Neurotransmitter release cycle (Homo sapiens)

From WikiPathways

Description

Quality Tags

Ontology Terms

Saving...

Bibliography

1. Sudhof TC.; ''The synaptic vesicle cycle.''; PubMed Europe PMC Scholia
2. Binda F, Dipace C, Bowton E, Robertson SD, Lute BJ, Fog JU, Zhang M, Sen N, Colbran RJ, Gnegy ME, Gether U, Javitch JA, Erreger K, Galli A.; ''Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux.''; PubMed Europe PMC Scholia
3. Jen JC, Wan J, Palos TP, Howard BD, Baloh RW.; ''Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures.''; PubMed Europe PMC Scholia
4. Quesada AR, Sanchez-Jimenez F, Perez-Rodriguez J, Marquez J, Medina MA, Nuñez de Castro I.; ''Purification of phosphate-dependent glutaminase from isolated mitochondria of Ehrlich ascites-tumour cells.''; PubMed Europe PMC Scholia
5. Sun L, Bittner MA, Holz RW.; ''Rim, a component of the presynaptic active zone and modulator of exocytosis, binds 14-3-3 through its N terminus.''; PubMed Europe PMC Scholia
6. Takamori S, Riedel D, Jahn R.; ''Immunoisolation of GABA-specific synaptic vesicles defines a functionally distinct subset of synaptic vesicles.''; PubMed Europe PMC Scholia
7. Barclay JW, Craig TJ, Fisher RJ, Ciufo LF, Evans GJ, Morgan A, Burgoyne RD.; ''Phosphorylation of Munc18 by protein kinase C regulates the kinetics of exocytosis.''; PubMed Europe PMC Scholia
8. Buddhala C, Hsu CC, Wu JY.; ''A novel mechanism for GABA synthesis and packaging into synaptic vesicles.''; PubMed Europe PMC Scholia
9. Hong SB, Li CM, Rhee HJ, Park JH, He X, Levy B, Yoo OJ, Schuchman EH.; ''Molecular cloning and characterization of a human cDNA and gene encoding a novel acid ceramidase-like protein.''; PubMed Europe PMC Scholia
10. Riento K, Galli T, Jansson S, Ehnholm C, Lehtonen E, Olkkonen VM.; ''Interaction of Munc-18-2 with syntaxin 3 controls the association of apical SNAREs in epithelial cells.''; PubMed Europe PMC Scholia
11. Martens S, Kozlov MM, McMahon HT.; ''How synaptotagmin promotes membrane fusion.''; PubMed Europe PMC Scholia
12. Henry JP, Botton D, Sagne C, Isambert MF, Desnos C, Blanchard V, Raisman-Vozari R, Krejci E, Massoulie J, Gasnier B.; ''Biochemistry and molecular biology of the vesicular monoamine transporter from chromaffin granules.''; PubMed Europe PMC Scholia
13. Melone M, Varoqui H, Erickson JD, Conti F.; ''Localization of the Na(+)-coupled neutral amino acid transporter 2 in the cerebral cortex.''; PubMed Europe PMC Scholia
14. Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA.; ''Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A.''; PubMed Europe PMC Scholia
15. Stein A, Radhakrishnan A, Riedel D, Fasshauer D, Jahn R.; ''Synaptotagmin activates membrane fusion through a Ca2+-dependent trans interaction with phospholipids.''; PubMed Europe PMC Scholia
16. Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S, Baumann C, Lang F, Busch AE, Koepsell H.; ''Cloning and characterization of two human polyspecific organic cation transporters.''; PubMed Europe PMC Scholia
17. Bak LK, Schousboe A, Waagepetersen HS.; ''The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer.''; PubMed Europe PMC Scholia
18. 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
19. Lin CI, Orlov I, Ruggiero AM, Dykes-Hoberg M, Lee A, Jackson M, Rothstein JD.; ''Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18.''; PubMed Europe PMC Scholia
20. Butz S, Okamoto M, Südhof TC.; ''A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain.''; PubMed Europe PMC Scholia
21. Sun L, Bittner MA, Holz RW.; ''Rab3a binding and secretion-enhancing domains in Rim1 are separate and unique. Studies in adrenal chromaffin cells.''; PubMed Europe PMC Scholia
