Phenylglycine analogs are inhibitors of the neutral amino acid transporters ASCT1 and ASCT2 and enhance NMDA receptor-mediated LTP in rat visual cortex slices

Foster, Alan C.; Rangel-Diaz, Natalie; Stäubli, Ursula; Yang, Jiaying; Penjwini, Mahmud; Viswanath, Veena; Li, Yongxin

doi:10.1016/j.neuropharm.2017.08.010

Cited by 22 publications

(27 citation statements)

References 67 publications

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“…2 A and B), a percentage that represents the estimated glial contamination in the synaptosomal preparation (14). We also monitored the effect of trans-4-hydroxy-L-proline (OH-Pro), a selective ASCT1 substrate that competes with other substrates (15). In agreement, OH-Pro inhibited D-serine transport in HEK293 transfected with ASCT1 to the same extent as excess L-alanine (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 82%

ASCT1 (Slc1a4) transporter is a physiologic regulator of brain d -serine and neurodevelopment

Kaplan

Zubedat

Radzishevsky

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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d-serine is a physiologic coagonist of NMDA receptors, but little is known about the regulation of its synthesis and synaptic turnover. The amino acid exchangers ASCT1 (Slc1a4) and ASCT2 (Slc1a5) are candidates for regulating d-serine levels. Using ASCT1 and ASCT2 KO mice, we report that ASCT1, rather than ASCT2, is a physiologic regulator of d-serine metabolism. ASCT1 is a major d-serine uptake system in astrocytes and can also export l-serine via heteroexchange, supplying neurons with the substrate for d-serine synthesis. ASCT1-KO mice display lower levels of brain d-serine along with higher levels of l-alanine, l-threonine, and glycine. Deletion of ASCT1 was associated with neurodevelopmental alterations including lower hippocampal and striatal volumes and changes in the expression of neurodevelopmental-relevant genes. Furthermore, ASCT1-KO mice exhibited deficits in motor function, spatial learning, and affective behavior, along with changes in the relative contributions of d-serine vs. glycine in mediating NMDA receptor activity. In vivo microdialysis demonstrated lower levels of extracellular d-serine in ASCT1-KO mice, confirming altered d-serine metabolism. These alterations are reminiscent of some of the neurodevelopmental phenotypes exhibited by patients with ASCT1 mutations. ASCT1-KO mice provide a useful model for potential therapeutic interventions aimed at correcting the metabolic impairments in patients with ASCT1 mutations.

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Section: Resultsmentioning

confidence: 82%

ASCT1 (Slc1a4) transporter is a physiologic regulator of brain d -serine and neurodevelopment

Kaplan

Zubedat

Radzishevsky

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, high systemic levels of D-serine pose a risk of renal toxicity (Krug et al, 2007;Kantrowitz et al, 2010). We have previously shown that D-serine is transported by the neutral amino acid transporters ASCT1 (SLC1A4) and ASCT2 (SLC1A5; and that the inhibition of these transporters can potentiate NMDA receptor-mediated neuronal plasticity in a D-serine-dependent manner (Foster et al, 2017). This suggests that these predominantly glial transporters may play an important role in regulating extracellular D-serine in the brain and thereby NMDA receptor function.…”

Section: Introductionmentioning

confidence: 99%

“…We previously identified phenylglycine (PG) analogs that are inhibitors of ASCT1 and ASCT2 (Foster et al, 2017), and here we tested their effects in animal models of schizophrenia and visual dysfunction to evaluate whether systemically https://doi.org/10.1124/jpet.118.251116.…”

