GABA synthesis, release, reuptake and degradation (Homo sapiens)

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13, 142, 5, 73, 10, 17, 189, 114712, 15816GAD2 ActivityComplex[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]GAD2 ActivityComplex[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]Heterodimer of GAD1and GAD2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]Docked GABA loadedsynaptic veiscle[plasma membrane,clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]SNARE complex[plasma membrane]Homodimer of GAD2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]Homodimer of 4aminobutyrateaminotransferase[mitochondrialmatrix]GABA Loaded synapticvesicle[clathrin-sculptedgamma-aminobutyricacid transportvesicle, cytosol]GABA Loaded synapticvesicle[clathrin-sculptedgamma-aminobutyricacid transportvesicle, cytosol]Heterodimer of GAD1and GAD2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]Homodimer of GAD2[plasma membrane]Homodimer of GAD2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]GAD2 ActivityComplex[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]cytosolGAD2 ActivityComplex [plasmamembrane]Homodimer of GAD1[cytosol]GAD2 ActivityComplex[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]mitochondrial matrixEmpty GABA synapticvesicle[clathrin-sculptedgamma-aminobutyricacid transportvesicle, cytosol]Heterodimer of GAD1and GAD2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]Heterodimer of GAD1and GAD2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]clathrin-sculpted gamma-aminobutyric acid transport vesicle lumenHeterodimer of GAD1and GAD2 [plasmamembrane]GAD1 activity[cytosol]Homodimer of GAD2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]Homodimer of GAD2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]SLC32A1Na+ALDH5A1GABA[clathrin-sculptedgamma-aminobutyricacid transportvesicle lumen]GABA[clathrin-sculptedgamma-aminobutyricacid transportvesicle lumen]GAD1 [plasmamembrane]SYT1HSPA8[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]CPLX1 [cytosol]DNAJC5GABA2OGDNAJC5[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]Na+RAB3A[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]VAMP2 [plasmamembrane]VAMP2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]RAB3A[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]RIMS1 [plasmamembrane]H2OSUCCSAGABAGAD2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]ABAT [mitochondrialmatrix]HSPA8[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]GABACl-GAD2 ActivityComplexCPLX1GAD2 ActivityComplexSTXBP1-1SLC32A1[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]GAD1[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]SLC6A12GAD2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]DNAJC5[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]VAMP2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]SNAP25 [plasmamembrane]HSPA8[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]H+RAB3A[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]SNAP25 [plasmamembrane]NADHSYT1[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]RIMS1L-GluNAD+GAD1[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]GAD1 activityGAD2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]SUCCAHomodimer of 4aminobutyrateaminotransferaseSLC32A1SLC6A GABAtransportersGAD2 [plasmamembrane]STX1A [plasmamembrane]GABASNARE complexSLC32A1[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]VAMP2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]GAD1[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]Cl-ligands of SLC6A12(BGT-1)SLC32A1[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]SNAP25Empty GABA synapticvesicleHSPA8ligands of SLC6A12(BGT-1)GAD1[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]SYT1[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]STXBP1-1 [cytosol]GAD2[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]STX1A [plasmamembrane]DNAJC5[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]Docked GABA loadedsynaptic veiscleGABAGAD1[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]RAB3ACO2GABA Loaded synapticvesicleGluSYT1[clathrin-sculptedgamma-aminobutyricacid transportvesicle membrane]PXLPPXLP1616


Description

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.Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=888590

