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

From WikiPathways

Revision as of 11:46, 1 November 2018 by ReactomeTeam (Talk | contribs)
(diff) ←Older revision | Current revision (diff) | Newer revision→ (diff)
Jump to: navigation, search
2, 69, 151, 8, 131835, 171487, 10, 11, 164mitochondrial matrixcytosolclathrin-sculpted gamma-aminobutyric acid transport vesicle lumenPXLPPXLPligands of SLC6A12(BGT-1)GABA VAMP2 GABA STXBP1-1 RAB3AVAMP2 STX1A RIMS1STXBP1-1SNARE complexGAD1 GAD1 CO2H2OSLC6A12L-GluNAD+GABANADHCl-STX1ABET HSPA8BET b-Ala SNAP25 SLC32A1GAD1 SYT1 SUCCSA4 aminobutyrateaminotransferasehomodimerGAD1 homodimerVAMP2 DNAJC5 ABAT GABADocked GABA loadedsynaptic vesicleGAD1 GAD ComplexesSYT1 GAD2 Na+HSPA8 GABASLC32A1Na+GAD ComplexesCl-SLC32A1 CPLX1SNAP25STX1A GABA Loaded synapticvesicleRIMS1 H+DAB GABA GABA RAB3A HSPA8 SUCCASLC6A GABAtransportersGABAGAD1 GABAb-Ala GAD2 SLC32A1 SLC6A13 SNAP25 RAB3A ALDH5A1L-GluSYT1DNAJC52OGCPLX1 GAD2 SLC6A11 DAB SLC6A1 DNAJC5 GAD2 ligands of SLC6A12(BGT-1)1212


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. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 888590
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Mahajan, SS

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Deken SL, Beckman ML, Boos L, Quick MW.; ''Transport rates of GABA transporters: regulation by the N-terminal domain and syntaxin 1A.''; PubMed Europe PMC
  2. Buddhala C, Hsu CC, Wu JY.; ''A novel mechanism for GABA synthesis and packaging into synaptic vesicles.''; PubMed Europe PMC
  3. Boutin P, Dina C, Vasseur F, Dubois S, Corset L, Séron K, Bekris L, Cabellon J, Neve B, Vasseur-Delannoy V, Chikri M, Charles MA, Clement K, Lernmark A, Froguel P.; ''GAD2 on chromosome 10p12 is a candidate gene for human obesity.''; PubMed Europe PMC
  4. Kim YG, Lee S, Kwon OS, Park SY, Lee SJ, Park BJ, Kim KJ.; ''Redox-switch modulation of human SSADH by dynamic catalytic loop.''; PubMed Europe PMC
  5. Rasola A, Galietta LJ, Barone V, Romeo G, Bagnasco S.; ''Molecular cloning and functional characterization of a GABA/betaine transporter from human kidney.''; PubMed Europe PMC
  6. Bak LK, Schousboe A, Waagepetersen HS.; ''The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer.''; PubMed Europe PMC
  7. Loo DD, Eskandari S, Boorer KJ, Sarkar HK, Wright EM.; ''Role of Cl- in electrogenic Na+-coupled cotransporters GAT1 and SGLT1.''; PubMed Europe PMC
  8. Gasnier B.; ''The SLC32 transporter, a key protein for the synaptic release of inhibitory amino acids.''; PubMed Europe PMC
  9. Straub RE, Lipska BK, Egan MF, Goldberg TE, Callicott JH, Mayhew MB, Vakkalanka RK, Kolachana BS, Kleinman JE, Weinberger DR.; ''Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression.''; PubMed Europe PMC
  10. Nelson H, Mandiyan S, Nelson N.; ''Cloning of the human brain GABA transporter.''; PubMed Europe PMC
  11. Borden LA, Dhar TG, Smith KE, Branchek TA, Gluchowski C, Weinshank RL.; ''Cloning of the human homologue of the GABA transporter GAT-3 and identification of a novel inhibitor with selectivity for this site.''; PubMed Europe PMC
  12. 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
  13. Koch U, Magnusson AK.; ''Unconventional GABA release: mechanisms and function.''; PubMed Europe PMC
  14. De Biase D, Barra D, Simmaco M, John RA, Bossa F.; ''Primary structure and tissue distribution of human 4-aminobutyrate aminotransferase.''; PubMed Europe PMC
  15. Akbarian S, Huang HS.; ''Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders.''; PubMed Europe PMC
  16. Christiansen B, Meinild AK, Jensen AA, Braüner-Osborne H.; ''Cloning and characterization of a functional human gamma-aminobutyric acid (GABA) transporter, human GAT-2.''; PubMed Europe PMC
  17. Matskevitch I, Wagner CA, Stegen C, Bröer S, Noll B, Risler T, Kwon HM, Handler JS, Waldegger S, Busch AE, Lang F.; ''Functional characterization of the Betaine/gamma-aminobutyric acid transporter BGT-1 expressed in Xenopus oocytes.''; PubMed Europe PMC
  18. Quick MW.; ''The role of SNARE proteins in trafficking and function of neurotransmitter transporters.''; PubMed Europe PMC

