Neurotransmitter uptake and metabolism In glial cells (Homo sapiens)

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42, 31cytosolGLUL Astrocytic EAATsL-GlnSLC1A3 PiL-GluSLC38A1ADPL-GluL-GlnNH4+SLC1A2 GLUL decamerATP3


Neuotransmitter uptake by astrocytes is mediated by a specific transporter located on the astrocytic membrane. The imported neurotransmitter is metabolized and transported back to the neuron. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 112313
Reactome version: 66
Reactome Author 
Reactome Author: Mahajan, SS

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Ontology Terms



  1. Gegelashvili M, Rodriguez-Kern A, Pirozhkova I, Zhang J, Sung L, Gegelashvili G.; ''High-affinity glutamate transporter GLAST/EAAT1 regulates cell surface expression of glutamine/neutral amino acid transporter ASCT2 in human fetal astrocytes.''; PubMed Europe PMC
  2. Häberle J, Görg B, Rutsch F, Schmidt E, Toutain A, Benoist JF, Gelot A, Suc AL, Höhne W, Schliess F, Häussinger D, Koch HG.; ''Congenital glutamine deficiency with glutamine synthetase mutations.''; PubMed Europe PMC
  3. Krajewski WW, Collins R, Holmberg-Schiavone L, Jones TA, Karlberg T, Mowbray SL.; ''Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design.''; PubMed Europe PMC
  4. Maragakis NJ, Dietrich J, Wong V, Xue H, Mayer-Proschel M, Rao MS, Rothstein JD.; ''Glutamate transporter expression and function in human glial progenitors.''; PubMed Europe PMC


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101215view11:11, 1 November 2018ReactomeTeamreactome version 66
100753view20:36, 31 October 2018ReactomeTeamreactome version 65
100297view19:13, 31 October 2018ReactomeTeamreactome version 64
99843view15:57, 31 October 2018ReactomeTeamreactome version 63
99400view14:34, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94501view09:16, 14 September 2017Mkutmonreactome version 61
88046view13:40, 25 July 2016RyanmillerOntology Term : 'transport pathway' added !
88045view13:39, 25 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86681view09:24, 11 July 2016ReactomeTeamreactome version 56
83328view10:47, 18 November 2015ReactomeTeamVersion54
81479view13:01, 21 August 2015ReactomeTeamVersion53
76956view08:23, 17 July 2014ReactomeTeamFixed remaining interactions
76661view12:03, 16 July 2014ReactomeTeamFixed remaining interactions
75990view10:04, 11 June 2014ReactomeTeamRe-fixing comment source
75693view11:02, 10 June 2014ReactomeTeamReactome 48 Update
75049view13:56, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74693view08:45, 30 April 2014ReactomeTeamReactome46
72002view11:53, 24 October 2013EgonwSome layout work.
72000view11:50, 24 October 2013EgonwFixed the Uniprot-TrEMBL data source.
69044view17:53, 8 July 2013MaintBotUpdated to 2013 gpml schema
42090view21:56, 4 March 2011MaintBotAutomatic update
39898view05:55, 21 January 2011MaintBotNew pathway

External references


View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Astrocytic EAATsComplexR-HSA-210416 (Reactome)
GLUL ProteinP15104 (Uniprot-TrEMBL)
GLUL decamerComplexR-HSA-70604 (Reactome)
L-GlnMetaboliteCHEBI:58359 (ChEBI)
L-GluMetaboliteCHEBI:29985 (ChEBI)
NH4+MetaboliteCHEBI:28938 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
SLC1A2 ProteinP43004 (Uniprot-TrEMBL)
SLC1A3 ProteinP43003 (Uniprot-TrEMBL)
SLC38A1ProteinQ9H2H9 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-70606 (Reactome)
ATPR-HSA-70606 (Reactome)
Astrocytic EAATsmim-catalysisR-HSA-210439 (Reactome)
GLUL decamermim-catalysisR-HSA-70606 (Reactome)
L-GlnArrowR-HSA-212614 (Reactome)
L-GlnArrowR-HSA-70606 (Reactome)
L-GlnR-HSA-212614 (Reactome)
L-GluArrowR-HSA-210439 (Reactome)
L-GluR-HSA-210439 (Reactome)
L-GluR-HSA-70606 (Reactome)
NH4+R-HSA-70606 (Reactome)
PiArrowR-HSA-70606 (Reactome)
R-HSA-210439 (Reactome) There are two classes of glutamate transporters; the excitatory amino acid transporters (EAATs) which depend on an electrochemical gradient of Na+ ions and vesicular glutamate transporters (VGLUTs) which don't. Together, these transporters uptake and release glutamate to mediate this neurotransmitter's excitatory signal and are part of the glutamate-gluatamine cycle. The SLC1 gene family includes five high-affinity glutamate transporters encoded by SLC1, 2, 3, 6 and 7. These transporters can mediate transport of L-Glutamate (L-Glu), L-Aspartate and D-Aspartate with cotransport of 3 Na+ ions and H+ and antiport of a K+ ion. This mechanism allows glutamate into cells against a concentration gradient thus excess L-Glu released by the pre-synaptic neuron in the synaptic cleft is cleared. This is a crucial factor in the protection of neurons against glutamate excitotoxicity in the CNS. SLC1A2 and 3 are mainly expressed by astrocytes whereas SLC1A1 and 6 are predominantly neuronal.
SLC1A1 is expressed throughout the CNS however SLC1A6 is predominantly localized to purkinje cells. SLC1A7 is highly expressed in rod photoreceptor and bipolar cells of the retina. Astrocytic SLC1As are expressed in astrocytes in close apposition to the synapses and neuronal SLC1As are expressed in the extra-synaptic or peri-synaptic locations on the neurons. Astrocytic SLC1As 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 SLC1As is altered and glutamate receptors are expressed in the peri-synaptic region (Zhou & Danbolt 2014).
Defects in the SLC1A1 gene may be a cause of dicarboxylicamino aciduria (glutamate-aspartate transport defect in the kidney and intestine) (Jen et al. 2005).
PRA1 family protein 3 (ARL6IP5 aka ADP-ribosylation factor-like protein 6-interacting protein 5) is a microtuble-associated protein that is able to regulate intracellular concentrations of glutamate as well as tuarine. It negatively regulates SLC1A1 by decreasing its affinity for glutamate (L-Glu). The activity of human SLC1A1 is based on similarity to rat Eaac1 (aka GTRAP3-18) (Lin et al. 2001).
R-HSA-212614 (Reactome) Glutamine from the astrocytes is exported to the extracellular compartment via the system N amino acid transporter. The system N transporter is Na+ dependant transporter that has substrate specificity to aspargine, glutamine and histidine.
R-HSA-70606 (Reactome) Cytosolic glutamine synthetase (glutamate-ammonia ligase - GLUL) catalyzes the reaction of glutamate, ammonia, and ATP to form glutamine, ADP, and orthophosphate. The enzyme is a decamer (Krajewski et al. 2008). Mutations in the gene encoding GLUL cause glutamine deficiency in vivo (Haberle et al. 2005).
SLC38A1mim-catalysisR-HSA-212614 (Reactome)
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