22. Mueller HT, Borg JP, Margolis B, Turner RS.; ''Modulation of amyloid precursor protein metabolism by X11alpha /Mint-1. A deletion analysis of protein-protein interaction domains.''; PubMed Europe PMC Scholia
23. Gómez-Fabre PM, Aledo JC, Del Castillo-Olivares A, Alonso FJ, Núñez De Castro I, Campos JA, Márquez J.; ''Molecular cloning, sequencing and expression studies of the human breast cancer cell glutaminase.''; PubMed Europe PMC Scholia
24. Iioka H, Moriyama I, Kyuma M, Ito K, Amasaki M, Ichijo M.; ''[Studies on L-glutamate transport mechanism in human placental trophoblast microvilli membrane vesicles].''; PubMed Europe PMC Scholia
25. Tsuboi K, Sun YX, Okamoto Y, Araki N, Tonai T, Ueda N.; ''Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase.''; PubMed Europe PMC Scholia
26. Surratt CK, Persico AM, Yang XD, Edgar SR, Bird GS, Hawkins AL, Griffin CA, Li X, Jabs EW, Uhl GR.; ''A human synaptic vesicle monoamine transporter cDNA predicts posttranslational modifications, reveals chromosome 10 gene localization and identifies TaqI RFLPs.''; PubMed Europe PMC Scholia
27. Augustin I, Rosenmund C, Südhof TC, Brose N.; ''Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles.''; PubMed Europe PMC Scholia
28. Johnson RG.; ''Accumulation of biological amines into chromaffin granules: a model for hormone and neurotransmitter transport.''; PubMed Europe PMC Scholia
29. Elgadi KM, Meguid RA, Qian M, Souba WW, Abcouwer SF.; ''Cloning and analysis of unique human glutaminase isoforms generated by tissue-specific alternative splicing.''; PubMed Europe PMC Scholia
30. Okuda T, Haga T.; ''Functional characterization of the human high-affinity choline transporter.''; PubMed Europe PMC Scholia
31. Gopalakrishnan A, Sievert M, Ruoho AE.; ''Identification of the substrate binding region of vesicular monoamine transporter-2 (VMAT-2) using iodoaminoflisopolol as a novel photoprobe.''; PubMed Europe PMC Scholia
32. Zhou Y, Danbolt NC.; ''Glutamate as a neurotransmitter in the healthy brain.''; PubMed Europe PMC Scholia
33. Michaelson DM, Angel I.; ''Determination of delta pH in cholinergic synaptic vesicles: its effect on storage and release of acetylcholine.''; PubMed Europe PMC Scholia
34. Khvotchev M, Dulubova I, Sun J, Dai H, Rizo J, Südhof TC.; ''Dual modes of Munc18-1/SNARE interactions are coupled by functionally critical binding to syntaxin-1 N terminus.''; PubMed Europe PMC Scholia
35. Toonen RF, de Vries KJ, Zalm R, Südhof TC, Verhage M.; ''Munc18-1 stabilizes syntaxin 1, but is not essential for syntaxin 1 targeting and SNARE complex formation.''; PubMed Europe PMC Scholia
36. Toussaint JL, Geoffroy V, Schmitt M, Werner A, Garnier JM, Simoni P, Kempf J.; ''Human choline acetyltransferase (CHAT): partial gene sequence and potential control regions.''; PubMed Europe PMC Scholia
37. Apparsundaram S, Ferguson SM, George AL, Blakely RD.; ''Molecular cloning of a human, hemicholinium-3-sensitive choline transporter.''; PubMed Europe PMC Scholia
38. Becherer U, Rettig J.; ''Vesicle pools, docking, priming, and release.''; PubMed Europe PMC Scholia
39. Schoch S, Gundelfinger ED.; ''Molecular organization of the presynaptic active zone.''; PubMed Europe PMC Scholia
40. de Vrij W, Bulthuis RA, van Iwaarden PR, Konings WN.; ''Mechanism of L-glutamate transport in membrane vesicles from Bacillus stearothermophilus.''; PubMed Europe PMC Scholia
41. Edwards RH.; ''The neurotransmitter cycle and quantal size.''; PubMed Europe PMC Scholia
42. Dulubova I, Khvotchev M, Liu S, Huryeva I, Südhof TC, Rizo J.; ''Munc18-1 binds directly to the neuronal SNARE complex.''; PubMed Europe PMC Scholia
