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

doi:10.1371/journal.pone.0156551

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 journal › Article › peer-review

54 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 language	English
Article number	e0156551
Journal	PLoS ONE
Volume	11
Issue number	6
DOIs	https://doi.org/10.1371/journal.pone.0156551
State	Published - Jun 1 2016

Funding

The following authors were employees of Allergan, Inc. at the time of the conduct of this study: ACF, Y-XL, JY, VD, MP, VV, and US. Allergan provided support in the form of salaries for authors ACF, Y-XL, JY, VD, MP, VV, and US, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. JF, GEL, and MPK were supported by a grant from NIH (R15 GM110690).

Funder number
R15 GM110690

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10.1371/journal.pone.0156551

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Foster, A. C., Farnsworth, J., Lind, G. E., Li, Y. X., Yang, J. Y., Dang, V., Penjwini, M., Viswanath, V., Staubli, U., & Kavanaugh, M. P. (2016). 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. PLoS ONE, 11(6), Article e0156551. https://doi.org/10.1371/journal.pone.0156551

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title = "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.",

author = "Foster, \{Alan C.\} and Jill Farnsworth and Lind, \{Genevieve E.\} and Li, \{Yong Xin\} and Yang, \{Jia Ying\} and Van Dang and Mahmud Penjwini and Veena Viswanath and Ursula Staubli and Kavanaugh, \{Michael P.\}",

note = "Publisher Copyright: {\textcopyright} 2016 Foster et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

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Foster, AC, Farnsworth, J, Lind, GE, Li, YX, Yang, JY, Dang, V, Penjwini, M, Viswanath, V, Staubli, U & Kavanaugh, MP 2016, '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', PLoS ONE, vol. 11, no. 6, e0156551. https://doi.org/10.1371/journal.pone.0156551

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AU - Foster, Alan C.

AU - Farnsworth, Jill

AU - Lind, Genevieve E.

AU - Li, Yong Xin

AU - Yang, Jia Ying

AU - Dang, Van

AU - Penjwini, Mahmud

AU - Viswanath, Veena

AU - Staubli, Ursula

AU - Kavanaugh, Michael P.

N1 - Publisher Copyright: © 2016 Foster et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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.

AB - 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.

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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

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