Neurotransmitter clearance (Homo sapiens)

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7, 1381831, 2, 516, 1711, 12, 19141094, 10mitochondrial matrixcytosolSLC6A45HT-N-CH35HIALDALDH2 SLC22A2 H2ODAO2OCT2CDNBNH3Na+5HTNa+Na+SLC22A1 HIALDAdoMetCOMTH2ONH3NH3H2O2NAD+HCYSAcChoCho5HTNADHHIAAacetateMAOA:FADNa+H2O25HT-N-CH3FAD AdoMetH+AdoHcy3MTCl-NAdH2OH2OMAOA ACHE Cl-NAdLRTOMTCholinesteraseDASLC22A2O2SLC6A3BCHE ALDH2 tetramer6, 15


Neurotransmitter released in the synaptic cleft binds to specific receptors on the post-synaptic cell and the excess of the neurotransmitter is cleared to prevent over activation of the post-synaptic cell. The neurotransmitter is cleared by either re-uptake by the pre-synaptic neuron, diffusion in the perisynaptic area, uptake by astrocytes surrounding the synaptic cleft or enzymatic degradation of the neurotransmitter. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 112311
Reactome version: 66
Reactome Author 
Reactome Author: Mahajan, SS

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  1. Kryger G, Harel M, Giles K, Toker L, Velan B, Lazar A, Kronman C, Barak D, Ariel N, Shafferman A, Silman I, Sussman JL.; ''Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II.''; PubMed Europe PMC Scholia
  2. Velan B, Grosfeld H, Kronman C, Leitner M, Gozes Y, Lazar A, Flashner Y, Marcus D, Cohen S, Shafferman A.; ''The effect of elimination of intersubunit disulfide bonds on the activity, assembly, and secretion of recombinant human acetylcholinesterase. Expression of acetylcholinesterase Cys-580----Ala mutant.''; PubMed Europe PMC Scholia
  3. DEEDS F, BOOTH AN, JONES FT.; ''Methylation and dehydroxylation of phenolic compounds by rats and rabbits.''; PubMed Europe PMC Scholia
  4. Weyler W.; ''Monoamine oxidase A from human placenta and monoamine oxidase B from bovine liver both have one FAD per subunit.''; PubMed Europe PMC Scholia
  5. Weinstock M, Groner E.; ''Rational design of a drug for Alzheimer's disease with cholinesterase inhibitory and neuroprotective activity.''; PubMed Europe PMC Scholia
  6. Greenfield NJ, Pietruszko R.; ''Two aldehyde dehydrogenases from human liver. Isolation via affinity chromatography and characterization of the isozymes.''; PubMed Europe PMC Scholia
  7. Fernandez E, Koek W, Ran Q, Gerhardt GA, France CP, Strong R.; ''Monoamine metabolism and behavioral responses to ethanol in mitochondrial aldehyde dehydrogenase knockout mice.''; PubMed Europe PMC Scholia
  8. 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
  9. Vandenbergh DJ, Thompson MD, Cook EH, Bendahhou E, Nguyen T, Krasowski MD, Zarrabian D, Comings D, Sellers EM, Tyndale RF, George SR, O'Dowd BF, Uhl GR.; ''Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations.''; PubMed Europe PMC Scholia
  10. O'Carroll AM, Fowler CJ, Phillips JP, Tobbia I, Tipton KF.; ''The deamination of dopamine by human brain monoamine oxidase. Specificity for the two enzyme forms in seven brain regions.''; PubMed Europe PMC Scholia
  11. Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V, Blakely RD.; ''Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization.''; PubMed Europe PMC Scholia
  12. Brenner B, Harney JT, Ahmed BA, Jeffus BC, Unal R, Mehta JL, Kilic F.; ''Plasma serotonin levels and the platelet serotonin transporter.''; PubMed Europe PMC Scholia
  13. Beck O, Helander A, Carlsson S, Borg S.; ''Changes in serotonin metabolism during treatment with the aldehyde dehydrogenase inhibitors disulfiram and cyanamide.''; PubMed Europe PMC Scholia
  14. Guldberg HC, Sharman DF, Tegerdine PR.; ''Some observations on the estimation of 3-methoxytyramine in brain tissue.''; PubMed Europe PMC Scholia
  15. Hempel J, Kaiser R, Jörnvall H.; ''Mitochondrial aldehyde dehydrogenase from human liver. Primary structure, differences in relation to the cytosolic enzyme, and functional correlations.''; PubMed Europe PMC Scholia
  16. Du X, Schwander M, Moresco EM, Viviani P, Haller C, Hildebrand MS, Pak K, Tarantino L, Roberts A, Richardson H, Koob G, Najmabadi H, Ryan AF, Smith RJ, Müller U, Beutler B.; ''A catechol-O-methyltransferase that is essential for auditory function in mice and humans.''; PubMed Europe PMC Scholia
  17. Ahmed ZM, Masmoudi S, Kalay E, Belyantseva IA, Mosrati MA, Collin RW, Riazuddin S, Hmani-Aifa M, Venselaar H, Kawar MN, Tlili A, van der Zwaag B, Khan SY, Ayadi L, Riazuddin SA, Morell RJ, Griffith AJ, Charfedine I, Caylan R, Oostrik J, Karaguzel A, Ghorbel A, Riazuddin S, Friedman TB, Ayadi H, Kremer H.; ''Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans.''; PubMed Europe PMC Scholia
  18. Sotnikova TD, Beaulieu JM, Espinoza S, Masri B, Zhang X, Salahpour A, Barak LS, Caron MG, Gainetdinov RR.; ''The dopamine metabolite 3-methoxytyramine is a neuromodulator.''; PubMed Europe PMC Scholia
  19. Canli T, Lesch KP.; ''Long story short: the serotonin transporter in emotion regulation and social cognition.''; PubMed Europe PMC Scholia