43. Rilstone JJ, Alkhater RA, Minassian BA.; ''Brain dopamine-serotonin vesicular transport disease and its treatment.''; PubMed Europe PMC Scholia
44. Erickson JD, Varoqui H, Schäfer MK, Modi W, Diebler MF, Weihe E, Rand J, Eiden LE, Bonner TI, Usdin TB.; ''Functional identification of a vesicular acetylcholine transporter and its expression from a "cholinergic" gene locus.''; PubMed Europe PMC Scholia
45. Chaudhry FA, Schmitz D, Reimer RJ, Larsson P, Gray AT, Nicoll R, Kavanaugh M, Edwards RH.; ''Glutamine uptake by neurons: interaction of protons with system a transporters.''; PubMed Europe PMC Scholia
46. Takamori S, Rhee JS, Rosenmund C, Jahn R.; ''Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
3-Methoxy-4-hydroxyphenylglycol	Metabolite	CHEBI:16436 (ChEBI)
5HT [clathrin-sculpted monoamine transport vesicle lumen]	Metabolite	CHEBI:28790 (ChEBI)
5HT	Metabolite	CHEBI:28790 (ChEBI)
ADP	Metabolite	CHEBI:16761 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Ac-CoA	Metabolite	CHEBI:15351 (ChEBI)
AcCho	Metabolite	CHEBI:15355 (ChEBI)
Acetylcholine Loaded Synaptic Vesicle	Complex	REACT_17766 (Reactome)
CHAT	Protein	P28329 (Uniprot-TrEMBL)
CPLX1 [cytosol]	Protein	O14810 (Uniprot-TrEMBL)
CPLX1	Protein	O14810 (Uniprot-TrEMBL)
Cho	Metabolite	CHEBI:15354 (ChEBI)
CoA-SH	Metabolite	CHEBI:15346 (ChEBI)
DA [clathrin-sculpted monoamine transport vesicle lumen]	Metabolite	CHEBI:18243 (ChEBI)
DA	Metabolite	CHEBI:18243 (ChEBI)
Docked Glutamate Loaded Synaptic Vesicle	Complex	REACT_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	Complex	REACT_15843 (Reactome)
Docked acetylcholine loaded Synaptic Vesicle	Complex	REACT_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	Complex	REACT_15684 (Reactome)
Docked serotonin loaded synaptic vesicle	Complex	REACT_17565 (Reactome)
Dopamine loaded synaptic vesicle	Complex	REACT_15992 (Reactome)
Empty Acetylcholine Synaptic Vesicle	Complex	REACT_12740 (Reactome)
Empty Glutamate Synaptic Vesicle	Complex	REACT_14482 (Reactome)
FAD [mitochondrial outer membrane]	Metabolite	CHEBI:16238 (ChEBI)
GABA synthesis, release, reuptake and degradation	Pathway	WP2685 (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 dimers		REACT_21656 (Reactome)
Glu [clathrin-sculpted glutamate transport vesicle lumen]	Metabolite	CHEBI:16015 (ChEBI)
Glu	Metabolite	CHEBI:16015 (ChEBI)
Glutamate loaded synaptic vesicle	Complex	REACT_12769 (Reactome)
H+	Metabolite	CHEBI:15378 (ChEBI)
H2O2	Metabolite	CHEBI:16240 (ChEBI)
H2O	Metabolite	CHEBI:15377 (ChEBI)
L-Gln	Metabolite	CHEBI:18050 (ChEBI)
L-Glu	Metabolite	CHEBI:16015 (ChEBI)
MAOA [mitochondrial outer membrane]	Protein	P21397 (Uniprot-TrEMBL)
MAOA-FAD complex	Complex	REACT_5113 (Reactome)
NAd [clathrin-sculpted glutamate transport vesicle lumen]	Metabolite	CHEBI:18357 (ChEBI)
NAd	Metabolite	CHEBI:18357 (ChEBI)
NH3	Metabolite	CHEBI:16134 (ChEBI)
NH4+	Metabolite	CHEBI:28938 (ChEBI)
Na+	Metabolite	CHEBI:29101 (ChEBI)
Neuronal EAATs		REACT_14035 (Reactome)
Noradrenalin loaded synaptic vesicle	Complex	REACT_17964 (Reactome)
O-acetylcholine [clathrin-sculpted acetylcholine transport vesicle lumen]	Metabolite	CHEBI:15355 (ChEBI)
O2	Metabolite	CHEBI:15379 (ChEBI)
OCT2	Protein	REACT_160574 (Reactome)	This 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.
Pi	Metabolite	CHEBI:18367 (ChEBI)
RAB3A [clathrin-sculpted acetylcholine transport vesicle membrane]	Protein	P20336 (Uniprot-TrEMBL)	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.
RAB3A [clathrin-sculpted glutamate transport vesicle membrane]	Protein	P20336 (Uniprot-TrEMBL)	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.
