Veena Viswanath

D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1/SLC1A4 and ASCT2/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures.

N-methyl-D-aspartate (NMDA) receptors play critical roles in synaptic transmission and plasticity. Activation of NMDA receptors by synaptically released L-glutamate also requires occupancy of co-agonist binding sites in the tetrameric receptor by either glycine or D-serine. Although D-serine appears to be the predominant co-agonist at synaptic NMDA receptors, the transport mechanisms involved in D-serine homeostasis in brain are poorly understood. In this work we show that the SLC1 amino acid transporter family members SLC1A4 (ASCT1) and SLC1A5 (ASCT2) mediate homo- and hetero-exchange of D-serine with physiologically relevant kinetic parameters. In addition, the selectivity profile of D-serine uptake in cultured rat hippocampal astrocytes is consistent with uptake mediated by both ASCT1 and ASCT2. Together these data suggest that SLC1A4 (ASCT1) may represent an important route of Na-dependent D-serine flux in the brain that has the ability to regulate extracellular D-serine and thereby NMDA receptor activity.

Phenylglycine analogs are inhibitors of the neutral amino acid transporters ASCT1 and ASCT2 and enhance NMDA receptor-mediated LTP in rat visual cortex slices

&NA; The N‐methyl‐D‐aspartate receptor (NMDA) co‐agonist D‐serine is a substrate for the neutral amino acid transporters ASCT1 (SLC1A4) and ASCT2 (SLC1A5). We identified L‐phenylglycine (PG) and its analogs as inhibitors of ASCT1 and ASCT2. PG analogs were shown to be non‐substrate inhibitors of ASCT1 and ASCT2 with a range of activities relative to other amino acid transport systems, including sodium‐dependent glutamate transporters, the sodium‐independent D‐serine transporter asc‐1 and system L. L‐4‐chloroPG was the most potent and selective ASCT1/2 inhibitor identified. The PG analogs facilitated theta‐burst induced long‐term potentiation in rat visual cortex slices in a manner that was dependent on extracellular D‐serine. For structurally‐related PG analogs, there was an excellent correlation between ASCT1/2 transport inhibition and enhancement of LTP which was not the case for inhibition of asc‐1 or system L. The ability of PG analogs to enhance LTP is likely due to inhibition of D‐serine transport by ASCT1/2, leading to elevated extracellular levels of D‐serine and increased NMDA receptor activity. These results suggest that ASCT1/2 may play an important role in regulating extracellular D‐serine and NMDA receptor‐mediated physiological effects and that ASCT1/2 inhibitors have the potential for therapeutic benefit. HighlightsD‐serine is a substrate for the amino acid transporters ASCT1 and ASCT2.L‐phenylglycine (PG) analogs inhibited ASCT1 and ASCT2 and related transporters.PG analogs enhanced theta‐burst induced LTP in a D‐serine‐dependent manner.LTP enhancement by PG analogs correlated strongly with ASCT1/2 inhibition.ASCT1 and ASCT2 may regulate extracellular D‐serine and NMDA receptor activity.