Figure 2.

Schematic depiction of the astrocyte-related mechanisms in the metabolism, transport, uptake of glutamate and the regulation of glutamate transmission. Glutamate is synthesized de novo from α-KG via the TCA cycle (1). In the glutamate-glutamine cycle (2–4), glutamate is metabolized to glutamine by GS in the astrocyte and then transported to the neuron (2). Neuronal PAG catalyzes the conversion from glutamine into glutamate, which is released as the transmitter from presynaptic terminal (3). The synaptically released glutamate is rapidly uptake by EAATs back into the astrocytes (4). Glutamate can be released as a gliotransmitters by either Ca²⁺-dependent vesicular release (5) or efflux from transporters or large-conductance ion channels (6). D-serine is converted from L-serine, which is synthesized de novo from 3-phosphoglycerate in astrocytes (7). D-serine can be released via either vesicular or non-vesicular mechanisms and activate neuronal NMDA receptors (8). Glycine is transported across astrocytic membrane via glycine receptors (9). 3PG, 3-phosphoglycerate; α-KG, α-ketoglutarate; Glu, glutamate; Gln, glutamine; GS, glutamine synthetase; L-Ser, L-serine; D-Ser, D-serine; PAG, phosphate-activated glutaminase; SR, serine racemase; ASCT, alanine-serine-cysteine transporter; xCT, cystine-glutamate antiporter; GLAST, glutamate aspartate transporter; GLT-1, glutamate transporter 1; GlyT-1, glycine transporter 1; mGluR, metabotropic glutamate receptor; IP3R, inositol trisphosphate receptor.