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

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.

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

“…Activation of these receptors leads to enhanced release of D-serine (NMDA receptor coagonist) and glutamine (uptaken by excitatory terminals and converted to glutamate) 46,47 . Similarly, we detected a downregulation of Slc1a4 (Asct1) in neurons, which could also contribute to reduced clearance of D-serine 48 .…”

The neuronal and astrocytic proteinSLC38A10 transports glutamine, glutamate, and aspartate, suggesting a role in neurotransmission

“…L-serine is exported from astrocytes, a pathway suggested to be conducted by SLC1A4 [65] and SLC1A5 [66]. Furthermore, SLC1A4 and SLC1A5 are also transporters for D-serine in rat hippocampal astrocytes [67]. Effluxes of Fig.…”

“…l ‐serine is exported from astrocytes, a pathway suggested to be conducted by SLC1A4 and SLC1A5 . Furthermore, SLC1A4 and SLC1A5 are also transporters for d ‐serine in rat hippocampal astrocytes . Effluxes of l ‐serine were measured for SLC38A10 and it is possible that SLC38A10 transport l ‐serine from astrocytes, to serve neurons with l ‐serine for d ‐serine synthesis .…”

The Guillain–Barrè peptide signatures: from Zika virus to Campylobacter, and beyond

“…56 Hence, it draws our attention the presence of three pentapeptides (namely ALRGL, GAALR, and LLGLL) that are present in the amino acid transporter SATT (or SLC1A4 or ASCT1) (Table S2). SATT is essential in brain for d-serine transport 86 and is mostly expressed in hippocampal pyramidal and dentate granule neurons, and, in the cerebellum, Purkinje cells and their dendrites, thereby suggesting a role in pathophysiological processes that involve glutamate toxicity. 87 Indeed, activation of N-methyl-d-aspartate receptors (NMDARs) by synaptically released l-glutamate requires occupancy of coagonist binding sites in the tetrameric receptor by either glycine or d-serine, so that altered SATT and, thereby, altered d-serine flux in the brain would alter NMDAR activity.…”