History

View all...
CompareRevisionActionTimeUserComment
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

View all...
NameTypeDatabase referenceComment
2OGMetaboliteCHEBI:30915 (ChEBI)
4 aminobutyrate

aminotransferase

homodimer
ComplexR-HSA-916847 (Reactome)
ABAT ProteinP80404 (Uniprot-TrEMBL)
ALDH5A1ProteinP51649 (Uniprot-TrEMBL)
BET MetaboliteCHEBI:17750 (ChEBI)
CO2MetaboliteCHEBI:16526 (ChEBI)
CPLX1 ProteinO14810 (Uniprot-TrEMBL)
CPLX1ProteinO14810 (Uniprot-TrEMBL)
Cl-MetaboliteCHEBI:17996 (ChEBI)
DAB MetaboliteCHEBI:48950 (ChEBI)
DNAJC5 ProteinQ9H3Z4 (Uniprot-TrEMBL)
DNAJC5ProteinQ9H3Z4 (Uniprot-TrEMBL)
Docked GABA loaded synaptic vesicleComplexR-HSA-917774 (Reactome)
GABA MetaboliteCHEBI:59888 (ChEBI)
GABA Loaded synaptic vesicleComplexR-HSA-917748 (Reactome)
GABAMetaboliteCHEBI:59888 (ChEBI)
GAD ComplexesComplexR-HSA-888569 (Reactome)
GAD ComplexesComplexR-HSA-947479 (Reactome)
GAD1 ProteinQ99259 (Uniprot-TrEMBL)
GAD1 homodimerComplexR-HSA-888570 (Reactome)
GAD2 ProteinQ05329 (Uniprot-TrEMBL)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HSPA8 ProteinP11142 (Uniprot-TrEMBL)
HSPA8ProteinP11142 (Uniprot-TrEMBL)
L-GluMetaboliteCHEBI:29985 (ChEBI)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
Na+MetaboliteCHEBI:29101 (ChEBI)
PXLPMetaboliteCHEBI:18405 (ChEBI)
RAB3A 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 ProteinQ86UR5 (Uniprot-TrEMBL)
RIMS1ProteinQ86UR5 (Uniprot-TrEMBL)
SLC32A1 ProteinQ9H598 (Uniprot-TrEMBL)
SLC32A1ProteinQ9H598 (Uniprot-TrEMBL)
SLC6A GABA transportersComplexR-HSA-444011 (Reactome)
SLC6A1 ProteinP30531 (Uniprot-TrEMBL)
SLC6A11 ProteinP48066 (Uniprot-TrEMBL)
SLC6A12ProteinP48065 (Uniprot-TrEMBL)
SLC6A13 ProteinQ9NSD5 (Uniprot-TrEMBL)
SNAP25 ProteinP60880 (Uniprot-TrEMBL)
SNAP25ProteinP60880 (Uniprot-TrEMBL)
SNARE complexComplexR-HSA-210441 (Reactome)
STX1A ProteinQ16623 (Uniprot-TrEMBL)
STX1AProteinQ16623 (Uniprot-TrEMBL)
STXBP1-1 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 ProteinP21579 (Uniprot-TrEMBL)
SYT1ProteinP21579 (Uniprot-TrEMBL)
VAMP2 ProteinP63027 (Uniprot-TrEMBL)
b-Ala MetaboliteCHEBI:16958 (ChEBI)
ligands of SLC6A12 (BGT-1)ComplexR-ALL-351982 (Reactome)
ligands of SLC6A12 (BGT-1)ComplexR-ALL-352007 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2OGR-HSA-916855 (Reactome)
4 aminobutyrate

