| 17432963 |
Rutter AR, Fradley RL, Garrett EM, Chapman KL, Lawrence JM, Rosahl TW, Patel S: Evidence from gene knockout studies implicates Asc-1 as the primary transporter mediating d-serine reuptake in the mouse CNS. Eur J Neurosci. 2007 Mar;25(6):1757-66.
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. |
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