Neuron-derived D-Serine Release Provides a Novel Means to Activate N-Methyl-D-aspartate Receptors

Abstract

The N-methyl-D-aspartate (NMDA) 2 type of glutamate receptor plays prominent roles in excitatory neurotransmission (1). In addition to glutamate, the NMDA receptor requires the obligatory binding of a coagonist of the NR1 subunit to mediate ion influx (2). Although glycine was originally suggested as the NMDA receptor coagonist, recent data indicate that endogenous D-serine is a physiologically relevant NMDA receptor ligand at the coagonist site. D-Serine is present at high levels in the brain, with little levels in peripheral tissues (3-5). Destruction of endogenous D-serine by D-amino-acid oxidase in hippocampal cultures promotes a decrease in NMDA receptor responses (6). Likewise, NMDA receptor-mediated responses in the retina and induction of long-term hippocampal potentiation are also diminished by removing D-serine (7,8). Very recently, D-serine was shown to be required for granule cell migration in the developing cerebellum (9). It has been proposed that Bergman glial cells release D-serine and enhance cell migration through activation of NMDA receptors in migrating granule cells (9). In hippocampal organotypic slice cultures, endogenous D-serine was shown to be the dominant coagonist for NMDA receptor-elicited neurotoxicity, mediating virtually all cell death elicited by NMDA (10).D-Serine is synthesized from L-serine by serine racemase, a brain enriched enzyme (11-13). Serine racemase activity is stimulated by ATP, and the enzyme also catalyzes deamination of serine into pyruvate and ammonia (14, 15). Both D-serine and serine racemase were shown previously to be enriched in astrocytes (13, 16). Purified astrocytic cultures release D-serine following (Ϯ)-␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor activation (16 -18) and through an amino acid exchange mechanism by the neutral amino acid transporter ASCT (17). It has been proposed that D-serine released from astrocytes that ensheath the synapse will stimulate nearby neuronal NMDA receptors (16).The evidence that D-serine possesses a target receptor as well as a biosynthetic and degradative apparatus implies that D-serine is an important transmitter/neuromodulator in the brain (5, 19). On the other hand, the glial localization of D-serine is not compatible with the classical definition of neurotransmitter, which should be present in neurons. We have explored a possible neuronal localization of D-serine and serine racemase utilizing biochemical methods in cell cultures and new antibodies against D-serine and serine racemase. We demonstrate the unambiguous presence of serine racemase and D-serine in neurons. Neuronal release of D-serine mediates a significant fraction of NMDAelicited excitotoxicity in cortical cultures. Our data indicate that neuronal D-serine may play an important role in NMDA receptor activation, such as occurs in neurotoxicity. EXPERIMENTAL PROCEDURESMaterials-L-Serine and D-serine were purchased from Bachem. Acetonitrile, AMPA, trans-(Ϯ)-1-amino-1,3-cyclopentanedicarboxylic acid, bafilomycin A 1 , DNase I...

Brain-specific Phgdh Deletion Reveals a Pivotal Role for l-Serine Biosynthesis in Controlling the Level of d-Serine, an N-methyl-d-aspartate Receptor Co-agonist, in Adult Brain

“…2, C and D). The neuron-enriched localization of Srr is in agreement with recent immunohistological studies (51,52). We then examined the expression of the major types of NMDA receptor subunits, NR1 (also known as GluR1) and NR2B (also known as GluR⑀2) in the cerebral cortex and hippocampus.…”

Zinc reverses glycine-dependent inactivation of NMDARs in cultured rat hippocampal neurons

“…A property of the NMDARs is its voltage-dependent activation, a result of ion channel block by extracellular Mg 2+ ions, which allows the flow of Na + and small amounts of Ca 2+ ions into the cell and K + out of the cell [2]. Besides, the NMDAR requires co-activation of the glycine site located on its NR1 subunit by D-serine or glycine in addition to the synaptically released neurotransmitter glutamate [3,4].…”

“…A property of the NMDARs is its voltage-dependent activation, a result of ion channel block by extracellular Mg 2+ ions, which allows the flow of Na + and small amounts of Ca 2+ ions into the cell and K + out of the cell [2]. Besides, the NMDAR requires co-activation of the glycine site located on its NR1 subunit by D-serine or glycine in addition to the synaptically released neurotransmitter glutamate [3,4].However, the mechanistic connection between glutamate and glycine binding in the modulation of NMDAR activation and inactivation is unclear. Many mechanisms have been proposed to account for the mediation of the inactivation of NMDARs, including glycine-dependent desensitization, glycine-independent desensitization [5,6], Ca 2+ -dependent inactivation [7][8][9] and surface membrane receptors internalization [10].…”

Nitric oxide S -nitrosylates serine racemase, mediating feedback inhibition of d -serine formation

“…Recent studies indicate that in most portions of the brain, D-serine is the physiological coagonist because selective degradation of D-serine but not glycine markedly reduces NMDA transmission (1,2), whereas retraction of D-serine-producing glia in the hypothalamus of lactating rats also diminishes NMDA transmission (2). D-serine is formed from L-serine by serine racemase (SR), which, like D-serine, is selectively enriched in glia (2,3), although recent studies indicate some neuronal localization (4). SR, a pyridoxal phosphate-requiring enzyme, also displays an absolute requirement for ATP, which is not hydrolyzed during SR activation (5).…”