Fig. 5. The glutamate/glutamine cycle. High-affinity excitatory amino acid transporters (EAATs) of astrocytes primarily clear Glu in the synaptic cleft that is released from presynaptic neurons. GLT1 (glutamate transporter 1/EAAT2/SLC1A2) is the major regulator that transports Glu to astrocytes. In astrocytes, Glu is converted into Gln by glutamine synthetase (GS). Synthesized Gln is released from the astrocytes through sodium-coupled neutral amino acid transporters (SNAT3/SLC38A3 and SNAT5/SLC38A5). Released Gln is transported into neurons via SNAT1 and SNAT2 (SLC38A1 and SLC38A2) and converted back to Glu by phosphate-activated glutaminase (PAG or GLS1/2, mainly GLS2 in brain) for synaptic transmission of glutamatergic neurons. Glutamate is further transformed to γ-aminobutyric acid (GABA) by glutamic acid decarboxylases (GAD1 and GAD2) in the GABAergic neurons. Glu can be synthesized in the astrocytes from glucose via the tricarboxylic acid (TCA) cycle, followed by transamination of α-ketoglutarate (α-KG). Pyruvate carboxylase (PC) converts pyruvate to oxaloacetate that is converted to α-KG via the TCA cycle. Glutamate dehydrogenase (GDH) connects the TCA and Glu-Gln cycles by reversibly converting Glu into α-KG and vice versa. Expressional changes by chronic immobilization stress (CIS) and Gln supplementation are marked by red and green arrows, respectively.
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