RAB3A [clathrin-sculpted monoamine transport vesicle membrane]	Protein	P20336 (Uniprot-TrEMBL)	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.
RAB3A [plasma membrane]	Protein	P20336 (Uniprot-TrEMBL)	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.
RAB3A	Protein	P20336 (Uniprot-TrEMBL)	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.
RIMS1 [plasma membrane]	Protein	Q86UR5 (Uniprot-TrEMBL)
RIMS1	Protein	Q86UR5 (Uniprot-TrEMBL)
Rab3-RIM complex	Complex	REACT_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.
SLC17A7 [clathrin-sculpted glutamate transport vesicle membrane]	Protein	Q9P2U7 (Uniprot-TrEMBL)
SLC17A7	Protein	Q9P2U7 (Uniprot-TrEMBL)
SLC18A2 [clathrin-sculpted monoamine transport vesicle membrane]	Protein	Q05940 (Uniprot-TrEMBL)
SLC18A2	Protein	Q05940 (Uniprot-TrEMBL)
SLC18A3 [clathrin-sculpted acetylcholine transport vesicle membrane]	Protein	Q16572 (Uniprot-TrEMBL)
SLC18A3	Protein	Q16572 (Uniprot-TrEMBL)
SLC22A2	Protein	O15244 (Uniprot-TrEMBL)
SLC38A2	Protein	Q96QD8 (Uniprot-TrEMBL)
SLC5A7	Protein	Q9GZV3 (Uniprot-TrEMBL)
SNAP25 [plasma membrane]	Protein	P60880 (Uniprot-TrEMBL)
SNAP25	Protein	P60880 (Uniprot-TrEMBL)
SNARE complex	Complex	REACT_12700 (Reactome)
STX1A [plasma membrane]	Protein	Q16623 (Uniprot-TrEMBL)
STX1A	Protein	Q16623 (Uniprot-TrEMBL)
STXBP1-1 [cytosol]	Protein	P61764-1 (Uniprot-TrEMBL)	Munc 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	Protein	P61764-1 (Uniprot-TrEMBL)	Munc 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.
SYT1 [clathrin-sculpted acetylcholine transport vesicle membrane]	Protein	P21579 (Uniprot-TrEMBL)
SYT1 [clathrin-sculpted glutamate transport vesicle membrane]	Protein	P21579 (Uniprot-TrEMBL)
SYT1 [clathrin-sculpted monoamine transport vesicle membrane]	Protein	P21579 (Uniprot-TrEMBL)
SYT1	Protein	P21579 (Uniprot-TrEMBL)
Serotonin loaded synaptic vesicle	Complex	REACT_16110 (Reactome)
Synapsin	Protein	REACT_18217 (Reactome)
UNC13B	Protein	O14795 (Uniprot-TrEMBL)
VAMP2 [clathrin-sculpted glutamate transport vesicle membrane]	Protein	P63027 (Uniprot-TrEMBL)
VAMP2 [clathrin-sculpted monoamine transport vesicle membrane]	Protein	P63027 (Uniprot-TrEMBL)
VAMP2 [plasma membrane]	Protein	P63027 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	3-Methoxy-4-hydroxyphenylglycol	Arrow	REACT_15390 (Reactome)
	5HT	Arrow	REACT_15486 (Reactome)
	5HT	Arrow	REACT_15503 (Reactome)
5HT			REACT_15486 (Reactome)
	ADP	Arrow	REACT_13770 (Reactome)
	ADP	Arrow	REACT_15379 (Reactome)
ATP			REACT_13770 (Reactome)
ATP			REACT_15379 (Reactome)
Ac-CoA			REACT_15484 (Reactome)
	AcCho	Arrow	REACT_15404 (Reactome)
	AcCho	Arrow	REACT_15484 (Reactome)
AcCho			REACT_15317 (Reactome)
	Acetylcholine Loaded Synaptic Vesicle	Arrow	REACT_15317 (Reactome)
Acetylcholine Loaded Synaptic Vesicle			REACT_15483 (Reactome)
Acetylcholine Loaded Synaptic Vesicle		mim-catalysis	REACT_15483 (Reactome)
CHAT		mim-catalysis	REACT_15484 (Reactome)
	CPLX1	Arrow	REACT_12411 (Reactome)
	CPLX1	Arrow	REACT_15404 (Reactome)
	CPLX1	Arrow	REACT_15448 (Reactome)
	CPLX1	Arrow	REACT_15503 (Reactome)
	CPLX1	Arrow	REACT_15533 (Reactome)
CPLX1			REACT_12617 (Reactome)
CPLX1			REACT_15338 (Reactome)
CPLX1			REACT_15411 (Reactome)
CPLX1			REACT_15483 (Reactome)
CPLX1			REACT_15517 (Reactome)
	Cho	Arrow	REACT_15552 (Reactome)
Cho			REACT_15484 (Reactome)
