The Origin and Turnover of D-Serine in Brain

Dunlop, David S.; Neidle, Amos

doi:10.1006/bbrc.1997.6724

Cited by 89 publications

(49 citation statements)

References 16 publications

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“…D-Serine is synthesized in the brain from glycine via serine racemase, [33][34][35] and degraded by actions of Damino acid oxidase (DAAO), which is primarily expressed in the cerebellum with lower expression in the forebrain. DAAO is modulated by the recently described protein G72.…”

Section: Modulatory Sitesmentioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD. Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Approximately 60% of neurons in the brain, including all cortical pyramidal neurons and thalamic relay neurons, utilize glutamate as their primary neurotransmitter. 1 As a result, virtually all thalamocortical, corticocortical and corticofugal neurotransmission in the brain is mediated by glutamate. Glutamate is released from presynaptic terminals in response to neuronal depolarization, and is recycled by excitatory amino acid (EAA) transporters located on both neurons and glia. 2 Within glia, glutamate is converted to glutamine and released into extracellular fluid from which it is reabsorbed into presynaptic terminals and converted back to glutamate via action of neuronal glutaminase. Up to 2/3 of brain energy metabolism is related to reuptake and recycling of glutamate. 3 As such, functional imaging modalities, such as PET and fMRI, indexing activity primarily of brain glutamatergic systems. 4 The exchange of glutamine from glia to neurons is accomplished by coordinated actions of two transport systems, systems N and A, both of which are members of sodium-dependent neutral amino acid (SNAT) family of transporters. 5 These transport systems also transport precursors for cysteine and glycine, which are precursors to glutathione synthesis. 6 As these transporters are electrogenic, glutamate transporters may also participate in cellular signaling. 7 As with glutamate and GABA transporters, these recycling systems may constitute interesti...

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Section: Modulatory Sitesmentioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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“…29 30) These phenomena suggest the presence of a serine racemase that catalyzes the synthesis of D-serine from L-serine. Indeed, a pyridoxal 5Ј-phosphate-dependent serine racemase with D-and L-serine a,b-elimination activities has been reported in rat and human tissues.…”

Section: ) Synthesismentioning

confidence: 99%

Metabolism and Functional Roles of Endogenous D-Serine in Mammalian Brains

Nishikawa

2005

Biological & Pharmaceutical Bulletin

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“…The glycine cleavage enzyme catalyzes the conversion of glycine to serine through keto intermediates that might also involve racemization. Dunlop and Neidle (Dunlop et al, 1997) obtained evidence for the conversion of radio-labeled L-to D-serine in intact rats, but it is conceivable that this transformation might have been indirect and involved processes such as transamination.…”

Section: Serine Racemasementioning

confidence: 99%

D-Serine as a putative glial neurotransmitter

2004

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Abundant recent evidence favors a neurotransmitter/neuromodulator role for D-serine. D-serine is synthesized from L-serine by serine racemase in astrocytic glia that ensheath synapses, especially in regions of the brain that are enriched in NMDA-glutamate receptors. D-serine is more potent than glycine at activating the 'glycine' site of these receptors. Moreover, selective degradation of D-serine but not glycine by D-amino acid oxidase markedly reduces NMDA neurotransmission. D-serine appears to be released physiologically in response to activation by glutamate of AMPA-glutamate receptors on D-serine-containing glia. This causes glutamate-receptor-interacting protein, which binds serine racemase, to stimulate enzyme activity and D-serine release. Thus, glutamate triggers the release of D-serine so that the two amino acids can act together on postsynaptic NMDA receptors. D-serine also plays a role in neural development, being released from Bergmann glia to chemokinetically enhance the migration of granule cell cerebellar neurons from the external to the internal granular layer.

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The Origin and Turnover of D-Serine in Brain

Cited by 89 publications

References 16 publications

Glutamate as a therapeutic target in psychiatric disorders

Glutamate as a therapeutic target in psychiatric disorders

Metabolism and Functional Roles of Endogenous D-Serine in Mammalian Brains

D-Serine as a putative glial neurotransmitter

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