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.
Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, United States of America.
Alan C
AC
Foster
Center for Structural and Functional Neuroscience, The University of Montana, Missoula, MT 59812, United States of America.
Jill
J
Farnsworth
Center for Structural and Functional Neuroscience, The University of Montana, Missoula, MT 59812, United States of America.
Genevieve E
GE
Lind
Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, United States of America.
Yong-Xin
YX
Li
Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, United States of America.
Jia-Ying
JY
Yang
Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, United States of America.
Van
V
Dang
Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, United States of America.
Mahmud
M
Penjwini
Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, United States of America.
Veena
V
Viswanath
Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, United States of America.
Ursula
U
Staubli
Center for Structural and Functional Neuroscience, The University of Montana, Missoula, MT 59812, United States of America.
Michael P
MP
Kavanaugh
D026962:Amino Acid Transport System ASC / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001693:Biological Transport, Active / Q000502:physiology; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D006624:Hippocampus / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012694:Serine / Q000378:metabolism*
D026962:Amino Acid Transport System ASC; D015778:Minor Histocompatibility Antigens; D016194:Receptors, N-Methyl-D-Aspartate; C420504:Slc1a4 protein, rat; C498849:Slc1a5 protein, rat; D012694:Serine