Phenylglycine analogs are inhibitors of the neutral amino acid transporters ASCT1 and ASCT2 and enhance NMDA receptor-mediated LTP in rat visual cortex slices. (November 2017)

• Record Type: Journal Article
• Authors: Foster, Alan C.; Rangel-Diaz, Natalie; Staubli, Ursula; Yang, Jia-Ying; Penjwini, Mahmud; Viswanath, Veena; Li, Yong-Xin
• Is Part Of: Neuropharmacology. Volume 126(2017)
• Page Start: 70
• Page End: 83
• Publication Date: 2017-11
• Subjects: D-serine -- ASCT1 -- ASCT2 -- Phenylglycine -- LTP -- NMDA; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.08.010
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: The N -methyl-d -aspartate receptor (NMDA) co-agonistd -serine is a substrate for the neutral amino acid transporters ASCT1 (SLC1A4) and ASCT2 (SLC1A5). We identifiedl -phenylglycine (PG) and its analogs as inhibitors of ASCT1 and ASCT2. PG analogs were shown to be non-substrate inhibitors of ASCT1 and ASCT2 with a range of activities relative to other amino acid transport systems, including sodium-dependent glutamate transporters, the sodium-independentd -serine transporter asc-1 and system L. L-4-chloroPG was the most potent and selective ASCT1/2 inhibitor identified. The PG analogs facilitated theta-burst induced long-term potentiation in rat visual cortex slices in a manner that was dependent on extracellulard -serine. For structurally-related PG analogs, there was an excellent correlation between ASCT1/2 transport inhibition and enhancement of LTP which was not the case for inhibition of asc-1 or system L. The ability of PG analogs to enhance LTP is likely due to inhibition ofd -serine transport by ASCT1/2, leading to elevated extracellular levels ofd -serine and increased NMDA receptor activity. These results suggest that ASCT1/2 may play an important role in regulating extracellulard -serine and NMDA receptor-mediated physiological effects and that ASCT1/2 inhibitors have the potential for therapeutic benefit. Highlights: d -serine is a substrate for the amino acid transporters ASCT1 and ASCT2. l -phenylglycine (PG) analogs inhibited ASCT1 and ASCT2 and related transporters. PG analogs enhanced theta-burst induced LTP in ad -serine-dependent manner. LTP enhancement by PG analogs correlated strongly with ASCT1/2 inhibition. ASCT1 and ASCT2 may regulate extracellulard -serine and NMDA receptor activity.