Evidence from gene knockout studies implicates Asc‐1 as the primary transporter mediating d‐serine reuptake in the mouse CNS
- 1 March 2007
- journal article
- Published by Wiley in European Journal of Neuroscience
- Vol. 25 (6), 1757-1766
- https://doi.org/10.1111/j.1460-9568.2007.05446.x
Abstract
In the mammalian central nervous system, transporter-mediated reuptake may be critical for terminating the neurotransmitter action of D-serine at the strychnine insensitive glycine site of the NMDA receptor. The Na(+) independent amino acid transporter alanine-serine-cysteine transporter 1 (Asc-1) has been proposed to account for synaptosomal d-serine uptake by virtue of its high affinity for D-serine and widespread neuronal expression throughout the brain. Here, we sought to validate the contribution of Asc-1 to D-serine uptake in mouse brain synaptosomes using Asc-1 gene knockout (KO) mice. Total [(3)H]D-serine uptake in forebrain and cerebellar synaptosomes from Asc-1 knockout mice was reduced to 34 +/- 5% and 22 +/- 3% of that observed in wildtype (WT) mice, respectively. When the Na(+) dependent transport components were removed by omission of Na(+) ions in the assay buffer, D-serine uptake in knockout mice was reduced to 8 +/- 1% and 3 +/- 1% of that measured in wildtype mice in forebrain and cerebellum, respectively, suggesting Asc-1 plays a major role in the Na(+) independent transport of D-serine. Potency determination of D-serine uptake showed that Asc-1 mediated rapid high affinity Na(+) independent uptake with an IC(50) of 19 +/- 1 microm. The remaining uptake was mediated predominantly via a low affinity Na(+) dependent transporter with an IC(50) of 670 +/- 300 microm that we propose is the glial alanine-serine-cysteine transporter 2 (ASCT2) transporter. The results presented reveal that Asc-1 is the only high affinity D-serine transporter in the mouse CNS and is the predominant mechanism for D-serine reuptake.Keywords
This publication has 39 references indexed in Scilit:
- d-Amino acids in the central nervous system in health and diseaseMolecular Genetics and Metabolism, 2005
- d-Serine enhances impaired long-term potentiation in CA1 subfield of hippocampal slices from aged senescence-accelerated mouse prone/8Neuroscience Letters, 2005
- D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophreniaBiological Psychiatry, 2005
- Serine Racemase Modulates Intracellular D-Serine Levels through an α,β-Elimination ActivityPublished by Elsevier BV ,2005
- Glutamate as a therapeutic target in psychiatric disordersMolecular Psychiatry, 2004
- Spatial Memory Deficits Induced by Perinatal Treatment of Rats with PCP and Reversal Effect of D-SerineNeuropsychopharmacology, 2004
- D-Serine differently modulates NMDA receptor function in rat CA1 hippocampal pyramidal cells and interneuronsThe Journal of Physiology, 2003
- Uptake of D‐serine by synaptosomal P2 fraction isolated from rat brainSynapse, 2001
- Identification and Characterization of a Na+-independent Neutral Amino Acid Transporter That Associates with the 4F2 Heavy Chain and Exhibits Substrate Selectivity for Small Neutral d- and l-Amino AcidsJournal of Biological Chemistry, 2000
- Cloning and Functional Characterization of a System ASC-like Na+-dependent Neutral Amino Acid TransporterPublished by Elsevier BV ,1996