title: Activity of the enantiomers of erythro-3-hydroxyaspartate at glutamate transporters and NMDA receptors.
abstract: The enantiomers of erythro-3-hydroxyaspartate were tested for activity at glutamate transporters and NMDA receptors. Both enantiomers inhibited glutamate transporters in rat hippocampal crude synaptosomes and elicited substrate-like activity at excitatory amino acid transporter 1, 2, and 3 as measured by voltage clamp in the Xenopus oocyte expression system. The enantiomers had similar affinities, but the D-enantiomer showed a lower maximal effect at excitatory amino acid transporter 1, 2, and 3 than the L-enantiomer. Surprisingly, D-erythro-3-hydroxyaspartate was a potent NMDA receptor agonist with an EC50value in rat hippocampal neurons of 320 nM, whereas the L-enantiomer was 100-fold less potent. L-erythro-3-hydroxyaspartate showed activity at both glutamate transporters and NMDA receptors at concentrations that are reported to inhibit serine racemase, indicating a lack of selectivity. This enantiomeric pair may assist in shedding further light on the structural requirements for substrate activity at glutamate transporters and for agonist activity at NMDA receptors. The erythro enantiomers of 3-hydroxyaspartate had interesting and surprising effects on glutamate neurotransmitter systems. L-erythro-3-hydroxyaspartate had activity at both glutamate transporters (EAAT1/2/3) and NMDA receptors. D-erythro-3-hydroxyaspartate acted on EAATs, but was also identified as a highly potent NMDA receptor agonist. These enantiomers shed further light on the structural requirements for activity at EAATs and NMDA receptors.
authors.affiliation: Department of Biological Sciences, Allergan, Inc., Irvine, California, USA.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
authors.affiliation: Department of Biological Sciences, Allergan, Inc., Irvine, California, USA.
authors.forename: Yong-Xin
authors.identifier: http://orcid.org/0000-0001-7331-8333
authors.initials: YX
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, Allergan, Inc., Irvine, California, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Runyan
authors.affiliation: Department of Biological Sciences, Allergan, Inc., Irvine, California, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Dinh
authors.affiliation: Department of Biological Sciences, Allergan, Inc., Irvine, California, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Venadas
authors.affiliation: Department of Biological Sciences, Allergan, Inc., Irvine, California, USA.
authors.forename: June
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, USA.
authors.forename: Srinath
authors.initials: S
authors.lastname: Pashikanti
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, USA.
authors.forename: Apurba
authors.initials: A
authors.lastname: Datta
authors.affiliation: Department of Biological Sciences, Allergan, Inc., Irvine, California, USA.
authors.forename: George
authors.initials: G
authors.lastname: Ehring
authors.affiliation: Department of Biological Sciences, Allergan, Inc., Irvine, California, USA.
authors.forename: Ursula
authors.initials: U
authors.lastname: Staubli
keywords: Glutamate; NMDA receptor; aspartate; enantiomer; serine racemase; transporter