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Bibliography

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History

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CompareRevisionActionTimeUserComment
115038view16:57, 25 January 2021ReactomeTeamReactome version 75
113482view11:55, 2 November 2020ReactomeTeamReactome version 74
112681view16:07, 9 October 2020ReactomeTeamReactome version 73
101598view11:46, 1 November 2018ReactomeTeamreactome version 66
101134view21:31, 31 October 2018ReactomeTeamreactome version 65
100662view20:05, 31 October 2018ReactomeTeamreactome version 64
100212view16:50, 31 October 2018ReactomeTeamreactome version 63
99763view15:16, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99322view12:47, 31 October 2018ReactomeTeamreactome version 62
93751view13:33, 16 August 2017ReactomeTeamreactome version 61
93271view11:18, 9 August 2017ReactomeTeamreactome version 61
87450view13:57, 22 July 2016MkutmonOntology Term : 'gamma-aminobutyric acid metabolic pathway' added !
86348view09:15, 11 July 2016ReactomeTeamreactome version 56
83090view09:57, 18 November 2015ReactomeTeamVersion54
81414view12:56, 21 August 2015ReactomeTeamVersion53
76885view08:15, 17 July 2014ReactomeTeamFixed remaining interactions
76590view11:57, 16 July 2014ReactomeTeamFixed remaining interactions
75921view09:57, 11 June 2014ReactomeTeamRe-fixing comment source
75622view10:49, 10 June 2014ReactomeTeamReactome 48 Update
74977view13:49, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74621view08:40, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2OGMetaboliteCHEBI:30915 (ChEBI)
ABAT [mitochondrial matrix]ProteinP80404 (Uniprot-TrEMBL)
ALDH5A1ProteinP51649 (Uniprot-TrEMBL)
CO2MetaboliteCHEBI:16526 (ChEBI)
CPLX1 [cytosol]ProteinO14810 (Uniprot-TrEMBL)
CPLX1ProteinO14810 (Uniprot-TrEMBL)
Cl-MetaboliteCHEBI:17996 (ChEBI)
DNAJC5

[clathrin-sculpted gamma-aminobutyric acid transport

vesicle membrane]		ProteinQ9H3Z4 (Uniprot-TrEMBL)
DNAJC5ProteinQ9H3Z4 (Uniprot-TrEMBL)
Docked GABA loaded synaptic veiscleComplexREACT_24328 (Reactome)
Empty GABA synaptic vesicleComplexREACT_24125 (Reactome)
GABA

[clathrin-sculpted gamma-aminobutyric acid transport

vesicle lumen]		MetaboliteCHEBI:16865 (ChEBI)
GABA Loaded synaptic vesicleComplexREACT_24412 (Reactome)
GABAMetaboliteCHEBI:16865 (ChEBI)
GAD1

[clathrin-sculpted gamma-aminobutyric acid transport

vesicle membrane]		ProteinQ99259 (Uniprot-TrEMBL)
GAD1 [plasma membrane]ProteinQ99259 (Uniprot-TrEMBL)
GAD1 activityComplexREACT_24495 (Reactome)
GAD2

[clathrin-sculpted gamma-aminobutyric acid transport

vesicle membrane]		ProteinQ05329 (Uniprot-TrEMBL) GAD65 or GAD2 is concentrated in the nerve terminal region in the neurons and is involved in the synthesis of GABA which is used as a neurotransmitter.
GAD2 Activity ComplexComplexREACT_24233 (Reactome)
GAD2 Activity ComplexComplexREACT_24821 (Reactome)
GAD2 [plasma membrane]ProteinQ05329 (Uniprot-TrEMBL)
GluMetaboliteCHEBI:16015 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HSPA8

[clathrin-sculpted gamma-aminobutyric acid transport

vesicle membrane]		ProteinP11142 (Uniprot-TrEMBL)
HSPA8ProteinP11142 (Uniprot-TrEMBL)
Homodimer of 4

aminobutyrate

aminotransferase		ComplexREACT_24451 (Reactome)
L-GluMetaboliteCHEBI:16015 (ChEBI)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
Na+MetaboliteCHEBI:29101 (ChEBI)
PXLPMetaboliteCHEBI:18405 (ChEBI)
RAB3A

[clathrin-sculpted gamma-aminobutyric acid transport

vesicle membrane]		ProteinP20336 (Uniprot-TrEMBL)
RAB3AProteinP20336 (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]ProteinQ86UR5 (Uniprot-TrEMBL)
RIMS1ProteinQ86UR5 (Uniprot-TrEMBL)
SLC32A1

