The alanine‐serine‐cysteine‐1 (Asc‐1) transporter controls glycine levels in the brain and is required for glycinergic inhibitory transmission

Safory, Hazem; Neame, Samah; Shulman, Yoav; Zubedat, Salman; Radzishevsky, Inna; Rosenberg, Dina; Sason, Hagit; Engelender, Simone; Avital, Avi; Hülsmann, Swen; Schiller, Jackie; Wolosker, Herman

doi:10.15252/embr.201439561

Cited by 44 publications

(47 citation statements)

References 33 publications

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“…Indeed, recent studies indicate that mutations in the neutral amino acid transporter Asc-1 cause HPX-like dysfunctions in mice, and the corresponding gene (SLC7A10) is considered as a candidate gene for human HPX [59]. This transporter has been localized by immunohistochemistry in nerve terminals, although a detailed study about the nature of these terminals is still missing.…”

Section: Movement Diseases: Hyperekplexiamentioning

confidence: 99%

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

2016

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Glycinergic neurons are major contributors to the regulation of neuronal excitability, mainly in caudal areas of the nervous system. These neurons control fluxes of sensory information between the periphery and the CNS and diverse motor activities like locomotion, respiration or vocalization. The phenotype of a glycinergic neuron is determined by the expression of at least two proteins: GlyT2, a plasma membrane transporter of glycine, and VIAAT, a vesicular transporter shared by glycine and GABA. In this article, we review recent advances in understanding the role of GlyT2 in the pathophysiology of inhibitory glycinergic neurotransmission. GlyT2 mutations are associated to decreased glycinergic function that results in a rare movement disease termed hyperekplexia (HPX) or startle disease. In addition, glycinergic neurons control pain transmission in the dorsal spinal cord and their function is reduced in chronic pain states. A moderate inhibition of GlyT2 may potentiate glycinergic inhibition and constitutes an attractive target for pharmacological intervention against these devastating conditions.

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Section: Movement Diseases: Hyperekplexiamentioning

confidence: 99%

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

2016

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“…glycinergic inhibition and NMDAR-mediated glutamatergic transmission but increased GABAergic neurotransmission caused by the reduced levels of glycine 2,14 .…”

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confidence: 99%

Asc-1 Transporter (SLC7A10): Homology Models And Molecular Dynamics Insights Into The First Steps Of The Transport Mechanism

Mikou

Cabayé

Goupil

et al. 2020

Sci Rep

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The alanine-serine-cysteine transporter Asc-1 regulates the synaptic availability of d-serine and glycine (the two co-agonists of the NMDA receptor) and is regarded as an important drug target. To shuttle the substrate from the extracellular space to the cytoplasm, this transporter undergoes multiple distinct conformational states. In this work, homology modeling, substrate docking and molecular dynamics simulations were carried out to learn more about the transition between the "outwardopen" and "outward-open occluded" states. We identified a transition state involving the highlyconserved unwound TM6 region in which the Phe243 flips close to the d-serine substrate without major movements of TM6. This feature and those of other key residues are proposed to control the binding site and substrate translocation. Competitive inhibitors ACPP, LuAE00527 and SMLC were docked and their binding modes at the substrate binding site corroborated the key role played by Phe243 of TM6. For ACPP and LuAE00527, strong hydrophobic interactions with this residue hinder its mobility and prevent the uptake and the efflux of substrates. As for SMLC, the weaker interactions maintain the flexibility of Phe243 and the efflux process. Overall, we propose a molecular basis for the inhibition of substrate translocation of the Asc-1 transporter that should be valuable for rational drug design.The alanine-serine-cysteine transporter (referred to as SLC7A10 or Asc-1) is the light chain of the heterodimer amino acid transporter (HAT), and is a Na + -independent antiporter distributed throughout the central nervous system (CNS). Asc-1 is present at both astrocytes and neurons 1-3 , and displays high affinity for neutral amino acids and uses diverse substrates, such as l-serine, l-alanine, l-cysteine along with glycine and d-serine 4 . However, glycine and d-serine serve as two necessary and positive allosteric modulators of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors, and bind to the strychnine insensitive binding site (referred to as the 'glycine site') of those receptors (Fig. 1a) 5,6 . For these reasons, Asc-1 is a promising druggable target relevant for treating cognitive affections during normal or pathological aging but also in disorders like schizophrenia 7-12 . Indeed, Asc-1 primarily mediates the efflux of d-serine and glycine through the hetero-exchange with other neutral amino acids, and thus regulates glutamatergic neurotransmission and synaptic plasticity in the forebrain 13 . But, recent studies suggest that Asc-1 is also involved in the control of glycinergic transmission in the caudal brain and spinal cord 2,3,14 . SLC7a10-null mice display reduced levels of glycine, but not d-serine, and show rigidity and myoclonus characteristic of the clinical condition called hyperekplexia 2,14 .Given the important physiological function of Asc-1 in regulating d-serine and glycine levels, modulating Asc-1 function could provide therapeutical benefits for alleviating the symptoms caused notably by the hypofunction of NMDARs ...

