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

Alan C. Foster, Jill Farnsworth, Genevieve E. Lind, Yong Xin Li, Jia Ying Yang, Van Dang, Mahmud Penjwini, Veena Viswanath, Ursula Staubli, Michael P. Kavanaugh

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere0156551
JournalPLoS ONE
Volume11
Issue number6
DOIs
StatePublished - Jun 1 2016

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