[clathrin-sculpted gamma-aminobutyric acid transport

vesicle membrane]		ProteinQ9H598 (Uniprot-TrEMBL)
SLC32A1ProteinQ9H598 (Uniprot-TrEMBL)
SLC6A GABA transportersProteinREACT_20690 (Reactome)
SLC6A12ProteinP48065 (Uniprot-TrEMBL)
SNAP25 [plasma membrane]ProteinP60880 (Uniprot-TrEMBL)
SNAP25ProteinP60880 (Uniprot-TrEMBL)
SNARE complexComplexREACT_12700 (Reactome)
STX1A [plasma membrane]ProteinQ16623 (Uniprot-TrEMBL)
STXBP1-1 [cytosol]ProteinP61764-1 (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.
STXBP1-1ProteinP61764-1 (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.
SUCCAMetaboliteCHEBI:15741 (ChEBI)
SUCCSAMetaboliteCHEBI:16265 (ChEBI)
SYT1

[clathrin-sculpted gamma-aminobutyric acid transport

vesicle membrane]		ProteinP21579 (Uniprot-TrEMBL)
SYT1ProteinP21579 (Uniprot-TrEMBL)
VAMP2

[clathrin-sculpted gamma-aminobutyric acid transport

vesicle membrane]		ProteinP63027 (Uniprot-TrEMBL)
VAMP2 [plasma membrane]ProteinP63027 (Uniprot-TrEMBL)
ligands of SLC6A12 (BGT-1)REACT_14225 (Reactome)
ligands of SLC6A12 (BGT-1)REACT_14644 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2OGREACT_23980 (Reactome)
ALDH5A1mim-catalysisREACT_24017 (Reactome)
CO2ArrowREACT_23866 (Reactome)
CO2ArrowREACT_23937 (Reactome)
CPLX1ArrowREACT_23813 (Reactome)
CPLX1REACT_23973 (Reactome)
Cl-ArrowREACT_13561 (Reactome)
Cl-ArrowREACT_20659 (Reactome)
Cl-REACT_13561 (Reactome)
Cl-REACT_20659 (Reactome)
DNAJC5ArrowREACT_23813 (Reactome)
Docked GABA loaded synaptic veiscleArrowREACT_23973 (Reactome)
Docked GABA loaded synaptic veiscleREACT_23813 (Reactome)
Docked GABA loaded synaptic veisclemim-catalysisREACT_23813 (Reactome)
Empty GABA synaptic vesicleREACT_23968 (Reactome)
GABA Loaded synaptic vesicleArrowREACT_23968 (Reactome)
GABA Loaded synaptic vesicleREACT_23973 (Reactome)
GABA Loaded synaptic vesiclemim-catalysisREACT_23973 (Reactome)
GABAArrowREACT_20659 (Reactome)
GABAArrowREACT_23813 (Reactome)
GABAArrowREACT_23866 (Reactome)
GABAArrowREACT_23937 (Reactome)
GABAArrowREACT_23968 (Reactome)
GABAREACT_20659 (Reactome)
GABAREACT_23968 (Reactome)
GABAREACT_23980 (Reactome)
GAD1 activitymim-catalysisREACT_23937 (Reactome)
GAD2 Activity ComplexArrowREACT_23813 (Reactome)
GAD2 Activity Complexmim-catalysisREACT_23866 (Reactome)
GluArrowREACT_23980 (Reactome)
H+REACT_23866 (Reactome)
H+REACT_23937 (Reactome)
H2OREACT_24017 (Reactome)
HSPA8ArrowREACT_23813 (Reactome)
Homodimer of 4

aminobutyrate

aminotransferase		mim-catalysisREACT_23980 (Reactome)
L-GluREACT_23866 (Reactome)
L-GluREACT_23937 (Reactome)
NAD+REACT_24017 (Reactome)
NADHArrowREACT_24017 (Reactome)
Na+ArrowREACT_13561 (Reactome)
Na+ArrowREACT_20659 (Reactome)
Na+REACT_13561 (Reactome)
Na+REACT_20659 (Reactome)
PXLPArrowREACT_23866 (Reactome)
PXLPArrowREACT_23937 (Reactome)
PXLPArrowREACT_23980 (Reactome)
PXLPREACT_23866 (Reactome)
PXLPREACT_23937 (Reactome)
PXLPREACT_23980 (Reactome)
RAB3AArrowREACT_23813 (Reactome)
REACT_13561 (Reactome) The plasma membrane transport protein SLC6A12 (BGT-1) mediates the uptake of GABA (gamma-aminobutyrate) and betaine and, less efficiently, of diminobutyrate (DABA) and beta-alanine. Together with each amino acid molecule, 3 sodium ions and 2 chloride ions are taken up. In the body, SLC6A12 is expressed in the proximal tubules of the kidney and cells of the central nervous system (Rasola et al. 1995; Matskevitch et al. 1999).
REACT_20659 (Reactome) Four transporters mediate GABA uptake in the brain, GAT1-3 and BGT1. They terminates the action of GABA by high affinity sodium-dependent reuptake into presynaptic terminals. Transport of GABA by GAT1-3 is proposed to be accompanied by 2Na+ ions and 1 Cl- ion (Loo DD et al, 2000).