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“…These transporters are known to transport small neutral amino acids without stereoselectivity (Fukasawa et al, 2000;Ribeiro et al, 2002). In particular, asc-1 exhibits a central nervous system-enriched expression pattern including spinal cord and selective expression in neurons (Fukasawa et al, 2000;Safory et al, 2015). Furthermore, the uptake of D-Ser was greatly reduced in the synaptosomes obtained from the hippocampus of asc-1 knockout mice (Rutter et al, 2007).…”

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confidence: 99%

A novel Na⁺‐Independent alanine‐serine‐cysteine transporter 1 inhibitor inhibits both influx and efflux of D‐Serine

Sakimura

Nakao

Yoshikawa

et al. 2016

J of Neuroscience Research

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NMDA receptor dysfunctions are hypothesized to underlie the pathophysiology of schizophrenia, and treatment with D-serine (D-Ser), an NMDA receptor coagonist, may improve the clinical symptoms of schizophrenia. Thus, upregulating the synaptic D-Ser level is a novel strategy for schizophrenia treatment. Na(+) -independent alanine-serine-cysteine transporter 1 (asc-1) is a transporter responsible for regulating the extracellular D-Ser levels in the brain. In this study, we discovered a novel asc-1 inhibitor, (+)-amino(1-(3,5-dichlorophenyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid (ACPP), and assessed its pharmacological profile. ACPP inhibited the D-[(3) H]Ser uptake in human asc-1-expressing CHO cells and rat primary neurons with IC50 values of 0.72 ± 0.13 and 0.89 ± 0.30 μM, respectively. In accordance with the lower asc-1 expression levels in astrocytes, ACPP did not inhibit D-Ser uptake in rat primary astrocytes. In a microdialysis study, ACPP dose dependently decreased the extracellular D-Ser levels in the rat hippocampus under the same conditions in which the asc-1 inhibitor S-methyl-L-cysteine (SMLC) increased it. To obtain insights into this difference, we conducted a D-[(3) H]Ser efflux assay using asc-1-expressing CHO cells. ACPP inhibited D-[(3) H]Ser efflux, whereas SMLC increased it. These results suggest that ACPP is a novel inhibitor of asc-1. © 2016 Wiley Periodicals, Inc.

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The alanine‐serine‐cysteine‐1 (Asc‐1) transporter controls glycine levels in the brain and is required for glycinergic inhibitory transmission

Cited by 44 publications

References 33 publications

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

Asc-1 Transporter (SLC7A10): Homology Models And Molecular Dynamics Insights Into The First Steps Of The Transport Mechanism

A novel Na⁺‐Independent alanine‐serine‐cysteine transporter 1 inhibitor inhibits both influx and efflux of D‐Serine

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The alanine‐serine‐cysteine‐1 (Asc‐1) transporter controls glycine levels in the brain and is required for glycinergic inhibitory transmission

Cited by 44 publications

References 33 publications

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

Asc-1 Transporter (SLC7A10): Homology Models And Molecular Dynamics Insights Into The First Steps Of The Transport Mechanism

A novel Na+‐Independent alanine‐serine‐cysteine transporter 1 inhibitor inhibits both influx and efflux of D‐Serine

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A novel Na⁺‐Independent alanine‐serine‐cysteine transporter 1 inhibitor inhibits both influx and efflux of D‐Serine