Cho			REACT_15552 (Reactome)
	CoA-SH	Arrow	REACT_15484 (Reactome)
	DA	Arrow	REACT_15524 (Reactome)
	DA	Arrow	REACT_15533 (Reactome)
DA			REACT_15524 (Reactome)
	Docked Glutamate Loaded Synaptic Vesicle	Arrow	REACT_12617 (Reactome)
Docked Glutamate Loaded Synaptic Vesicle			REACT_12411 (Reactome)
Docked Glutamate Loaded Synaptic Vesicle		mim-catalysis	REACT_12411 (Reactome)
	Docked Noradrenalin loaded synaptic vesicle	Arrow	REACT_15411 (Reactome)
Docked Noradrenalin loaded synaptic vesicle			REACT_15448 (Reactome)
Docked Noradrenalin loaded synaptic vesicle		mim-catalysis	REACT_15448 (Reactome)
	Docked acetylcholine loaded Synaptic Vesicle	Arrow	REACT_15483 (Reactome)
Docked acetylcholine loaded Synaptic Vesicle			REACT_15404 (Reactome)
Docked acetylcholine loaded Synaptic Vesicle		mim-catalysis	REACT_15404 (Reactome)
	Docked dopamine loaded synaptic vesicle	Arrow	REACT_15517 (Reactome)
Docked dopamine loaded synaptic vesicle			REACT_15533 (Reactome)
Docked dopamine loaded synaptic vesicle		mim-catalysis	REACT_15533 (Reactome)
	Docked serotonin loaded synaptic vesicle	Arrow	REACT_15338 (Reactome)
Docked serotonin loaded synaptic vesicle			REACT_15503 (Reactome)
Docked serotonin loaded synaptic vesicle		mim-catalysis	REACT_15503 (Reactome)
Dopamine loaded synaptic vesicle			REACT_15517 (Reactome)
Dopamine loaded synaptic vesicle		mim-catalysis	REACT_15517 (Reactome)
Empty Acetylcholine Synaptic Vesicle			REACT_15317 (Reactome)
Empty Glutamate Synaptic Vesicle			REACT_12503 (Reactome)
Empty Glutamate Synaptic Vesicle		mim-catalysis	REACT_12503 (Reactome)
GLS dimers		mim-catalysis	REACT_1700 (Reactome)
	Glu	Arrow	REACT_12411 (Reactome)
	Glu	Arrow	REACT_1700 (Reactome)
Glu			REACT_13574 (Reactome)
Glu			REACT_13790 (Reactome)
	Glutamate loaded synaptic vesicle	Arrow	REACT_12503 (Reactome)
Glutamate loaded synaptic vesicle			REACT_12617 (Reactome)
Glutamate loaded synaptic vesicle		mim-catalysis	REACT_12617 (Reactome)
	H+	Arrow	REACT_13770 (Reactome)
	H+	Arrow	REACT_15317 (Reactome)
	H+	Arrow	REACT_15379 (Reactome)
H+			REACT_13770 (Reactome)
H+			REACT_15317 (Reactome)
H+			REACT_15379 (Reactome)
	H2O2	Arrow	REACT_15390 (Reactome)
H2O			REACT_15390 (Reactome)
H2O			REACT_1700 (Reactome)
	L-Gln	Arrow	REACT_13703 (Reactome)
	L-Gln	Arrow	REACT_13763 (Reactome)
L-Gln			REACT_13703 (Reactome)
L-Gln			REACT_13763 (Reactome)
L-Gln			REACT_1700 (Reactome)
	L-Glu	Arrow	REACT_13574 (Reactome)
	L-Glu	Arrow	REACT_13790 (Reactome)
L-Glu			REACT_12503 (Reactome)
MAOA-FAD complex		mim-catalysis	REACT_15390 (Reactome)
	NAd	Arrow	REACT_15448 (Reactome)
	NAd	Arrow	REACT_15472 (Reactome)
NAd			REACT_15390 (Reactome)
NAd			REACT_15472 (Reactome)
	NH3	Arrow	REACT_15390 (Reactome)
	NH4+	Arrow	REACT_1700 (Reactome)
	Na+	Arrow	REACT_13763 (Reactome)
	Na+	Arrow	REACT_15552 (Reactome)
Na+			REACT_13763 (Reactome)
Na+			REACT_15552 (Reactome)
Neuronal EAATs		mim-catalysis	REACT_13574 (Reactome)
Noradrenalin loaded synaptic vesicle			REACT_15411 (Reactome)
Noradrenalin loaded synaptic vesicle		mim-catalysis	REACT_15411 (Reactome)
O2			REACT_15390 (Reactome)
OCT2		mim-catalysis	REACT_15472 (Reactome)
	Pi	Arrow	REACT_15379 (Reactome)
	RAB3A	Arrow	REACT_15338 (Reactome)
	RAB3A	Arrow	REACT_15503 (Reactome)
	RAB3A	Arrow	REACT_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).
