion the members of V and T SNARES lie on the same membrane formin the cis-SNARES. The fusion of release causes the release of the neurotransmitter into the synaptic cleft.
REACT_15552 (Reactome) Choline transporter symports Na ion and Choline from the extracellular region into the cytosol. The choline transporters are located in the nerve terminals of cholinergic neurons.
REACT_1700 (Reactome) Mitochondrial glutaminase (GLS) catalyzes the hydrolysis of glutamine to yield glutamate and ammonia. Two GLS enzymes have been identified, one abundantly expressed in the liver (GLS - Elgadi et al. 1999) and one abundantly expressed in kidney (GLS2 - Gomez-Fabre et al. 2000). Their biochemical properties are similar. The enzymes are inferred to function as dimers based on unpublished crystallographic data for GLS (PDB 3CZD) and studies of glutaminase enzyme purified from Ehrlich Ascites cells (Quesada et al. 1988).
RIMS1ArrowREACT_15503 (Reactome)
RIMS1ArrowREACT_15533 (Reactome)
RIMS1REACT_12617 (Reactome)
RIMS1REACT_15411 (Reactome)
RIMS1REACT_15483 (Reactome)
Rab3-RIM complexArrowREACT_12411 (Reactome)
Rab3-RIM complexArrowREACT_15404 (Reactome)
Rab3-RIM complexArrowREACT_15448 (Reactome)
Rab3-RIM complexREACT_15338 (Reactome)
Rab3-RIM complexREACT_15517 (Reactome)
SLC17A7ArrowREACT_12411 (Reactome)
SLC18A2ArrowREACT_15448 (Reactome)
SLC18A2ArrowREACT_15503 (Reactome)
SLC18A2ArrowREACT_15533 (Reactome)
SLC18A2mim-catalysisREACT_15486 (Reactome)
SLC18A2mim-catalysisREACT_15524 (Reactome)
SLC18A3ArrowREACT_15404 (Reactome)
SLC18A3mim-catalysisREACT_15317 (Reactome)
SLC38A2mim-catalysisREACT_13763 (Reactome)
SLC5A7mim-catalysisREACT_15552 (Reactome)
SNAP25REACT_12617 (Reactome)
SNAP25REACT_15338 (Reactome)
SNAP25REACT_15411 (Reactome)
SNAP25REACT_15483 (Reactome)
SNAP25REACT_15517 (Reactome)
SNARE complexArrowREACT_12411 (Reactome)
SNARE complexArrowREACT_15404 (Reactome)
SNARE complexArrowREACT_15448 (Reactome)
SNARE complexArrowREACT_15503 (Reactome)
SNARE complexArrowREACT_15533 (Reactome)
STX1AREACT_12617 (Reactome)
STX1AREACT_15338 (Reactome)
STX1AREACT_15411 (Reactome)
STX1AREACT_15483 (Reactome)
STX1AREACT_15517 (Reactome)
STXBP1-1ArrowREACT_12411 (Reactome)
STXBP1-1ArrowREACT_15404 (Reactome)
STXBP1-1ArrowREACT_15448 (Reactome)
STXBP1-1ArrowREACT_15503 (Reactome)
STXBP1-1ArrowREACT_15533 (Reactome)
STXBP1-1REACT_12617 (Reactome)
STXBP1-1REACT_15338 (Reactome)
STXBP1-1REACT_15411 (Reactome)
STXBP1-1REACT_15483 (Reactome)
STXBP1-1REACT_15517 (Reactome)
SYT1ArrowREACT_12411 (Reactome)
SYT1ArrowREACT_15404 (Reactome)
SYT1ArrowREACT_15448 (Reactome)
SYT1ArrowREACT_15503 (Reactome)
SYT1ArrowREACT_15533 (Reactome)
Serotonin loaded synaptic vesicleREACT_15338 (Reactome)
Serotonin loaded synaptic vesiclemim-catalysisREACT_15338 (Reactome)
SynapsinArrowREACT_15503 (Reactome)
SynapsinArrowREACT_15533 (Reactome)
SynapsinREACT_15338 (Reactome)
SynapsinREACT_15517 (Reactome)
UNC13BArrowREACT_12617 (Reactome)
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