aminotransferase

homodimer
mim-catalysisR-HSA-916855 (Reactome)
ALDH5A1mim-catalysisR-HSA-888548 (Reactome)
CO2ArrowR-HSA-888572 (Reactome)
CO2ArrowR-HSA-888577 (Reactome)
CPLX1ArrowR-HSA-888589 (Reactome)
CPLX1R-HSA-917744 (Reactome)
Cl-ArrowR-HSA-352029 (Reactome)
Cl-ArrowR-HSA-444007 (Reactome)
Cl-R-HSA-352029 (Reactome)
Cl-R-HSA-444007 (Reactome)
DNAJC5ArrowR-HSA-888589 (Reactome)
Docked GABA loaded synaptic vesicleArrowR-HSA-917744 (Reactome)
Docked GABA loaded synaptic vesicleR-HSA-888589 (Reactome)
Docked GABA loaded synaptic vesiclemim-catalysisR-HSA-888589 (Reactome)
GABA Loaded synaptic vesicleR-HSA-917744 (Reactome)
GABA Loaded synaptic vesiclemim-catalysisR-HSA-917744 (Reactome)
GABAArrowR-HSA-444007 (Reactome)
GABAArrowR-HSA-888572 (Reactome)
GABAArrowR-HSA-888577 (Reactome)
GABAArrowR-HSA-888589 (Reactome)
GABAArrowR-HSA-888592 (Reactome)
GABAR-HSA-444007 (Reactome)
GABAR-HSA-888592 (Reactome)
GABAR-HSA-916855 (Reactome)
GAD ComplexesArrowR-HSA-888589 (Reactome)
GAD Complexesmim-catalysisR-HSA-888577 (Reactome)
GAD1 homodimermim-catalysisR-HSA-888572 (Reactome)
H+R-HSA-888572 (Reactome)
H+R-HSA-888577 (Reactome)
H2OR-HSA-888548 (Reactome)
HSPA8ArrowR-HSA-888589 (Reactome)
L-GluArrowR-HSA-916855 (Reactome)
L-GluR-HSA-888572 (Reactome)
L-GluR-HSA-888577 (Reactome)
NAD+R-HSA-888548 (Reactome)
NADHArrowR-HSA-888548 (Reactome)
Na+ArrowR-HSA-352029 (Reactome)
Na+ArrowR-HSA-444007 (Reactome)
Na+R-HSA-352029 (Reactome)
Na+R-HSA-444007 (Reactome)
PXLPArrowR-HSA-888572 (Reactome)
PXLPArrowR-HSA-888577 (Reactome)
PXLPArrowR-HSA-916855 (Reactome)
PXLPR-HSA-888572 (Reactome)
PXLPR-HSA-888577 (Reactome)
PXLPR-HSA-916855 (Reactome)
R-HSA-352029 (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).
R-HSA-444007 (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).
R-HSA-888548 (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.
R-HSA-888572 (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.
R-HSA-888577 (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.
R-HSA-888589 (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.
R-HSA-888592 (Reactome) GABA is loaded into the synaptic vesicle by inihibitory amino acid transport, VIAAT or VGAT.
R-HSA-916855 (Reactome) GABA is converted to succinate semialdehyde by 4-aminobutyrate aminotransferase
R-HSA-917744 (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.
RAB3AArrowR-HSA-888589 (Reactome)
RIMS1ArrowR-HSA-888589 (Reactome)
RIMS1R-HSA-917744 (Reactome)
SLC32A1ArrowR-HSA-888589 (Reactome)
SLC32A1mim-catalysisR-HSA-888592 (Reactome)
SLC6A GABA transportersmim-catalysisR-HSA-444007 (Reactome)
SLC6A12mim-catalysisR-HSA-352029 (Reactome)
SNAP25R-HSA-917744 (Reactome)
SNARE complexArrowR-HSA-888589 (Reactome)
STX1AR-HSA-917744 (Reactome)
STXBP1-1ArrowR-HSA-888589 (Reactome)
STXBP1-1R-HSA-917744 (Reactome)
SUCCAArrowR-HSA-888548 (Reactome)
SUCCSAArrowR-HSA-916855 (Reactome)
SUCCSAR-HSA-888548 (Reactome)
SYT1ArrowR-HSA-888589 (Reactome)
ligands of SLC6A12 (BGT-1)ArrowR-HSA-352029 (Reactome)
ligands of SLC6A12 (BGT-1)R-HSA-352029 (Reactome)
Personal tools