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101216view11:11, 1 November 2018ReactomeTeamreactome version 66
100754view20:36, 31 October 2018ReactomeTeamreactome version 65
100298view19:13, 31 October 2018ReactomeTeamreactome version 64
99844view15:57, 31 October 2018ReactomeTeamreactome version 63
99401view14:34, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99092view12:39, 31 October 2018ReactomeTeamreactome version 62
94498view09:04, 14 September 2017Mkutmonreactome version 61
87768view10:01, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
87767view10:00, 25 July 2016RyanmillerOntology Term : 'signaling pathway pertinent to the brain and nervous system' added !
86397view09:17, 11 July 2016ReactomeTeamreactome version 56
83079view09:53, 18 November 2015ReactomeTeamVersion54
81400view12:55, 21 August 2015ReactomeTeamVersion53
76869view08:14, 17 July 2014ReactomeTeamFixed remaining interactions
76574view11:55, 16 July 2014ReactomeTeamFixed remaining interactions
75907view09:56, 11 June 2014ReactomeTeamRe-fixing comment source
75607view10:46, 10 June 2014ReactomeTeamReactome 48 Update
74962view13:48, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74606view08:39, 30 April 2014ReactomeTeamReactome46
58006view22:02, 5 February 2013AriuttaPeriodical save, work in progress
42088view21:56, 4 March 2011MaintBotAutomatic update
39896view05:55, 21 January 2011MaintBotNew pathway

