Neurotransmitter clearance (Homo sapiens)

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121, 5, 927, 836, 10mitochondrial matrixcytosolAcChoO2BCHE COMTH2ONH3ACHE SLC6A3HCYS5HT-N-CH3SLC22A2 FAD ChoMAOA:FADALDH2 HIAAH2ONAdMAOA H2OSodium dependentSerotonintransporterAdoHcy5HTO2H2O2DASLC22A1 AdoMetNAD+Na+5HTHIALDNADHALDH2 tetramerCDNBNAd5HIALDNa+Na+OCT2H2OCholinesteraseH+AdoMet5HT-N-CH3acetateSLC22A2Na+NH3H2O2NH3DA4, 11


Description

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.
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Bibliography

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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
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  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
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  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
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  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
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  14. Guldberg HC, Sharman DF, Tegerdine PR.; ''Some observations on the estimation of 3-methoxytyramine in brain tissue.''; PubMed Europe PMC Scholia
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History

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CompareRevisionActionTimeUserComment
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

DataNodes

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NameTypeDatabase referenceComment
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.
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)
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)
Sodium dependent

Serotonin

transporter
R-HSA-380618 (Reactome)
acetateMetaboliteCHEBI:30089 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
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-380620 (Reactome)
5HTR-HSA-141186 (Reactome)
5HTR-HSA-380620 (Reactome)
ALDH2 tetramermim-catalysisR-HSA-380608 (Reactome)
AcChoR-HSA-372519 (Reactome)
AdoHcyArrowR-HSA-379387 (Reactome)
AdoMetR-HSA-379387 (Reactome)
AdoMetR-HSA-379464 (Reactome)
CDNBArrowR-HSA-379387 (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)
DAArrowR-HSA-379393 (Reactome)
DAR-HSA-379382 (Reactome)
DAR-HSA-379387 (Reactome)
DAR-HSA-379393 (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)
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-380620 (Reactome)
Na+R-HSA-379393 (Reactome)
Na+R-HSA-380620 (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.
R-HSA-379387 (Reactome) Dopamine in the cytosol is metabolized to 3-methoxytyramine by catecholamine o-methyltransferase (COMT), which uses s-adenosylmethionine as a methyl group donor.
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
R-HSA-379464 (Reactome) 3,4-dihydroxyphenylacetic acid, generated after oxidation of dopamine by monoamineoxidase, is methylated by catecholamine o-methyltransferase to homovanillic acid.
R-HSA-380608 (Reactome) 5-hydroxyindole acetaldehyde is then catalyzed by aldehyde dehydrogenase to form 5-hydroxyindole acetic acid
R-HSA-380620 (Reactome) The human gene SLC6A4 encodes the sodium-dependent serotonin transporter 5HTT which mediates the re-uptake of serotonin from the synaptic cleft thus terminating the action of serotonin (Canli T and Lesch KP, 2007). The serotonin taken up in the cytosol from the synaptic cleft may be recycled into synaptic vesicles or metabolized.
SLC6A3mim-catalysisR-HSA-379393 (Reactome)
Sodium dependent

Serotonin

transporter
mim-catalysisR-HSA-380620 (Reactome)
acetateArrowR-HSA-372519 (Reactome)
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