Neurotransmitter uptake and metabolism In glial cells (Homo sapiens)

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Bibliography

1. 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 Scholia
2. 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 Scholia
3. 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 Scholia
4. 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 Scholia

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DataNodes

Name	Type	Database reference	Comment
ADP	Metabolite	CHEBI:456216 (ChEBI)
ATP	Metabolite	CHEBI:30616 (ChEBI)
Astrocytic EAATs	Complex	R-HSA-210416 (Reactome)
GLUL	Protein	P15104 (Uniprot-TrEMBL)
GLUL decamer	Complex	R-HSA-70604 (Reactome)
L-Gln	Metabolite	CHEBI:58359 (ChEBI)
L-Glu	Metabolite	CHEBI:29985 (ChEBI)
NH4+	Metabolite	CHEBI:28938 (ChEBI)
Pi	Metabolite	CHEBI:43474 (ChEBI)
SLC1A2	Protein	P43004 (Uniprot-TrEMBL)
SLC1A3	Protein	P43003 (Uniprot-TrEMBL)
SLC38A1	Protein	Q9H2H9 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	ADP	Arrow	R-HSA-70606 (Reactome)
ATP			R-HSA-70606 (Reactome)
Astrocytic EAATs		mim-catalysis	R-HSA-210439 (Reactome)
GLUL decamer		mim-catalysis	R-HSA-70606 (Reactome)
	L-Gln	Arrow	R-HSA-212614 (Reactome)
	L-Gln	Arrow	R-HSA-70606 (Reactome)
L-Gln			R-HSA-212614 (Reactome)
	L-Glu	Arrow	R-HSA-210439 (Reactome)
L-Glu			R-HSA-210439 (Reactome)
L-Glu			R-HSA-70606 (Reactome)
NH4+			R-HSA-70606 (Reactome)
	Pi	Arrow	R-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).
SLC38A1		mim-catalysis	R-HSA-212614 (Reactome)