External references


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NameTypeDatabase referenceComment
3MTMetaboliteCHEBI:1582 (ChEBI)
5HIALDMetaboliteCHEBI:50157 (ChEBI)
5HT-N-CH3MetaboliteCHEBI:3210 (ChEBI)
5HTMetaboliteCHEBI:28790 (ChEBI)
ACHE ProteinP22303 (Uniprot-TrEMBL)
ALDH2 ProteinP05091 (Uniprot-TrEMBL)
ALDH2 tetramerComplexR-HSA-71721 (Reactome)
AcChoMetaboliteCHEBI:15355 (ChEBI)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
BCHE ProteinP06276 (Uniprot-TrEMBL)
CDNBMetaboliteCHEBI:34718 (ChEBI)
COMTProteinP21964 (Uniprot-TrEMBL)
ChoMetaboliteCHEBI:15354 (ChEBI)
CholinesteraseComplexR-HSA-3640837 (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.
Cl-MetaboliteCHEBI:17996 (ChEBI)
DAMetaboliteCHEBI:18243 (ChEBI)
FAD MetaboliteCHEBI:16238 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HCYSMetaboliteCHEBI:17230 (ChEBI)
HIAAMetaboliteCHEBI:27823 (ChEBI)
HIALDMetaboliteCHEBI:50157 (ChEBI)
LRTOMTProteinQ8WZ04 (Uniprot-TrEMBL)
MAOA ProteinP21397 (Uniprot-TrEMBL)
MAOA:FADComplexR-HSA-141332 (Reactome)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
NAdMetaboliteCHEBI:18357 (ChEBI)
NH3MetaboliteCHEBI:16134 (ChEBI)
Na+MetaboliteCHEBI:29101 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
OCT2ComplexR-HSA-2901780 (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.
SLC22A1 ProteinO15245 (Uniprot-TrEMBL)
SLC22A2 ProteinO15244 (Uniprot-TrEMBL)
SLC22A2ProteinO15244 (Uniprot-TrEMBL)
SLC6A3ProteinQ01959 (Uniprot-TrEMBL)
SLC6A4ProteinP31645 (Uniprot-TrEMBL)
acetateMetaboliteCHEBI:30089 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
3MTArrowR-HSA-379387 (Reactome)
3MTArrowR-HSA-8955010 (Reactome)
5HIALDArrowR-HSA-141186 (Reactome)
5HT-N-CH3ArrowR-HSA-379382 (Reactome)
5HT-N-CH3ArrowR-HSA-379395 (Reactome)
5HT-N-CH3ArrowR-HSA-379464 (Reactome)
5HT-N-CH3R-HSA-379464 (Reactome)
5HTArrowR-HSA-444008 (Reactome)
5HTR-HSA-141186 (Reactome)
5HTR-HSA-444008 (Reactome)
ALDH2 tetramermim-catalysisR-HSA-380608 (Reactome)
AcChoR-HSA-372519 (Reactome)
AdoHcyArrowR-HSA-379387 (Reactome)
AdoHcyArrowR-HSA-8955010 (Reactome)
AdoMetR-HSA-379387 (Reactome)
AdoMetR-HSA-379464 (Reactome)
AdoMetR-HSA-8955010 (Reactome)
CDNBArrowR-HSA-379395 (Reactome)
CDNBR-HSA-379395 (Reactome)
COMTmim-catalysisR-HSA-379387 (Reactome)
COMTmim-catalysisR-HSA-379464 (Reactome)
ChoArrowR-HSA-372519 (Reactome)
Cholinesterasemim-catalysisR-HSA-372519 (Reactome)
Cl-ArrowR-HSA-444008 (Reactome)
Cl-R-HSA-444008 (Reactome)
DAArrowR-HSA-379393 (Reactome)
DAR-HSA-379382 (Reactome)
DAR-HSA-379387 (Reactome)
DAR-HSA-379393 (Reactome)
DAR-HSA-8955010 (Reactome)
H+ArrowR-HSA-380608 (Reactome)
H2O2ArrowR-HSA-141186 (Reactome)
H2O2ArrowR-HSA-379395 (Reactome)
H2OR-HSA-141186 (Reactome)
H2OR-HSA-372519 (Reactome)
H2OR-HSA-379382 (Reactome)
H2OR-HSA-379395 (Reactome)
HCYSArrowR-HSA-379464 (Reactome)
HIAAArrowR-HSA-380608 (Reactome)
HIALDR-HSA-380608 (Reactome)
LRTOMTmim-catalysisR-HSA-8955010 (Reactome)
MAOA:FADmim-catalysisR-HSA-141186 (Reactome)
MAOA:FADmim-catalysisR-HSA-379382 (Reactome)
MAOA:FADmim-catalysisR-HSA-379395 (Reactome)
NAD+R-HSA-380608 (Reactome)
NADHArrowR-HSA-380608 (Reactome)
NAdArrowR-HSA-374919 (Reactome)
NAdR-HSA-374919 (Reactome)
NH3ArrowR-HSA-141186 (Reactome)
NH3ArrowR-HSA-379382 (Reactome)
NH3ArrowR-HSA-379395 (Reactome)
Na+ArrowR-HSA-379393 (Reactome)
Na+ArrowR-HSA-444008 (Reactome)
Na+R-HSA-379393 (Reactome)
Na+R-HSA-444008 (Reactome)
O2R-HSA-141186 (Reactome)
O2R-HSA-379382 (Reactome)
O2R-HSA-379395 (Reactome)
OCT2mim-catalysisR-HSA-374919 (Reactome)
R-HSA-141186 (Reactome) Amine oxidase (flavin-containing) A (MAOA) catalyses the oxidative deamination of biogenic and dietary amines, the regulation of which is critical for mental state homeostasis. MAOA, located on the mitochondrial outer membrane and requiring FAD as cofactor (Weyler 1989), preferentially oxidises biogenic amines such as 5-hydroxytryptamine (5HT), dopamine, noradrenaline and adrenaline (latter three not shown here). 5HT is deaminated to 5-hydroxyindolacetaldehyde (5HIALD).
R-HSA-372519 (Reactome) Acetylcholinesterase (ACHE) oligomers (comprising monomers, dimers and tetramers), anchored to the extracellular side of the plasma membrane, hydrolyze acetylcholine (AcCho) to form choline (Cho) and acetate (Weinstock & Groner 2008, Velan et al. 1991, Kryger et al. 2000).

