Asc-1 Transporter Regulation of Synaptic Activity via the Tonic Release of d-Serine in the Forebrain

Cerebral Cortex
Hagit SasonHerman Wolosker

Abstract

d-Serine is a co-agonist of NMDA receptors (NMDARs) whose activity is potentially regulated by Asc-1 (SLC7A10), a transporter that displays high affinity for d-serine and glycine. Asc-1 operates as a facilitative transporter and as an antiporter, though the preferred direction of d-serine transport is uncertain. We developed a selective Asc-1 blocker, Lu AE00527, that blocks d-serine release mediated by all the transport modes of Asc-1 in primary cultures and neocortical slices. Furthermore, d-serine release is reduced in slices from Asc-1 knockout (KO) mice, indicating that d-serine efflux is the preferred direction of Asc-1. The selectivity of Lu AE00527 is assured by the lack of effect on slices from Asc-1-KO mice, and the lack of interaction with the co-agonist site of NMDARs. Moreover, in vivo injection of Lu AE00527 in P-glycoprotein-deficient mice recapitulates a hyperekplexia-like phenotype similar to that in Asc-1-KO mice. In slices, Lu AE00527 decreases the long-term potentiation at the Schaffer collateral-CA1 synapses, but does not affect the long-term depression. Lu AE00527 blocks NMDAR synaptic potentials when typical Asc-1 extracellular substrates are present, but it does not affect AMPAR transmission. Our data de...Continue Reading

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Citations

Jan 18, 2017·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Thomas PapouinPhilip G Haydon
Jan 20, 2018·Physiological Reviews·Alexei Verkhratsky, Maiken Nedergaard
Jun 16, 2016·Journal of Neuroscience Research·Katsuya SakimuraHaruhide Kimura
May 24, 2020·Cellular and Molecular Neurobiology·Shunsuke TakagiJoseph T Coyle
Dec 17, 2020·International Journal of Molecular Sciences·Eva PlouxJean-Marie Billard
Feb 20, 2021·Neurochemical Research·Ekaitz Errasti-Murugarren, Manuel Palacín
Jul 25, 2021·International Journal of Molecular Sciences·Mark W SherwoodAude Panatier
Aug 27, 2021·Membranes·Adrià Nicolàs-AragóEkaitz Errasti-Murugarren
Mar 2, 2019·ACS Chemical Neuroscience·Ivan R TorrecillasGary Tresadern

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