SLC6A1 encodes a sodium- and chloride-dependent GABA transporter 1, GAT1, which is the predominant GABA transporter in brain. It is widely distributed in the brain and co-localized to GABAergic neurons (Nelson H et al, 1990). SLC6A13 encodes a sodium- and chloride-dependent GABA transporter 2, GAT2, which is localized to GABAergic neurons in the brain. It is also found in retina, liver and kidney (Christiansen B et al, 2007). SLC6A11 encodes a sodium- and chloride-dependent GABA transporter 3, GAT3. It is expressed in the brain and localizes to GABAergic neurons (Borden LA et al, 1994).
REACT_23813 (Reactome) GABA synaptic vesicles are fused to the presynaptic terminal membrane with the help of SNARE complex proteins, synaptobrevin located in the synaptic vesicle, SNAP 25 and syntaxin located in the plasma membrane. Complexin optimizes partially assembled SNARES for Ca2+ dependent exocytosis. Fusion of the synaptic vesicle is triggered by the influx of Ca2+ through N, P/Q Ca2+ channels, which binds to synaptobrevin on the synaptic vesicles triggering a series of steps leading to fusion of the synaptic vesicle to the presynatic terminal membrane and release of GABA.
REACT_23866 (Reactome) GAD65 or GAD2 is concentrated in the nerve terminal region in the neurons and is involved in the synthesis of GABA which is used as a neurotransmitter.
REACT_23937 (Reactome) GAD1 or GAD67 is evenly spread throghout the neuronal cytoplasm and is invoved in GABA synthesis that is used for synaptogenesis, in protection against neural injury and as energy source through GABA shunt.
REACT_23968 (Reactome) GABA is loaded into the synaptic vesicle by inihibitory amino acid transport, VIAAT or VGAT.
REACT_23973 (Reactome) GABA loaded synaptic vesicles are docked at the presynaptic terminal membrane by a number of proteins including Rab3a, RIM (Rab3a interaction protein) and Munc 13. The docked GABA vesicles are primed by the SNARE complex that includes synaptobrevin, SNAP 25 and syntaxin1.
REACT_23980 (Reactome) GABA is converted to succinate semialdehyde by 4-aminobutyrate aminotransferase
REACT_24017 (Reactome) Succinate semialdehyde dehydrogenase (SSADH) converts succinate semialdehyde, in a final step of GABA degradation, into succinate. SSADH uses one water molecule and one molecule of NAD+ per molecule of succinyate semialdehyde.
RIMS1ArrowREACT_23813 (Reactome)
RIMS1REACT_23973 (Reactome)
SLC32A1ArrowREACT_23813 (Reactome)
SLC32A1mim-catalysisREACT_23968 (Reactome)
SLC6A GABA transportersmim-catalysisREACT_20659 (Reactome)
SLC6A12mim-catalysisREACT_13561 (Reactome)
SNAP25REACT_23973 (Reactome)
SNARE complexArrowREACT_23813 (Reactome)
STXBP1-1ArrowREACT_23813 (Reactome)
STXBP1-1REACT_23973 (Reactome)
SUCCAArrowREACT_24017 (Reactome)
SUCCSAArrowREACT_23980 (Reactome)
SUCCSAREACT_24017 (Reactome)
SYT1ArrowREACT_23813 (Reactome)
ligands of SLC6A12 (BGT-1)ArrowREACT_13561 (Reactome)
ligands of SLC6A12 (BGT-1)REACT_13561 (Reactome)
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