	RIMS1	Arrow	REACT_15503 (Reactome)
	RIMS1	Arrow	REACT_15533 (Reactome)
RIMS1			REACT_12617 (Reactome)
RIMS1			REACT_15411 (Reactome)
RIMS1			REACT_15483 (Reactome)
	Rab3-RIM complex	Arrow	REACT_12411 (Reactome)
	Rab3-RIM complex	Arrow	REACT_15404 (Reactome)
	Rab3-RIM complex	Arrow	REACT_15448 (Reactome)
Rab3-RIM complex			REACT_15338 (Reactome)
Rab3-RIM complex			REACT_15517 (Reactome)
	SLC17A7	Arrow	REACT_12411 (Reactome)
	SLC18A2	Arrow	REACT_15448 (Reactome)
	SLC18A2	Arrow	REACT_15503 (Reactome)
	SLC18A2	Arrow	REACT_15533 (Reactome)
SLC18A2		mim-catalysis	REACT_15486 (Reactome)
SLC18A2		mim-catalysis	REACT_15524 (Reactome)
	SLC18A3	Arrow	REACT_15404 (Reactome)
SLC18A3		mim-catalysis	REACT_15317 (Reactome)
SLC38A2		mim-catalysis	REACT_13763 (Reactome)
SLC5A7		mim-catalysis	REACT_15552 (Reactome)
SNAP25			REACT_12617 (Reactome)
SNAP25			REACT_15338 (Reactome)
SNAP25			REACT_15411 (Reactome)
SNAP25			REACT_15483 (Reactome)
SNAP25			REACT_15517 (Reactome)
	SNARE complex	Arrow	REACT_12411 (Reactome)
	SNARE complex	Arrow	REACT_15404 (Reactome)
	SNARE complex	Arrow	REACT_15448 (Reactome)
	SNARE complex	Arrow	REACT_15503 (Reactome)
	SNARE complex	Arrow	REACT_15533 (Reactome)
STX1A			REACT_12617 (Reactome)
STX1A			REACT_15338 (Reactome)
STX1A			REACT_15411 (Reactome)
STX1A			REACT_15483 (Reactome)
STX1A			REACT_15517 (Reactome)
	STXBP1-1	Arrow	REACT_12411 (Reactome)
	STXBP1-1	Arrow	REACT_15404 (Reactome)
	STXBP1-1	Arrow	REACT_15448 (Reactome)
	STXBP1-1	Arrow	REACT_15503 (Reactome)
	STXBP1-1	Arrow	REACT_15533 (Reactome)
STXBP1-1			REACT_12617 (Reactome)
STXBP1-1			REACT_15338 (Reactome)
STXBP1-1			REACT_15411 (Reactome)
STXBP1-1			REACT_15483 (Reactome)
STXBP1-1			REACT_15517 (Reactome)
	SYT1	Arrow	REACT_12411 (Reactome)
	SYT1	Arrow	REACT_15404 (Reactome)
	SYT1	Arrow	REACT_15448 (Reactome)
	SYT1	Arrow	REACT_15503 (Reactome)
	SYT1	Arrow	REACT_15533 (Reactome)
Serotonin loaded synaptic vesicle			REACT_15338 (Reactome)
Serotonin loaded synaptic vesicle		mim-catalysis	REACT_15338 (Reactome)
	Synapsin	Arrow	REACT_15503 (Reactome)
	Synapsin	Arrow	REACT_15533 (Reactome)
Synapsin			REACT_15338 (Reactome)
Synapsin			REACT_15517 (Reactome)
UNC13B		Arrow	REACT_12617 (Reactome)