In Vivod-Serine Hetero-Exchange through Alanine-Serine-Cysteine (ASC) Transporters Detected by Microelectrode Biosensors

Abstract

D-serine, a co-agonist of N-methyl D-aspartate (NMDA) receptors, has been implicated in neurological and psychiatric disorders such as cerebral ischemia, lateral amyotrophic sclerosis, or schizophrenia. D-serine signaling represents an important pharmacological target for treating these diseases; however, the biochemical mechanisms controlling extracellular D-serine levels in vivo are still unclear. D-serine heteroexchange through small neutral amino acid transporters has been shown in cell cultures and brain slices and could provide a biochemical mechanism for the control of D-serine extracellular concentration in vivo. Alternatively, exocytotic D-serine release has also been proposed. In this study, the dynamics of D-serine release and clearance were explored in vivo on a second-by-second time scale using microelectrode biosensors. The rate of D-serine clearance in the rat frontal cortex after a microionophoretic injection revealed a transporter-mediated uptake mechanism. D-serine uptake was blocked by small neutral l-amino acids, implicating alanine-serine-cysteine (ASC) transporters, in particular high affinity Asc-1 and low affinity ASCT2 transporters. Interestingly, changes in alanine, serine, or threonine levels resulted in D-serine release through ASC transporters. Asc-1, but not ASCT2, appeared to release D-serine in response to changes in amino acid concentrations. Finally, neuronal silencing by tetrodotoxin increased D-serine extracellular concentration by an ASC-transporter-dependent mechanism. Together, these results indicate that D-serine heteroexchange through ASC transporters is present in vivo and may constitute a key component in the regulation of D-serine extracellular concentration.

Neuronal serine racemase regulates extracellular d-serine levels in the adult mouse hippocampus

“…Because l -alanine has been suggested to facilitate the extracellular d -serine release through Asc-1 by a heteroexchange mechanism (Maucler et al 2013; Rosenberg et al 2013), the reduced extracellular and tissue levels of d -serine could be accompanied by a change in the efflux and tissue accumulation of l -alanine in the hippocampus. The slight, but significant, decrease in the hippocampal tissue levels of l -glutamate would be accounted for by a compensatory increase in the efflux of l -glutamate from the cells for the reduced NMDA receptor activity produced by the drop in the extracellular d -serine concentrations.…”

Effects of lead exposure on d-serine metabolism in the hippocampus of mice at the early developmental stages

“…Otherwise, enhanced protein expression might also result from decreased protein degradation that targets asc-1 or DAAO. Because asc-1 could mediate the release and uptake of D-serine via the neurons (Helboe et al, 2003;Maucler et al, 2013;Rosenberg et al, 2013), enhanced expression of asc-1 might be related to the abnormal release and uptake of D-serine, which was possibly due to the reduced levels of D-serine in the neurons. But the exact underlying mechanisms need more studies.…”

“…On the other hand, D-serine catabolism is carried out by the DAAO in peroxisomes via the oxidative deamination (Ohide et al, 2011;Sasabe et al, 2012). Otherwise, the recent studies also disclosed that the extracellular D-serine concentrations are regulated by two types of transporters, the Na + -dependent and Na + -independent alanine-serine-cysteine transporter, such as ASCT1, ASCT2 and asc-1 (Fukasawa et al, 2000;Helboe et al, 2003;Maucler et al, 2013;Rosenberg et al, 2013). ASCT1 and ASCT2 are widely expressed but exhibit low affinity for D-serine.…”

Physical and functional interactions between the serotonin transporter and the neutral amino acid transporter ASCT2

“…It has been proposed that ASCT2 mediates efflux of glutamine from astrocytes, a process critical for recycling synaptically released glutamate through the glutamine/glutamate cycle [54]. ASCT2 might also modulate glutamatergic transmission by contributing to the astrocytic uptake of D-serine, an endogenous co-agonist of glutamatergic NMDA (N-methyl-D-aspartate) receptors [55,56]. In contrast, the role of ASCT2 in serotonergic transmission remained unexplored.…”