The astrocytic transporter SLC7A10 (Asc-1) mediates glycinergic inhibition of spinal cord motor neurons

Ehmsen, Jeffrey T.; Liu, Yong; Wang, Yue; Paladugu, Nikhil; Johnson, Anna E.; Rothstein, Jeffrey D.; du, Sascha; Mattson, Mark P.; Höke, Ahmet

doi:10.1038/srep35592

Cited by 38 publications

(43 citation statements)

References 44 publications

(52 reference statements)

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“…Although Lu AE00527 counteracted the effects of D-Ile, its lack of effect on glycinergic transmission when present alone was somewhat surprising and discrepant from the Asc1 knockout data 20 . This result indicates nonetheless that the basal activity of Asc-1 does not acutely regulate the glycinergic neurotransmission under our recording conditions.…”

Section: Discussionmentioning

confidence: 64%

“…However, our present results suggest that the effects of D-Ile on the inhibitory glycinergic transmission are compatible with a functional role of Asc-1 in neurons. The decrease in the frequency and amplitude of the glycinergic IPSCs cannot be explained by an expression of Asc-1 only in astroglia as proposed by Ehmsen and coworkers 20 . In case Asc-1 only facilitates glycine release from astroglia by hetero-exchange as proposed by Ehmsen et al ., one would expect an increase in glycinergic tone promoted by D-Ile due to higher glycine release from astrocytes, while the addition of Lu AE00527 would be predicted to have the opposite effects.…”

Section: Discussionmentioning

confidence: 78%

“…Asc-1 has been reported to be expressed in neurons 16 , 26 , 27 . However, Asc-1 was also found to be expressed in astrocytes in the brainstem 28 and the spinal cord 20 . Whether or not Asc-1 is quantitatively more expressed in astrocytes or in neurons still remains to be evaluated.…”

Section: Discussionmentioning

confidence: 97%

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A neuronal role of the Alanine-Serine-Cysteine-1 transporter (SLC7A10, Asc-1) for glycine inhibitory transmission and respiratory pattern

Mesuret

Khabbazzadeh

Bischoff

et al. 2018

Sci Rep

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The Alanine-Serine-Cysteine-1 transporter (SLC7A10, Asc-1) has been shown to play a role in synaptic availability of glycine although the exact mechanism remains unclear. We used electrophysiological recordings and biochemical experiments to investigate the role of Asc-1 transporter in glycinergic transmission in the brainstem respiratory network. Using both the Asc-1 substrate and transportable inhibitor D-isoleucine (D-Ile), and the non-transportable Asc-1 blocker Lu AE00527 (Lu), we found that D-Ile reduces glycinergic transmission and increases glycine release via hetero-exchange, whereas Lu has no acute effect on glycinergic synaptic transmission. Furthermore, D-Ile increases the frequency and reduces amplitude of the phrenic nerve activity in the arterially-perfused working heart brainstem preparation. These results suggest a role of Asc-1 in modulating presynaptic glycine levels that can impact on the respiratory network.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 78%

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A neuronal role of the Alanine-Serine-Cysteine-1 transporter (SLC7A10, Asc-1) for glycine inhibitory transmission and respiratory pattern

Mesuret

Khabbazzadeh

Bischoff

et al. 2018

Sci Rep

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“…S8A). Slc7a10 has previously been reported as a marker of an astrocyte subpopulation associated with glycinergic 10 signaling in mice (24). In ALS animals, the Prdx6 submodule displays escalating activity as disease progresses, while the Slc7a10 submodule is attenuated with progression.…”

mentioning

confidence: 93%

Spatiotemporal Dynamics of Molecular Pathology in Amyotrophic Lateral Sclerosis

Maniatis

Äijö

Vicković

et al. 2018

Preprint

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Paralysis occurring in amyotrophic lateral sclerosis (ALS) results from denervation of skeletal muscle as a consequence of motor neuron degeneration. Interactions between motor neurons and glia contribute to motor neuron loss, but the spatiotemporal ordering of molecular events that drive these processes in intact spinal tissue remains poorly understood. Here, we use spatial transcriptomics to obtain gene expression measurements of mouse spinal cords over the course of disease, as well as of postmortem tissue from ALS patients, to characterize the underlying molecular mechanisms in ALS. We identify novel pathway dynamics, regional differences between microglia and astrocyte populations at early time-points, and discern perturbations in several transcriptional pathways shared between murine models of ALS and human postmortem spinal cords.One Sentence SummaryAnalysis of the ALS spinal cord using Spatial Transcriptomics reveals spatiotemporal dynamics of disease driven gene regulation.

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

mentioning

confidence: 97%

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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The astrocytic transporter SLC7A10 (Asc-1) mediates glycinergic inhibition of spinal cord motor neurons

Cited by 38 publications

References 44 publications

A neuronal role of the Alanine-Serine-Cysteine-1 transporter (SLC7A10, Asc-1) for glycine inhibitory transmission and respiratory pattern

A neuronal role of the Alanine-Serine-Cysteine-1 transporter (SLC7A10, Asc-1) for glycine inhibitory transmission and respiratory pattern

Spatiotemporal Dynamics of Molecular Pathology in Amyotrophic Lateral Sclerosis

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

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