Section: Introductionmentioning

confidence: 99%

“…administered inhibitors of these transporters had efficacy in these models of NMDA receptor hypofunction. The compounds evaluated were L-4-fluoroPG (L-4FPG) and L-4-chloroPG (L-4ClPG) which are relatively potent and selective ASCT1/2 inhibitors, and L-4-hydroxyPG (L-4OHPG) which additionally inhibits asc-1 (SLC7A10) (Foster et al, 2017), and has previously been tested in humans (Bergman et al, 1980). We previously showed that L-4FPG, L-4OHPG and L-4ClPG have IC 50 's for inhibition of astrocyte-mediated ASCT1 and ASCT2 transport of 44, 283 and 25 mM, respectively (Foster et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…The compounds evaluated were L-4-fluoroPG (L-4FPG) and L-4-chloroPG (L-4ClPG) which are relatively potent and selective ASCT1/2 inhibitors, and L-4-hydroxyPG (L-4OHPG) which additionally inhibits asc-1 (SLC7A10) (Foster et al, 2017), and has previously been tested in humans (Bergman et al, 1980). We previously showed that L-4FPG, L-4OHPG and L-4ClPG have IC 50 's for inhibition of astrocyte-mediated ASCT1 and ASCT2 transport of 44, 283 and 25 mM, respectively (Foster et al, 2017). They were not active in a range of ionotropic and metabotropic glutamate receptor assays and L-4ClPG and L-4FPG were tested and found to be inactive in a broader selectivity screen including 137 receptor, enzyme and transporter recognition sites (Foster et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Inhibitors of the Neutral Amino Acid Transporters ASCT1 and ASCT2 Are Effective in In Vivo Models of Schizophrenia and Visual Dysfunction

Yang

Alcantara

et al. 2018

J Pharmacol Exp Ther

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The -methyl-d-aspartate receptor coagonist d-serine is a substrate for the neutral amino acid transporters ASCT1 and ASCT2, which may regulate its extracellular levels in the central nervous system (CNS). We tested inhibitors of ASCT1 and ASCT2 for their effects in rodent models of schizophrenia and visual dysfunction, which had previously been shown to be responsive to d-serine. L-4-fluorophenylglycine (L-4FPG), L-4-hydroxyPG (L-4OHPG), and L-4-chloroPG (L-4ClPG) all showed high plasma bioavailability when administered systemically to rats and mice. L-4FPG showed good brain penetration with brain/plasma ratios of 0.7-1.4; however, values for L-4OHPG and L-4ClPG were lower. Systemically administered L-4FPG potently reduced amphetamine-induced hyperlocomotion in mice, whereas L-4OHPG was 100-fold less effective and L-4ClPG inactive at the doses tested. L-4FPG and L-4OHPG did not impair visual acuity in naive rats, and acute systemic administration of L-4FPG significantly improved the deficit in contrast sensitivity in blue light-treated rats caused by retinal degeneration. The ability of L-4FPG to penetrate the brain makes this compound a useful tool to further evaluate the function of ASCT1 and ASCT2 transporters in the CNS.

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Inhibition of glial D‐serine release rescues synaptic damage after brain injury

Tapanes

Arizanovska

Díaz

et al. 2022

Glia

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Synaptic damage is one of the most prevalent pathophysiological responses to traumatic CNS injury and underlies much of the associated cognitive dysfunction; however, it is poorly understood. The D‐amino acid, D‐serine, serves as the primary co‐agonist at synaptic NMDA receptors (NDMARs) and is a critical mediator of NMDAR‐dependent transmission and synaptic plasticity. In physiological conditions, D‐serine is produced and released by neurons from the enzymatic conversion of L‐serine by serine racemase (SRR). However, under inflammatory conditions, glial cells become a major source of D‐serine. Here, we report that D‐serine synthesized by reactive glia plays a critical role in synaptic damage after traumatic brain injury (TBI) and identify the therapeutic potential of inhibiting glial D‐serine release though the transporter Slc1a4 (ASCT1). Furthermore, using cell‐specific genetic strategies and pharmacology, we demonstrate that TBI‐induced synaptic damage and memory impairment requires D‐serine synthesis and release from both reactive astrocytes and microglia. Analysis of the murine cortex and acutely resected human TBI brain also show increased SRR and Slc1a4 levels. Together, these findings support a novel role for glial D‐serine in acute pathological dysfunction following brain trauma, whereby these reactive cells provide the excess co‐agonist levels necessary to initiate NMDAR‐mediated synaptic damage.

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Phenylglycine analogs are inhibitors of the neutral amino acid transporters ASCT1 and ASCT2 and enhance NMDA receptor-mediated LTP in rat visual cortex slices

Cited by 22 publications

References 67 publications

ASCT1 (Slc1a4) transporter is a physiologic regulator of brain d -serine and neurodevelopment

ASCT1 (Slc1a4) transporter is a physiologic regulator of brain d -serine and neurodevelopment

Inhibitors of the Neutral Amino Acid Transporters ASCT1 and ASCT2 Are Effective in In Vivo Models of Schizophrenia and Visual Dysfunction

Inhibition of glial D‐serine release rescues synaptic damage after brain injury

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