Acetylcholine from the synaptic cleft is degraded into inactive molecules, Cho and acetate by ACHE, which is located in the synaptic cleft (Weinstock & Groner 2008).
R-HSA-374919 (Reactome) Noradrenaline is cleared from the synaptic cleft by Noaradrenaline uptake transporter. This reaction is carried out by neurons as well as astrocytes.
R-HSA-379382 (Reactome) Dopamine is oxidized to 3,4-dihydroxyphenylacetic acid by monoamine oxidase (O'Caroll et al.1983).
R-HSA-379387 (Reactome) Dopamine (DA) in the cytosol is metabolized to 3-methoxytyramine (3MT) by catecholamine o-methyltransferase (COMT), which uses s-adenosylmethionine as a methyl group donor (Männistö and Kaakkola 1991, Westerink and Spaan 1989).
R-HSA-379393 (Reactome) The human gene SLC6A3 encodes the sodium-dependent dopamine transporter, DAT which mediates the re-uptake of dopamine from the synaptic cleft (Vandenbergh DJ et al, 2000). Dopamine can then be degraded by either COMT or monoamine oxidase.
R-HSA-379395 (Reactome) 3-methoxytyramine generated by COMT after methylation of dopamine is oxidized into homovanillic acid by monoamine oxidase A (Guldberg et al. 1997).
R-HSA-379464 (Reactome) 3,4-dihydroxyphenylacetic acid, generated after oxidation of dopamine by monoamineoxidase, is methylated by catecholamine o-methyltransferase to homovanillic acid (Deeds et al.1957).
R-HSA-380608 (Reactome) 5-hydroxyindole acetaldehyde is then catalyzed by aldehyde dehydrogenase to form 5-hydroxyindole acetic acid
R-HSA-444008 (Reactome) Serotonin (5HT) is a monoamine neurotransmitter. It's clearance (and therefore termination) from the synaptic cleft is mediated by the sodium- and chloride-dependent serotonin transporter SERT (SLC6A4, aka 5HTT). SERT is encoded by the human gene SLC6A4 and is expressed in the CNS, PNS and platelets (Ramamoorthy et al. 1993, Brenner et al. 2007, Canli & Lesch 2007).
R-HSA-8955010 (Reactome) Transmembrane O-methyltransferase (LRTOMT aka COMT2) catalyses the O-methylation of catecholamine neurotransmitters, thereby inactivating them (Du et al. 2008). LRTOMT is highly expressed in sensory hair cells of the inner ear. Defects in LRTOMT can cause autosomal recessive deafness 63 (DFNB63), a form of non-syndromic sensorineural hearing loss (Ahmed et al. 2008, Du et al. 2008). In this example, dopamine (DA) is O-methylated using S-adenosyl-L-methionine (AdoMet) as the methyl donor to form 3-methyltyramine (3MT) and S-adenosyl-L-homocysteine (AdoHcy).
SLC6A3mim-catalysisR-HSA-379393 (Reactome)
SLC6A4mim-catalysisR-HSA-444008 (Reactome)
acetateArrowR-HSA-372519 (Reactome)
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